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Sample records for autosomal recessive mental

  1. Autosomal recessive

    MedlinePlus

    ... and the other gene comes from the father. Recessive inheritance means both genes in a pair must be abnormal to cause ... born to parents who carry the same autosomal recessive change ... abnormal gene from both parents and developing the disease. You ...

  2. [Autosomal recessive cerebellar ataxias].

    PubMed

    Tranchant, Christine; Anheim, Mathieu

    2009-12-01

    Friedreich ataxia is the most frequent recessive cerebral ataxia d should always be researched first. Ataxia with isolated vitamin E deficiency and abetalipoproteinemia have a specific treatment. Associated neurological signs such polyneuroapthy, ophtalmologic or oculomotor signs, pyramidal signs, and cerebellar MRI can lead to the etiological diagnosis. Biological tests should be: vitamin E, cholesterol, alpha-fetoprotein levels, acanthocytes, than phytanic acid, cholestanol, lysosomal enzymes. Numerous autosomal recessive cerebellar ataxia remain without etiology.

  3. Autosomal recessive cerebellar ataxias

    PubMed Central

    Palau, Francesc; Espinós, Carmen

    2006-01-01

    Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia. PMID:17112370

  4. Autosomal recessive hypercholesterolemia.

    PubMed

    Soutar, Anne K; Naoumova, Rossitza P

    2004-08-01

    Autosomal recessive hypercholesterolemia (ARH) presents with a clinical phenotype similar to that of classical homozygous familial hypercholesterolemia (FH) caused by defects in the low-density lipoprotein (LDL) receptor gene but is more variable, generally less severe, and more responsive to lipid-lowering therapy than homozygous FH; furthermore, FH is inherited with a dominant pattern. The approximately 50 known affected ARH individuals are mostly of Sardinian or Middle Eastern origin, but rare cases of ARH have occurred worldwide. The physiological defect in ARH is a failure of some, but not all, cell types to mediate LDL receptor-dependent internalization of LDL and is caused by mutations in the gene for a putative adaptor protein called ARH. In affected cells, the LDL receptor gene is normal but LDL receptor protein accumulates at the cell surface; this also occurs in livers of recombinant mice lacking ARH, providing an explanation for the failure of clearance of LDL from plasma in ARH patients. The structural features of the ARH protein and its capacity to interact with the internalization sequence of the LDL receptor, plasma membrane phospholipids, and the clathrin endocytic machinery suggest that it plays a key role in the LDL receptor pathway.

  5. Computational analysis of TRAPPC9: candidate gene for autosomal recessive non-syndromic mental retardation.

    PubMed

    Khattak, Naureen Aslam; Mir, Asif

    2014-01-01

    Mental retardation (MR)/ intellectual disability (ID) is a neuro-developmental disorder characterized by a low intellectual quotient (IQ) and deficits in adaptive behavior related to everyday life tasks such as delayed language acquisition, social skills or self-help skills with onset before age 18. To date, a few genes (PRSS12, CRBN, CC2D1A, GRIK2, TUSC3, TRAPPC9, TECR, ST3GAL3, MED23, MAN1B1, NSUN1) for autosomal-recessive forms of non syndromic MR (NS-ARMR) have been identified and established in various families with ID. The recently reported candidate gene TRAPPC9 was selected for computational analysis to explore its potentially important role in pathology as it is the only gene for ID reported in more than five different familial cases worldwide. YASARA (12.4.1) was utilized to generate three dimensional structures of the candidate gene TRAPPC9. Hybrid structure prediction was employed. Crystal Structure of a Conserved Metalloprotein From Bacillus Cereus (3D19-C) was selected as best suitable template using position-specific iteration-BLAST. Template (3D19-C) parameters were based on E-value, Z-score and resolution and quality score of 0.32, -1.152, 2.30°A and 0.684 respectively. Model reliability showed 93.1% residues placed in the most favored region with 96.684 quality factor, and overall 0.20 G-factor (dihedrals 0.06 and covalent 0.39 respectively). Protein-Protein docking analysis demonstrated that TRAPPC9 showed strong interactions of the amino acid residues S(253), S(251), Y(256), G(243), D(131) with R(105), Q(425), W(226), N(255), S(233), its functional partner 1KBKB. Protein-protein interacting residues could facilitate the exploration of structural and functional outcomes of wild type and mutated TRAPCC9 protein. Actively involved residues can be used to elucidate the binding properties of the protein, and to develop drug therapy for NS-ARMR patients.

  6. Dentinogenesis imperfecta associated with short stature, hearing loss and mental retardation: a new syndrome with autosomal recessive inheritance?

    PubMed

    Cauwels, R G E C; De Coster, P J; Mortier, G R; Marks, L A M; Martens, L C

    2005-08-01

    The follow-up history and oral findings in two brothers from consanguineous parents suggest that the association of dentinogenesis imperfecta (DI), delayed tooth eruption, mild mental retardation, proportionate short stature, sensorineural hearing loss and dysmorphic facies may represent a new syndrome with autosomal recessive inheritance. Histological examination of the dentin matrix of a permanent molar from one of the siblings reveals morphological similarities with defective dentinogenesis as presenting in patients affected with Osteogenesis Imperfecta (OI), a condition caused by deficiency of type I collagen. A number of radiographic and histological characteristics, however, are inconsistent with classical features of DI. These findings suggest that DI may imply greater genetical heterogeneity than currently assumed.

  7. A new autosomal recessive syndrome characterized by ocular hypertelorism, distinctive face, mental retardation, brachydactyly, and genital abnormalities.

    PubMed

    Spiegel, Ronen; Horovitz, Yoseph; Peters, Hartmut; Erdogan, Fikret; Chervinsky, Ilana; Shalev, Stavit A

    2009-12-01

    We report on three individuals of Muslim Arab origin from a village located in Northern Israel affected by an apparent autosomal recessive syndrome characterized by distinctive facial phenotype of which the most prominent feature is ocular hypertelorism. The other clinical features of the syndrome include variable degree of mental retardation, genital abnormalities dominated by short penis, and skeletal abnormalities including chest deformity (combination of upper pectus carinatum with lower pectus excavatum), and short palms with broad short fingers. Affected individuals displayed distinctive facial features including upslanting palpebral fissures, thick eyebrows, long philtrum, wide mouth with thin upper lip and upturned corners of the mouth, widow's peak, broad nasal bridge, and simple ears with fleshy overfolded helices. This phenotype does not fully meet typical diagnostic features of any known condition.

  8. Genetics Home Reference: autosomal recessive primary microcephaly

    MedlinePlus

    ... This Page Cox J, Jackson AP, Bond J, Woods CG. What primary microcephaly can tell us about ... Mannon J, Rashid Y, Crow Y, Bond J, Woods CG. Autosomal recessive primary microcephaly: an analysis of ...

  9. Genetics Home Reference: autosomal recessive congenital methemoglobinemia

    MedlinePlus

    ... it alters a molecule within these cells called hemoglobin . Hemoglobin carries oxygen to cells and tissues throughout the ... autosomal recessive congenital methemoglobinemia , some of the normal hemoglobin is replaced by an abnormal form called methemoglobin, ...

  10. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13.

    PubMed

    Çalışkan, Minal; Chong, Jessica X; Uricchio, Lawrence; Anderson, Rebecca; Chen, Peixian; Sougnez, Carrie; Garimella, Kiran; Gabriel, Stacey B; dePristo, Mark A; Shakir, Khalid; Matern, Dietrich; Das, Soma; Waggoner, Darrel; Nicolae, Dan L; Ober, Carole

    2011-04-01

    Exome sequencing is a powerful tool for discovery of the Mendelian disease genes. Previously, we reported a novel locus for autosomal recessive non-syndromic mental retardation (NSMR) in a consanguineous family [Nolan, D.K., Chen, P., Das, S., Ober, C. and Waggoner, D. (2008) Fine mapping of a locus for nonsyndromic mental retardation on chromosome 19p13. Am. J. Med. Genet. A, 146A, 1414-1422]. Using linkage and homozygosity mapping, we previously localized the gene to chromosome 19p13. The parents of this sibship were recently included in an exome sequencing project. Using a series of filters, we narrowed the putative causal mutation to a single variant site that segregated with NSMR: the mutation was homozygous in five affected siblings but in none of eight unaffected siblings. This mutation causes a substitution of a leucine for a highly conserved proline at amino acid 182 in TECR (trans-2,3-enoyl-CoA reductase), a synaptic glycoprotein. Our results reveal the value of massively parallel sequencing for identification of novel disease genes that could not be found using traditional approaches and identifies only the seventh causal mutation for autosomal recessive NSMR.

  11. New autosomal recessive faciodigitogenital syndrome.

    PubMed Central

    Teebi, A S; Naguib, K K; Al-Awadi, S; Al-Saleh, Q A

    1988-01-01

    Most pedigrees of Aarskog's faciodigitogenital syndrome have suggested X linked inheritance. However, sex influenced autosomal dominant inheritance is also a possibility in some families. We describe an Arab family of normal consanguineous parents with five children (three males and two females) with some features of Aarskog syndrome in addition to some unusual hair changes. The possibility that this family represents a distinct previously unrecognised faciodigitogenital syndrome with short stature and hair abnormalities is suggested and discussed. Images PMID:3398008

  12. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation

    PubMed Central

    Mallaret, Martial; Synofzik, Matthis; Lee, Jaeho; Sagum, Cari A.; Mahajnah, Muhammad; Sharkia, Rajech; Drouot, Nathalie; Renaud, Mathilde; Klein, Fabrice A. C.; Anheim, Mathieu; Tranchant, Christine; Mignot, Cyril; Mandel, Jean-Louis; Bedford, Mark; Bauer, Peter; Salih, Mustafa A.; Schüle, Rebecca; Schöls, Ludger; Aldaz, C. Marcelo

    2014-01-01

    We previously localized a new form of recessive ataxia with generalized tonic-clonic epilepsy and mental retardation to a 19 Mb interval in 16q21-q23 by homozygosity mapping of a large consanguineous Saudi Arabian family. We now report the identification by whole exome sequencing of the missense mutation changing proline 47 into threonine in the first WW domain of the WW domain containing oxidoreductase gene, WWOX, located in the linkage interval. Proline 47 is a highly conserved residue that is part of the WW motif consensus sequence and is part of the hydrophobic core that stabilizes the WW fold. We demonstrate that proline 47 is a key amino acid essential for maintaining the WWOX protein fully functional, with its mutation into a threonine resulting in a loss of peptide interaction for the first WW domain. We also identified another highly conserved homozygous WWOX mutation changing glycine 372 to arginine in a second consanguineous family. The phenotype closely resembled the index family, presenting with generalized tonic-clonic epilepsy, mental retardation and ataxia, but also included prominent upper motor neuron disease. Moreover, we observed that the short-lived Wwox knock-out mouse display spontaneous and audiogenic seizures, a phenotype previously observed in the spontaneous Wwox mutant rat presenting with ataxia and epilepsy, indicating that homozygous WWOX mutations in different species causes cerebellar ataxia associated with epilepsy. PMID:24369382

  13. Autosomal recessive nonsyndromic deafness genes: a review.

    PubMed

    Duman, Duygu; Tekin, Mustafa

    2012-06-01

    More than 50 Percent of prelingual hearing loss is genetic in origin, and of these up to 93 Percent are monogenic autosomal recessive traits. Some forms of genetic deafness can be recognized by their associated syndromic features, but in most cases, hearing loss is the only finding and is referred to as nonsyndromic deafness. To date, more than 700 different mutations have been identified in one of 42 genes in individuals with autosomal recessive nonsyndromic hearing loss (ARNSHL). Reported mutations in GJB2, encoding connexin 26, makes this gene the most common cause of hearing loss in many populations. Other relatively common deafness genes include SLC26A4, MYO15A, OTOF, TMC1, CDH23, and TMPRSS3. In this report we summarize genes and mutations reported in families with ARNSHL. Founder effects were demonstrated for some recurrent mutations but the most significant findings are the extreme locus and allelic heterogeneity and different spectrum of genes and mutations in each population.

  14. Non-syndromic, autosomal-recessive deafness.

    PubMed

    Petersen, M B; Willems, P J

    2006-05-01

    Non-syndromic deafness is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Autosomal-recessive genes are responsible for about 80% of the cases of hereditary non-syndromic deafness of pre-lingual onset with 23 different genes identified to date. In the present article, we review these 23 genes, their function, and their contribution to genetic deafness in different populations. The wide range of functions of these DFNB genes reflects the heterogeneity of the genes involved in hearing and hearing loss. Several of these genes are involved in both recessive and dominant deafness, or in both non-syndromic and syndromic deafness. Mutations in the GJB2 gene encoding connexin 26 are responsible for as much as 50% of pre-lingual, recessive deafness. By contrast, mutations in most of the other DFNB genes have so far been detected in only a small number of families, and their contribution to deafness on a population scale might therefore be limited. Identification of all genes involved in hereditary hearing loss will help in our understanding of the basic mechanisms underlying normal hearing, in early diagnosis and therapy.

  15. Molecular mechanisms of autosomal recessive hypercholesterolemia.

    PubMed

    Wilund, Kenneth R; Yi, Ming; Campagna, Filomena; Arca, Marcello; Zuliani, Giovanni; Fellin, Renato; Ho, Yiu-Kee; Garcia, J Victor; Hobbs, Helen H; Cohen, Jonathan C

    2002-11-15

    Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced in the liver but is normal or only moderately impaired in cultured fibroblasts of ARH patients. To define the molecular mechanism underlying ARH we examined ARH mRNA and protein in fibroblasts and lymphocytes from six probands with different ARH mutations. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. Five probands were homozygous for mutations that introduced premature termination codons. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA. (125)I-LDL degradation was normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. These data indicate that all ARH mutations characterized to date preclude the synthesis of full-length ARH and that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts. Residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia who have no functional LDLRs.

  16. Unilateral Autosomal Recessive Anophthalmia in a Patient with Cystic Craniopharyngioma

    PubMed Central

    Kumar, Amandeep; Bansal, Ankit; Garg, Ajay; Sharma, Bhawani S.

    2014-01-01

    Abstract Anophthalmia is a rare ocular malformation. It is a genetically determined disorder and is typically associated with syndromes. However, sporadic nonsyndromic familial as well as non-familial cases of anophthalmia have also been reported. Non-syndromic familial cases are usually bilateral and have been attributed to autosomal recessive, autosomal dominant, and X-linked inheritance patterns. The authors hereby report a rare case of autosomal recessive unilateral anophthalmia in a patient with no other associated congenital anomaly. Patient was operated for craniopharyngioma. The clinical, radiological and intraoperative findings are discussed. PMID:27928292

  17. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila.

    PubMed

    Zweier, Christiane; de Jong, Eiko K; Zweier, Markus; Orrico, Alfredo; Ousager, Lilian B; Collins, Amanda L; Bijlsma, Emilia K; Oortveld, Merel A W; Ekici, Arif B; Reis, André; Schenck, Annette; Rauch, Anita

    2009-11-01

    Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of the neurexin superfamily, have been repeatedly associated with a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, autism spectrum disorders, epilepsy, and schizophrenia. We now identified homozygous and compound-heterozygous deletions and mutations via molecular karyotyping and mutational screening in CNTNAP2 and NRXN1 in four patients with severe mental retardation (MR) and variable features, such as autistic behavior, epilepsy, and breathing anomalies, phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated neuropsychiatric disorders and to severe MR as reported here, evidence for a synaptic role of the CNTNAP2-encoded protein CASPR2 has so far been lacking. Using Drosophila as a model, we now show that, as known for fly Nrx-I, the CASPR2 ortholog Nrx-IV might also localize to synapses. Overexpression of either protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx-I and Nrx-IV mutant conditions. We therefore propose that an analogous shared synaptic mechanism contributes to the similar clinical phenotypes resulting from defects in human NRXN1 and CNTNAP2.

  18. Autosomal recessive disorders among Arabs: an overview from Kuwait.

    PubMed Central

    Teebi, A S

    1994-01-01

    Kuwait has a cosmopolitan population of 1.7 million, mostly Arabs. This population is a mosaic of large and small minorities representing most Arab communities. In general, Kuwait's population is characterized by a rapid rate of growth, large family size, high rates of consanguineous marriages within the Arab communities with low frequency of intermarriage between them, and the presence of genetic isolates and semi-isolates in some extended families and Bedouin tribes. Genetic services have been available in Kuwait for over a decade. During this time it has become clear that Arabs have a high frequency of genetic disorders, and in particular autosomal recessive traits. Their pattern is unique and some disorders are relatively common. Examples are Bardet-Biedl and Meckel syndromes, phenylketonuria, and familial Mediterranean fever. A relatively large number of new syndromes and variants have been delineated in Kuwait's population, many being the result of homozygosity for autosomal recessive genes that occurred because of inbreeding. Some of these syndromes have subsequently been found in other parts of the world, negating the concept of the private syndrome. This paper provides an overview of autosomal recessive disorders among the Arabs in Kuwait from a personal perspective and published studies, and highlights the need for genetic services in Arab countries with the goal of prevention and treatment of genetic disorders. PMID:8014972

  19. Mutations of the tyrosinase gene produce autosomal recessive ocular albinism

    SciTech Connect

    King, R.A.; Summers, C.G.; Oetting, W.S.

    1994-09-01

    Albinism has historically been divided into ocular (OA) and oculocutaneous (OCA) types based on the presence or absence of clinically apparent skin and hair involvement in an individual with the ocular features of albinism. The major genes for OCA include the tyrosinase gene in OCA1 and the P gene in OCA2. X-linked and autosomal recessive OA have been described and the responsible genes have not been identified. We now present six Caucasian individuals who have the phenotype of autosomal recessive OA but who have OCA1 as shown by the presence of mutations of the tyrosinase. They had white or very light hair and white skin at birth, and cutaneous pigment developed in the first decade of life. At ages ranging from 1.5-23 years, hair color was dark blond to light brown. The skin had generalized pigment and well developed tan was present on the exposed arm and face skin of four. Iris pigment was present and iris translucency varied. Molecular analysis of the tyrosinase gene, using PCR amplification and direct di-deoxy sequencing showed the following mutations: E398Z/E398Q, P406S/g346a, R402E/T373K, ?/D383N, and H211N/T373K. The homozygous individual was not from a known consanguineous mating. T373K is the most common tyrosinase gene mutation in our laboratory. Three of these mutations are associated with a total loss of tyrosinase activity (g346a splice-site, T373K, and D383N), while four are associated with residual enzyme activity (H211N, R402E, E398Q, and P406S). These studies show that mutations of the tyrosinase gene can produce the phenotype of autosomal recessive OA in an individual who has normal amounts of cutaneous pigment and the ability to tan after birth. This extends the phenotypic range of OCA1 to normal cutaneous pigment after early childhood, and suggest that mutations of the tyrosinase gene account for a significant number of individuals with autosomal recessive OA.

  20. STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly.

    PubMed

    Kakar, Naseebullah; Ahmad, Jamil; Morris-Rosendahl, Deborah J; Altmüller, Janine; Friedrich, Katrin; Barbi, Gotthold; Nürnberg, Peter; Kubisch, Christian; Dobyns, William B; Borck, Guntram

    2015-01-01

    Holoprosencephaly is a clinically and genetically heterogeneous midline brain malformation associated with neurologic manifestations including developmental delay, intellectual disability and seizures. Although mutations in the sonic hedgehog gene SHH and more than 10 other genes are known to cause holoprosencephaly, many patients remain without a molecular diagnosis. Here we show that a homozygous truncating mutation of STIL not only causes severe autosomal recessive microcephaly, but also lobar holoprosencephaly in an extended consanguineous Pakistani family. STIL mutations have previously been linked to centrosomal defects in primary microcephaly at the MCPH7 locus. Our results thus expand the clinical phenotypes associated with biallellic STIL mutations to include holoprosencephaly.

  1. The Autosomal Recessive Inheritance of Hereditary Gingival Fibromatosis

    PubMed Central

    Nair, Vineet; Mukherjee, Malancha; Ghosh, Sujoy; Dey, Subrata Kumar

    2013-01-01

    Hereditary gingival fibromatosis (HGF) is a rare condition which is marked by enlargement of gingival tissue that covers teeth to various extents leading to aesthetic disfigurement. This study presents a case of a 28-year-old female patient and 18-year-old male who belong to the same family suffering from HGF with chief complaint of overgrowing swelling gingiva. The presence of enlarged gingiva with the same eruption was found in their other family members with no concomitant drug or medical history, and the occurrence of HGF has been found in one generation of this family which may indicate the autosomal recessive inheritance pattern of HGF. Hereditary gingival fibromatosis is an idiopathic condition as its etiology is unknown and it was found to recur in some cases even after surgical treatment. Both patients underwent thorough oral prophylaxis and later surgical therapy to correct the deformity. PMID:24416600

  2. Genetic linkage studies in autosomal recessive retinitis pigmentosa

    SciTech Connect

    Mansfield, D.C.; Teague, P.W.; Barber, A.

    1994-09-01

    Autosomal recessive retinitis pigmentosa (arRP) is a severe retinal dystrophy characterized by night blindness, progressive constriction of the visual fields and loss of central vision in the fourth or fifth decades. The frequency of this form of retinitis pigmentosa (RP) varies in different populations. Mutations within the rhodopsin, cyclic GMP phosphodiesterase-{beta} subunit and cGMP-gated channel genes have been reported in some arRP families. The genetic loci responsible for the majority of cases have yet to be identified. Genetic heterogeneity is likely to be extensive. In order to minimize the amount of genetic heterogenity, a set of arRP families was ascertained within the South-Central Sardinian population, in which 81% of families with a known mode of inheritance show an autosomal recessive form of RP. The Sardinian population is an ethnic {open_quotes}outlier{close_quotes}, having remained relatively isolated from mainland and other cultures. Genetic linkage data has been obtained in a set of 11 Sardinian arRP kindreds containing 26 affected members. Under the assumption of genetic homogeneity, no evidence of linkage was found in the arRP kindreds using 195 markers, which excluded 62% of the genome (Z<-2). Positive lod scores were obtained with D14S80 which showed no recombination in a subset of 5 families. Heterogeneity testing using D14S80 and arRP showed no significant evidence of heterogeneity (p=0.18) but evidence of linkage ({chi}{sup 2}=3.64, p=0.028). We are currently screening the neural retina-specific leucine zipper gene (NRL) in 14q11 for mutations as a candidate locus.

  3. Rare genetic causes of autosomal dominant or recessive hypercholesterolaemia.

    PubMed

    Soutar, Anne K

    2010-02-01

    Familial hypercholesterolaemia (FH) is a human inherited disorder of metabolism characterised by increased serum low-density lipoprotein (LDL) cholesterol. It is caused by defects in the LDL-receptor pathway that impair normal uptake and clearance of LDL by the liver. The commonest cause of FH is mutations in LDLR, the gene for the LDL receptor, but defects also occur in APOB that encodes its major protein ligand. More recently, defects in two other genes, LDLRAP1 and PCSK9, have been found in patients with FH and investigation of these has shed new light on the functioning and complexity of the LDL receptor pathway. Cells from patients with autosomal recessive hypercholesterolaemia (ARH) fail to internalise the LDL receptor because they carry two defective alleles of LDLRAP1, a gene that encodes a specific clathrin adaptor protein. PCSK9 encodes proprotein convertase subtilisin kexin type 9, a secreted protein that binds to the LDL receptor and promotes its degradation. Gain-of function mutations in PCSK9 are autosomal dominant and cause hypercholesterolaemia because they increase the affinity of PCSK9 protein for the LDL receptor, whereas loss-of-function mutations reduce serum cholesterol because LDL-receptor protein is exposed to reduced PCSK9-mediated degradation. Thus, PCSK9 has become a new target for cholesterol-lowering drug therapy.

  4. Congenital vocal cord paralysis with possible autosomal recessive inheritance: Case report and review of the literature

    SciTech Connect

    Koppel, R.; Friedman, S.; Fallet, S.

    1996-08-23

    We describe an infant with congenital vocal cord paralysis born to consanguineous parents. While autosomal dominant and X-linked inheritance have been previously reported in this condition, we conclude that the degree of parental consanguinity in this case strongly suggests autosomal recessive inheritance. Although we cannot exclude X-linked inheritance, evidence from animal studies demonstrates autosomal recessive inheritance and provides a possible molecular basis for congenital vocal cord paralysis. 14 refs., 1 fig.

  5. An exome sequencing strategy to diagnose lethal autosomal recessive disorders.

    PubMed

    Ellard, Sian; Kivuva, Emma; Turnpenny, Peter; Stals, Karen; Johnson, Matthew; Xie, Weijia; Caswell, Richard; Lango Allen, Hana

    2015-03-01

    Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0-4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies.

  6. An exome sequencing strategy to diagnose lethal autosomal recessive disorders

    PubMed Central

    Ellard, Sian; Kivuva, Emma; Turnpenny, Peter; Stals, Karen; Johnson, Matthew; Xie, Weijia; Caswell, Richard; Lango Allen, Hana

    2015-01-01

    Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0–4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies. PMID:24961629

  7. Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.

    PubMed

    Harada-Shiba, Mariko; Takagi, Atsuko; Miyamoto, Yoshihiro; Tsushima, Motoo; Ikeda, Yasuyuki; Yokoyama, Shinji; Yamamoto, Akira

    2003-06-01

    Previously we have reported on siblings with severe hypercholesterolemia, xanthomas, and premature atherosclerosis without any impairment of low-density lipoprotein receptor in their fibroblasts as a first characterization of autosomal recessive hypercholesterolemia (ARH). Recently, mutations were identified for this disease in a gene encoding a putative adaptor protein. The purpose of this study was to examine the molecular pathogenesis of ARH in Japanese siblings. A novel insertion mutation was discovered in the ARH gene of the siblings. An insertion of an extra cytosine residue was identified in a locus comprising eight consecutive cytosines at positions 599 through 606 in exon 6, resulting in a sequence of nine cytosines and generating an early stop codon at 657-659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. A single nucleotide polymorphism was discovered among the normal control subjects at position 604 (cytosine to thymine: ARH-604C to ARH-604T), which changes the proline residue at 202 to serine. Interestingly, ARH is caused by a mutation of cytosine to adenine at this same position. Both siblings exhibited fatty liver, which may also be related to this mutation.

  8. Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis.

    PubMed Central

    Hennies, H C; Küster, W; Wiebe, V; Krebsová, A; Reis, A

    1998-01-01

    Autosomal recessive lamellar ichthyosis is a severe congenital disorder of keratinization, characterized by variable erythema of the whole body surface and by different scaling patterns. Recently, mutations have been identified in patients with lamellar ichthyosis in the TGM1 gene coding for keratinocyte transglutaminase, and a second locus has been mapped to chromosome 2. We have now analyzed the genotype/phenotype correlation in a total of 14 families with lamellar ichthyosis. Linkage analyses using microsatellites in the region of the TGM1 gene confirmed genetic heterogeneity. In patients not linked to the TGM1 gene, the second region identified on chromosome 2 and a further candidate region on chromosome 20 were excluded, confirming as well the existence of at least three loci for lamellar ichthyosis. Sequence analyses of the TGM1 gene in families compatible with linkage to this locus revealed seven different missense mutations, five of these unpublished so far, and one splice mutation. No genotype/phenotype correlation for mutations in the TGM1 gene was found in this group of patients, which included two unrelated patients homozygous for the same mutation. Similarly, no clear difference in the clinical picture was seen between patients with TGM1 mutations and those unlinked to the TGM1 locus. Comparison of genetic and clinical classifications for patients with lamellar ichthyosis shows no consistency and thus indicates that clinical criteria currently in use cannot discriminate between the molecularly different forms of the disease. PMID:9545389

  9. Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q

    SciTech Connect

    Russell, L.J.; Compton, J.G.; Bale, S.J.; DiGiovanna, J.J.; Hashem, N.

    1994-12-01

    The authors have mapped the locus for lamellar ichthyosis (LI), an autosomal recessive skin disease characterized by abnormal cornification of the epidermis. Analysis using both inbred and outbred families manifesting severe LI showed complete linkage to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were also found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. Several transcribed genes have been mapped to the chromosome 14 region containing the LI gene. The transglutaminase 1 gene (TGM1), which encodes one of the enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus was completely linked to LI (Z = 9.11), suggesting that TGM1 is a good candidate for further investigation of this disorder. The genes for four serine proteases also map to this region but are expressed only in hematopoietic or mast cells, making them less likely candidates.

  10. Autosomal recessive multiple pterygium syndrome: a new variant?

    PubMed

    Aslan, Y; Erduran, E; Kutlu, N

    2000-07-31

    Multiple pterygium syndromes include at least 15 different entities characterized by multiple pterygia or webs of the skin and multiple congenital anomalies. We describe a female infant who presented with a distinct constellation of multiple anomalies consisting of pterygia of the inguinal, intercrural and popliteal areas, flexion contractures and arthrogryposis of some joints, craniofacial anomalies including ectropion, medial canthal web, blepharophimosis, hypoplasia of nose, oral and nasopharyngeal cavities, vocal cords and tongue, micrognathia, orolabial synechiae secondary to pterygia, low set ears, alopecia, sad and expressionless face, short neck, asymmetric nipples, anal stenosis, rectal polyp, hypoplastic labia majora, complete syndactyly of all fingers and toes, pes equinovarus, bandlike web between feet, and absence of the nails and phalangeal-palmar creases. Radiological examination showed synostosis, absence or hypoplasia of metacarpal, metatarsal and phalangeal bones on feet and hands, and hypoplasia of pelvic bones and scapulae. This pattern of anomalies does not fit entirely any of the known multiple pterygium syndromes. Autosomal recessive inheritance is most likely due to the presence of three similarly affected siblings and normal parents.

  11. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene.

    PubMed

    Balci, Burcu; Uyanik, Gökhan; Dincer, Pervin; Gross, Claudia; Willer, Tobias; Talim, Beril; Haliloglu, Göknur; Kale, Gülsev; Hehr, Ute; Winkler, Jürgen; Topaloğlu, Haluk

    2005-04-01

    Mutations of the protein O-mannosyltransferase (POMT1) gene affect glycosylation of alpha-dystroglycan, leading to Walker-Warburg syndrome, a lethal disorder in early life with severe congenital muscular dystrophy, and brain and eye malformations. Recently, we described a novel form of recessive limb girdle muscular dystrophy with mild mental retardation, associated with an abnormal alpha-dystroglycan pattern in the muscle, suggesting a glycosylation defect. Here, we present evidence that this distinct phenotype results from a common mutation (A200P) in the POMT1 gene. Our findings further expand the phenotype of glycosylation disorders linked to POMT1 mutations. Furthermore, the A200P mutation is part of a conserved core haplotype, indicating an ancestral founder mutation.

  12. HDR: a statistical two-step approach successfully identifies disease genes in autosomal recessive families.

    PubMed

    Imai, Atsuko; Kohda, Masakazu; Nakaya, Akihiro; Sakata, Yasushi; Murayama, Kei; Ohtake, Akira; Lathrop, Mark; Okazaki, Yasushi; Ott, Jurg

    2016-11-01

    In the search for sequence variants underlying disease, commonly applied filtering steps usually result in a number of candidate variants that cannot further be narrowed down. In autosomal recessive families, disease usually occurs only in one generation so that genetic linkage analysis is unlikely to help. Because homozygous recessive mutations tend to be inherited together with flanking homozygous variants, we developed a statistical method to detect pathogenic variants in autosomal recessive families: We look for differences in patterns of homozygosity around candidate variants between patients and control individuals and expect that such differences are greater for pathogenic variants than random candidate variants. In six autosomal recessive mitochondrial disease families, in which pathogenic homozygous variants have already been identified, our approach succeeded in prioritizing pathogenic mutations. Our method is applicable to single patients from recessive families with at least a few dozen control individuals from the same population; it is easy to use and is highly effective for detecting causative mutations in autosomal recessive families.

  13. Fine genetic mapping of a gene for autosomal recessive retinitis pigmentosa on chromosome 6p21

    SciTech Connect

    Shugart, Yin Y.; Banerjee, P.; Knowles, J.A.

    1995-08-01

    The inherited retinal degenerations known as retinitis pigmentosa (RP) can be caused by mutations at many different loci and can be inherited as an autosomal recessive, autosomal dominant, or X-linked recessive trait. Two forms of autosomal recessive (arRP) have been reported to cosegregate with mutations in the rhodopsin gene and the beta-subunit of rod phosphodiesterase on chromosome 4p. Genetic linkage has been reported on chromosomes 6p and 1q. In a large Dominican family, we reported an arRp gene near the region of the peripherin/RDS gene. Four recombinations were detected between the disease locus and an intragenic marker derived from peripherin/RDS. 26 refs., 2 figs., 1 tab.

  14. A case report: Autosomal recessive microcephaly caused by a novel mutation in MCPH1 gene.

    PubMed

    Ghafouri-Fard, Soudeh; Fardaei, Majid; Gholami, Milad; Miryounesi, Mohammad

    2015-10-15

    Autosomal Recessive Primary Microcephaly (MCPH-MIM 251200) is distinguished by congenital decrease in occipito-frontal head circumference (OFC) of at least 2 standard deviations (SD) below population average in addition to non-progressive mental retardation, without any prominent neurological disorder. Mutations in MCPH1, which encodes the protein microcephalin have been detected in this disorder. Here we report a consanguineous Iranian family with 2 children affected with microcephaly. Despite the severe mental retardation observed in the male patient, the female patient had normal intelligent with no delay in motor milestones or speech. A novel splice-acceptor site homozygous mutation has been detected in intron 4 of MCPH1 gene (c.322-2A>T) which results in an RNA processing defect with a 15-nucleotide deletion in exon 5 of the mRNA transcript (r.322_336del15, p.R108_Q112del5). This novel mutation has resulted in different phenotypes in affected male and female patients of this family. The sex-specific variations in gene regulation during brain development may partially explain such difference in phenotypes probably in addition to other mechanisms such as modifier genes.

  15. Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

    PubMed

    Mets, Sarah; Tryon, Rebecca; Veach, Patricia McCarthy; Zierhut, Heather A

    2016-04-01

    The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

  16. Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction

    PubMed Central

    Naz, S; Griffith, A; Riazuddin, S; Hampton, L; Battey, J; Khan, S; Riazuddin, S; Wilcox, E; Friedman, T

    2004-01-01

    We mapped a human deafness locus DFNB36 to chromosome 1p36.3 in two consanguineous families segregating recessively inherited deafness and vestibular areflexia. This phenotype co-segregates with either of two frameshift mutations, 1988delAGAG and 2469delGTCA, in ESPN, which encodes a calcium-insensitive actin-bundling protein called espin. A recessive mutation of ESPN is known to cause hearing loss and vestibular dysfunction in the jerker mouse. Our results establish espin as an essential protein for hearing and vestibular function in humans. The abnormal vestibular phenotype associated with ESPN mutations will be a useful clinical marker for refining the differential diagnosis of non-syndromic deafness. PMID:15286153

  17. Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis.

    PubMed

    Greene, V Bennouna; Stoetzel, C; Pelletier, V; Perdomo-Trujillo, Y; Liebermann, L; Marion, V; De Korvin, H; Boileau, C; Dufier, J L; Dollfus, H

    2010-03-01

    Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.

  18. Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations.

    PubMed

    Depondt, Chantal; Donatello, Simona; Simonis, Nicolas; Rai, Myriam; van Heurck, Roxane; Abramowicz, Marc; D'Hooghe, Marc; Pandolfo, Massimo

    2014-05-13

    Autosomal recessive ataxias affect about 1 person in 20,000. Friedreich ataxia accounts for one-third of the cases in Caucasians; the others are due to a growing list of very rare molecular defects, including mild forms of metabolic diseases. In nearly 50%, the genetic cause remains undetermined.

  19. Infantile variant of Bartter syndrome and sensorineural deafness: A new autosomal recessive disorder

    SciTech Connect

    Landau, D.; Shalev, H.; Carmi, Rivka; Ohaly, M.

    1995-12-04

    The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appearance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association between the IBS and SND has not been reported so far. Here we describe 5 children of an extended consanguineous Bedouin family with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, suggesting either coincidental homozygotization of 2 recessive genes or a pleiotropic effect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS. 35 refs., 2 figs., 2 tabs.

  20. Economic recession and mental health: an overview.

    PubMed

    Cooper, Brian

    2011-01-01

    Effects of the current global economic downturn on population mental health will emerge in the years ahead. Judging from earlier experience of financial crises in various parts of the world, stresses associated with rising unemployment, poverty and social insecurity will lead to upward trends in many national suicide rates, as well as to less readily charted increase in the prevalence of psychiatric illness, alcohol-related disorders and illicit drug use. At the same time, mental health services are being cut back as part of government austerity programs. Budget cuts will thus affect psychiatric services adversely just when economic stressors are raising the levels of need and demand in affected populations. Proactive fiscal and social policies could, however, help to mitigate the health consequences of recession. Evidence- based preventive measures include active labor market and family support programs, regulation of alcohol prices and availability, community care for known high-risk groups, and debt relief projects. Economic mental health care could best be achieved, not by decimating services but by planning and deploying these to meet the needs of defined area populations.

  1. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    PubMed

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot

  2. The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism.

    PubMed

    Oetting, William S; Pietsch, Jacy; Brott, Marcia J; Savage, Sarah; Fryer, James P; Summers, C Gail; King, Richard A

    2009-03-01

    Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism.

  3. New form of autosomal-recessive axonal hereditary sensory motor neuropathy.

    PubMed

    Eckhardt, S M; Hicks, E M; Herron, B; Morrison, P J; Aicardi, J

    1998-09-01

    Two siblings, a male and a female, had severe axonal neuropathy and sideroblastic anemia. Despite a distinct clinical picture with areflexia, ataxia, hypotonia, optic atrophy, and progressive sensory neural hearing loss, no definite diagnosis could be reached and the older sibling died at 6 years of age of respiratory failure. It is proposed that the two affected siblings have a new form of autosomal-recessive axonal hereditary sensory motor neuropathy.

  4. [Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case].

    PubMed

    Rostol'tsev, K V; Burenkov, R A; Kuz'micheva, I A

    2012-01-01

    Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance.

  5. Identification of CHIP as a Novel Causative Gene for Autosomal Recessive Cerebellar Ataxia

    PubMed Central

    Shi, Yuting; Wang, Junling; Li, Jia-Da; Ren, Haigang; Guan, Wenjuan; He, Miao; Yan, Weiqian; Zhou, Ying; Hu, Zhengmao; Zhang, Jianguo; Xiao, Jingjing; Su, Zheng; Dai, Meizhi; Wang, Jun; Jiang, Hong; Guo, Jifeng; Zhou, Yafang; Zhang, Fufeng; Li, Nan; Du, Juan; Xu, Qian; Hu, Yacen; Pan, Qian; Shen, Lu; Wang, Guanghui; Xia, Kun; Zhang, Zhuohua; Tang, Beisha

    2013-01-01

    Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia. PMID:24312598

  6. Autosomal Recessive Hypophosphatasia Manifesting in Utero with Long Bone Deformity but Showing Spontaneous Postnatal Improvement

    PubMed Central

    Stevenson, David A.; Carey, John C.; Coburn, Stephen P.; Ericson, Karen L.; Byrne, Janice L. B.; Mumm, Steven; Whyte, Michael P.

    2008-01-01

    Context: Hypophosphatasia (HPP) is a heritable metabolic disorder of the skeleton that includes variable expressivity conditioned by gene dosage effect and the variety of mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene. Patient age when skeletal problems first manifest generally predicts the clinical course, with perinatal HPP causing bone disease in utero with postnatal lethality. Objective: Our objective was to identify TNSALP mutations and characterize the inheritance pattern of a family with clinically variable HPP with one child manifesting in utero with long bone deformity but showing spontaneous prenatal and postnatal improvement. Design: TNSALP enzyme and substrate analysis and TNSALP mutation analysis were performed on all family members. Patients: A boy with HPP showing long bone deformity that spontaneously improved in utero and after birth is described. His older brother has the childhood form of HPP without findings until after infancy. His parents and twin sister are clinically unaffected. Results: Both boys are compound heterozygotes for the same missense mutations in TNSALP, documenting autosomal recessive inheritance for their HPP. The parents each carry one defective allele. Conclusions: The patient is an autosomal recessive case of HPP with prenatal long bone deformity but with spontaneous prenatal and postnatal improvement. Thus, prenatal detection by sonography of bowing of long bones from HPP, even with autosomal recessive inheritance, does not necessarily predict lethality but can represent variable expressivity or the effects of modifiers on the TNSALP defect(s). PMID:18559907

  7. Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations

    SciTech Connect

    Rudnik-Schoeneborn, S.; Zerres, K.; Hahnen, E.

    1996-11-01

    With the evidence that deletions in the region responsible for childhood- and juvenile-onset proximal spinal muscular atrophy (SMA) are on chromosome 5 it is now possible to confirm autosomal recessive inheritance in most patients (denoted {open_quotes}SMA 5q{close_quotes}). Homozygous deletions in the telomeric copy of the survival motor neuron (SMN) gene can be detected in 95%-98% of patients with early-onset SMA (types I and II), whereas as many as 10%-20% of patients with the milder, juvenile-onset form (type III SMA) do not show deletions. In families with affected subjects in two generations, it is difficult to decide whether they are autosomal dominantly inherited or caused by three independent recessive mutations (pseudodominant inheritance). Given an incidence of >1/10,000 of SMA 5q, patients with autosomal recessive SMA have an {approximately}1% recurrence risk to their offspring. Although the dominant forms are not linked to chromosome 5q, pseudodominant families can now be identified by the presence of homozygous deletions in the SMN gene. 5 refs., 1 fig., 1 tab.

  8. Autosomal recessive Charcot-Marie-Tooth disease: from genes to phenotypes.

    PubMed

    Tazir, Meriem; Bellatache, Mounia; Nouioua, Sonia; Vallat, Jean-Michel

    2013-06-01

    The prevalence of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR-CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino-varus, claw-like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR-CMT.

  9. Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

    PubMed

    Kelly, K J; Zhang, Jizhong; Han, Ling; Kamocka, Malgorzata; Miller, Caroline; Gattone, Vincent H; Dominguez, Jesus H

    2015-01-01

    Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.

  10. Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype.

    PubMed

    Gurgel-Giannetti, Juliana; Senkevics, Adriano S; Zilbersztajn-Gotlieb, Dinorah; Yamamoto, Lydia U; Muniz, Viviane P; Pavanello, Rita C M; Oliveira, Acary B; Zatz, Mayana; Vainzof, Mariz

    2012-02-01

    We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia.

  11. Medical Devices; Immunology and Microbiology Devices; Classification of Autosomal Recessive Carrier Screening Gene Mutation Detection System. Final order.

    PubMed

    2015-10-27

    The Food and Drug Administration (FDA) has classified an autosomal recessive carrier screening gene mutation detection system into class II (special controls). The special controls that apply to this device are identified in this order and will be part of the codified language for the autosomal recessive carrier screening gene mutation detection system classification. The Agency has classified the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device.

  12. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    PubMed

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

    2013-03-07

    Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans.

  13. Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

    PubMed Central

    Boycott, Kym M.; Flavelle, Shauna; Bureau, Alexandre; Glass, Hannah C.; Fujiwara, T. Mary; Wirrell, Elaine; Davey, Krista; Chudley, Albert E.; Scott, James N.; McLeod, D. Ross; Parboosingh, Jillian S.

    2005-01-01

    An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population. An identity-by-descent mapping approach using eight patients from three interrelated Hutterite families localized the gene for this syndrome to chromosome region 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. A 199-kb homozygous deletion encompassing the entire very low density lipoprotein receptor (VLDLR) gene was present in all affected individuals. VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. To our knowledge, this syndrome represents the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect. PMID:16080122

  14. Mutations in GBA2 Cause Autosomal-Recessive Cerebellar Ataxia with Spasticity

    PubMed Central

    Hammer, Monia B.; Eleuch-Fayache, Ghada; Schottlaender, Lucia V.; Nehdi, Houda; Gibbs, J. Raphael; Arepalli, Sampath K.; Chong, Sean B.; Hernandez, Dena G.; Sailer, Anna; Liu, Guoxiang; Mistry, Pramod K.; Cai, Huaibin; Shrader, Ginamarie; Sassi, Celeste; Bouhlal, Yosr; Houlden, Henry; Hentati, Fayçal; Amouri, Rim; Singleton, Andrew B.

    2013-01-01

    Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid β-glucosidase 1. β-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding β-glucosidase 2, GBA2. Two nonsense mutations (c.363C>A [p.Tyr121∗] and c.1018C>T [p.Arg340∗]) and a substitution (c.2618G>A [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans. PMID:23332917

  15. Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.

    PubMed

    Ravenscroft, Gianina; Miyatake, Satoko; Lehtokari, Vilma-Lotta; Todd, Emily J; Vornanen, Pauliina; Yau, Kyle S; Hayashi, Yukiko K; Miyake, Noriko; Tsurusaki, Yoshinori; Doi, Hiroshi; Saitsu, Hirotomo; Osaka, Hitoshi; Yamashita, Sumimasa; Ohya, Takashi; Sakamoto, Yuko; Koshimizu, Eriko; Imamura, Shintaro; Yamashita, Michiaki; Ogata, Kazuhiro; Shiina, Masaaki; Bryson-Richardson, Robert J; Vaz, Raquel; Ceyhan, Ozge; Brownstein, Catherine A; Swanson, Lindsay C; Monnot, Sophie; Romero, Norma B; Amthor, Helge; Kresoje, Nina; Sivadorai, Padma; Kiraly-Borri, Cathy; Haliloglu, Goknur; Talim, Beril; Orhan, Diclehan; Kale, Gulsev; Charles, Adrian K; Fabian, Victoria A; Davis, Mark R; Lammens, Martin; Sewry, Caroline A; Manzur, Adnan; Muntoni, Francesco; Clarke, Nigel F; North, Kathryn N; Bertini, Enrico; Nevo, Yoram; Willichowski, Ekkhard; Silberg, Inger E; Topaloglu, Haluk; Beggs, Alan H; Allcock, Richard J N; Nishino, Ichizo; Wallgren-Pettersson, Carina; Matsumoto, Naomichi; Laing, Nigel G

    2013-07-11

    Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.

  16. Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy

    PubMed Central

    Ravenscroft, Gianina; Miyatake, Satoko; Lehtokari, Vilma-Lotta; Todd, Emily J.; Vornanen, Pauliina; Yau, Kyle S.; Hayashi, Yukiko K.; Miyake, Noriko; Tsurusaki, Yoshinori; Doi, Hiroshi; Saitsu, Hirotomo; Osaka, Hitoshi; Yamashita, Sumimasa; Ohya, Takashi; Sakamoto, Yuko; Koshimizu, Eriko; Imamura, Shintaro; Yamashita, Michiaki; Ogata, Kazuhiro; Shiina, Masaaki; Bryson-Richardson, Robert J.; Vaz, Raquel; Ceyhan, Ozge; Brownstein, Catherine A.; Swanson, Lindsay C.; Monnot, Sophie; Romero, Norma B.; Amthor, Helge; Kresoje, Nina; Sivadorai, Padma; Kiraly-Borri, Cathy; Haliloglu, Goknur; Talim, Beril; Orhan, Diclehan; Kale, Gulsev; Charles, Adrian K.; Fabian, Victoria A.; Davis, Mark R.; Lammens, Martin; Sewry, Caroline A.; Manzur, Adnan; Muntoni, Francesco; Clarke, Nigel F.; North, Kathryn N.; Bertini, Enrico; Nevo, Yoram; Willichowski, Ekkhard; Silberg, Inger E.; Topaloglu, Haluk; Beggs, Alan H.; Allcock, Richard J.N.; Nishino, Ichizo; Wallgren-Pettersson, Carina; Matsumoto, Naomichi; Laing, Nigel G.

    2013-01-01

    Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM. PMID:23746549

  17. A novel frameshift mutation of DDHD1 in a Japanese patient with autosomal recessive spastic paraplegia.

    PubMed

    Miura, Shiroh; Morikawa, Takuya; Fujioka, Ryuta; Kosaka, Kengo; Yamada, Kohei; Hattori, Gohsuke; Motomura, Manabu; Taniwaki, Takayuki; Shibata, Hiroki

    2016-08-01

    Spastic paraplegia (SPG) type 28 is an autosomal recessive SPG caused by mutations in the DDHD1 gene. We examined a Japanese 54-years-old male patient with autosomal recessive SPG. His parents were consanguineous. He needed a wheelchair for transfer due to spastic paraplegia. There was a history of operations for bilateral hallux valgus, thoracic ossification of the yellow ligament, bilateral carpal tunnel syndrome, bilateral ankle contracture, and lumbar spinal canal stenosis. He noticed gait disturbance at age 14. He used a cane for walking in his 40s. On neurological examination, he showed hyperreflexia, spasticity, and weakness in the lower extremities and bilateral Babinski reflexes. Urinary dysfunctions and impaired vibration sense in the lower limbs were observed. By exome sequencing analysis using Agilent SureSelect and Illumina MiSeq, we identified 17,248 homozygous nucleotide variants in the patient. Through the examination of 48 candidate genes known to be responsible for autosomal recessive SPG, we identified a novel homozygous 4-bp deletion, c.914_917delGTAA, p.Ser305Ilefs*2 in exon2 of the DDHD1 gene encoding phosphatidic acid-preferring phospholipase A1 (PA-PLA1). The mutation is expected to cause a frameshift generating a premature stop codon 3-bp downstream from the deletion. In consequence, the DDHD domain that is known to be critical for PLA1 activity is completely depleted in the mutated DDHD1 protein, predicted to be a functionally null mutation of the DDHD1 gene. By Sanger sequencing, we confirmed that both parents are heterozygous for the mutation. This variation was not detected in 474 Japanese control subjects as well as the data of the 1,000G Project. We conclude that the novel mutation in DDHD1 is the causative variant for the SPG28 patient that is the first record of the disease in Japanese population.

  18. Autosomal recessive micrencephaly with simplified gyral pattern, abnormal myelination and arthrogryposis.

    PubMed

    Sztriha, L; Al-Gazali, L I; Várady, E; Goebel, H H; Nork, M

    1999-06-01

    The clinical courses, neuroimaging and muscle biopsy findings of two infants born to an inbred Arab family are described. They had a syndrome of micrencephaly with simplified gyral pattern, abnormal myelin formation and arthrogryposis. Increased variation of fiber size was seen in the muscle biopsy, creatine kinase, however was normal. Large areas of muscle were replaced by adipofibrous tissue. The infants had dysmorphic features consistent with the fetal akinesia/hypokinesia sequence. The abnormalities were suggestive of microlissencephaly probably associated with a dysgenetic process in the muscles. The syndrome showed an autosomal recessive inheritance.

  19. Autosomal recessive bilateral frontal polymicrogyria with ectopia lentis and chorioretinal dystrophy.

    PubMed

    Nooraine, Javeria; Vasudha, Kemmanu; Natesh, Sribhargava; Iyer, Rajesh B; Raghavendra, Seetharam

    2013-10-01

    Polymicrogyria is a type of cortical dysplasia with cortical organizational defect. Bilateral polymicrogyria are distinct with genetic basis in a subset. We hereby report a case of bilateral frontal polymicrogyria (BFP) in association with chorioretinal dystrophy and ectopia lentis (EL) in a 26-year-old lady born of a consanguineous parentage. Her male sibling also had chorioretinal dystrophy and EL. This combination of autosomal recessive inheritance has not been reported earlier in the literature and suggests a role of connective tissue genes in BFP.

  20. Mutations in TNK2 in severe autosomal recessive infantile onset epilepsy.

    PubMed

    Hitomi, Yuki; Heinzen, Erin L; Donatello, Simona; Dahl, Hans-Henrik; Damiano, John A; McMahon, Jacinta M; Berkovic, Samuel F; Scheffer, Ingrid E; Legros, Benjamin; Rai, Myriam; Weckhuysen, Sarah; Suls, Arvid; De Jonghe, Peter; Pandolfo, Massimo; Goldstein, David B; Van Bogaert, Patrick; Depondt, Chantal

    2013-09-01

    We identified a small family with autosomal recessive, infantile onset epilepsy and intellectual disability. Exome sequencing identified a homozygous missense variant in the gene TNK2, encoding a brain-expressed tyrosine kinase. Sequencing of the coding region of TNK2 in 110 patients with a similar phenotype failed to detect further homozygote or compound heterozygote mutations. Pathogenicity of the variant is supported by the results of our functional studies, which demonstrated that the variant abolishes NEDD4 binding to TNK2, preventing its degradation after epidermal growth factor stimulation. Definitive proof of pathogenicity will require confirmation in unrelated patients.

  1. Mutations in TNK2 in severe autosomal recessive infantile-onset epilepsy

    PubMed Central

    Hitomi, Yuki; Heinzen, Erin L.; Donatello, Simona; Dahl, Hans-Henrik; Damiano, John A.; McMahon, Jacinta M.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Legros, Benjamin; Rai, Myriam; Weckhuysen, Sarah; Suls, Arvid; De Jonghe, Peter; Pandolfo, Massimo; Goldstein, David B.; Van Bogaert, Patrick; Depondt, Chantal

    2013-01-01

    We identified a small family with autosomal recessive, infantile-onset epilepsy and intellectual disability. Exome sequencing identified a homozygous missense variant in the gene TNK2, encoding a brain-expressed tyrosine kinase. Sequencing of the coding region of TNK2 in 110 patients with a similar phenotype failed to detect further homozygote or compound heterozygote mutations. Pathogenicity of the variant is supported by the results of our functional studies, which demonstrated that the variant abolishes NEDD4 binding to TNK2, preventing its degradation after epidermal growth factor stimulation. Definitive proof of pathogenicity will require confirmation in unrelated patients. PMID:23686771

  2. Recessive versus imprinted disorder: consanguinity can impede establishing the diagnosis of autosomal dominant pseudohypoparathyroidism type Ib

    PubMed Central

    Turan, Serap; Akin, Leyla; Akcay, Teoman; Adal, Erdal; Sarikaya, Sevil; Bastepe, Murat; Jüppner, Harald

    2010-01-01

    Hypocalcemia and hyperphosphatemia with low/normal parathyroid hormone (PTH) levels can be observed in hypoparathyroidism (HP), a disorder that may follow an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance. Similar biochemical changes are also observed in pseudohypoparathyroidism (PHP) type Ia and Ib, but affected patients usually show elevated PTH levels indicative of hormonal resistance. Features of Albright’s hereditary osteodystrophy (AHO) are typically not observed in patients affected by familial forms of PHP-Ib, which are most frequently caused by maternally inherited, heterozygous microdeletions within STX16 and are associated with isolated loss of methylation at GNAS exon A/B. We established the molecular defect in two children of consanguineous Turkish parents, who presented with hypocalcemia, hyperphosphatemia, and low 25-OH vitamin D levels, but initially normal or only mildly elevated PTH levels, i.e. findings that do not readily exclude HP. After normalizing serum magnesium levels, hypocalcemia and hyperphosphatemia persisted, and PTH levels increased, suggesting PTH-resistance rather than PTH-deficiency. Because of the absence of AHO and parental consanguinity, an AR form of PHP-Ib appeared plausible, which had previously been suggested for sporadic cases. However, loss of GNAS methylation was restricted to exon A/B, which led to the identification of the 3-kb STX16 microdeletion. The same mutation was also detected in the healthy mother, who did not show any GNAS methylation abnormality, indicating that her deletion resides on the paternal allele. Our findings emphasize the importance of considering a parentally imprinted, autosomal dominant disorder even if consanguinity suggests an autosomal recessive mode of inheritance. PMID:20538864

  3. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

    PubMed

    Bichet, Daniel G; Bockenhauer, Detlef

    2016-03-01

    Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration.

  4. Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss

    PubMed Central

    Atik, Tahir; Onay, Huseyin; Aykut, Ayca; Bademci, Guney; Kirazli, Tayfun; Tekin, Mustafa; Ozkinay, Ferda

    2015-01-01

    Comprehensive genetic testing has the potential to become the standard of care for individuals with hearing loss. In this study, we investigated the genetic etiology of autosomal recessive nonsyndromic hearing loss (ARNSHL) in a Turkish cohort including individuals with cochlear implant, who had a pedigree suggestive of an autosomal recessive inheritance. A workflow including prescreening of GJB2 and a targeted next generation sequencing panel (Illumına TruSightTM Exome) covering 2761 genes that we briefly called as mendelian exome sequencing was used. This panel includes 102 deafness genes and a number of genes causing Mendelian disorders. Using this approach, we identified causative variants in 21 of 29 families. Three different GJB2 variants were present in seven families. Remaining 14 families had 15 different variants in other known NSHL genes (MYO7A, MYO15A, MARVELD2, TMIE, DFNB31, LOXHD1, GPSM2, TMC1, USH1G, CDH23). Of these variants, eight are novel. Mutation detection rate of our workflow is 72.4%, confirming the usefulness of targeted sequencing approach in NSHL. PMID:26561413

  5. A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis.

    PubMed

    Ahram, Dina; Sato, T Shawn; Kohilan, Abdulghani; Tayeh, Marwan; Chen, Shan; Leal, Suzanne; Al-Salem, Mahmoud; El-Shanti, Hatem

    2009-02-01

    Ectopia lentis is a genetically heterogeneous condition that is characterized by the subluxation of the lens resulting from the disruption of the zonular fibers. Patients with ectopia lentis commonly present with a marked loss in visual acuity in addition to a number of possibly accompanying ocular complications including cataract, myopia, and retinal detachment. We here describe an isolated form of ectopia lentis in a large inbred family that shows autosomal-recessive inheritance. We map the ectopia lentis locus in this family to the pericentromeric region on chromosome 1 (1p13.2-q21.1). The linkage region contains well more than 60 genes. Mutation screening of four candidate genes revealed a homozygous nonsense mutation in exon 11 of ADAMTSL4 (p.Y595X; c.1785T-->G) in all affected individuals that is absent in 380 control chromosomes. The mutation would result in a truncated protein of half the original length, if the mRNA escapes nonsense-mediated decay. We conclude that mutations in ADAMTSL4 are responsible for autosomal-recessive simple ectopia lentis and that ADAMTS-like4 plays a role in the development and/or integrity of the zonular fibers.

  6. Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait.

    PubMed

    Takeichi, T; Nanda, A; Liu, L; Aristodemou, S; McMillan, J R; Sugiura, K; Akiyama, M; Al-Ajmi, H; Simpson, M A; McGrath, J A

    2015-02-01

    Only two homozygous nonsense mutations in the epidermal isoform of the dystonin gene, DST-e, have been reported previously in autosomal recessive epidermolysis bullosa simplex (EBS); the affected pedigrees were Kuwaiti and Iranian. This subtype of EBS is therefore considered to be a rare clinicopathological entity. In this study, we identified four seemingly unrelated Kuwaiti families in which a total of seven individuals had predominantly acral trauma-induced blistering since infancy. All affected individuals were homozygous for the mutation p.Gln1124* in DST-e, the same mutation that was identified in the originally reported family from Kuwait. Haplotype analysis in the five pedigrees (including the previous case) revealed a shared block of ~60 kb of genomic DNA across the site of the mutation, consistent with a founder effect. Most heterozygotes had no clinical abnormalities although one subject had mild transient skin fragility during childhood, an observation noted in the previously reported Iranian pedigree, suggesting that the condition may also be semidominant in some pedigrees rather than purely autosomal recessive. Our study reveals propagation of a mutant ancestral allele in DST-e throughout Kuwait, indicating that this subtype of EBS may be more common in Kuwait, and perhaps other Middle Eastern countries, than is currently appreciated.

  7. Autozygosity mapping of autosomal recessive non-syndromic sensorineural hearing loss (ARNSSNHL)

    SciTech Connect

    Brown, K.A.; Nobel, A.; Markham, A.F.

    1994-09-01

    Congenital deafness affects about 1 in 2000 persons and is of genetic origin in approximately half these cases. The majority of congenital deafness is non-syndromic and over 75% of cases are compatible with autosomal recessive inheritance. Mapping of the loci responsible for ARNSSNHL will be complicated by genetic heterogeneity. Our approach to isolating genes involved in ARNSSNHL is by autozygosity mapping which involves the genetic analysis of children resulting from consanguineous marriages with the aim of identifying regions of homozygosity unique to the genomes of affected individuals which have been inherited from a common ancestor. The population employed in this study is the Pakistani community of Leeds, Bradford and Manchester in the UK which originated from the Mirpur region of Pakistan. Microsatellite analysis of the genome with markers spaced, on average, 10 cM apart is in progress and the investigation of 15 consanguineous families has identified one family which shows linkage to human chromosome 13q. This family appears to be linked to the same autosomal recessive deafness locus as two Tunisian families recently described and confirms that this chromosome 13q locus is also responsible, although as a minor contributor, to the deafness observed in the Pakistani population.

  8. The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery.

    PubMed

    Mishra, Sanjay K; Watkins, Simon C; Traub, Linton M

    2002-12-10

    The low density lipoprotein (LDL) receptor plays a pivotal role in cholesterol metabolism. Inherited mutations that disturb the activity of the receptor lead to elevations in plasma cholesterol levels and early-onset coronary atherosclerosis. Defects in either the LDL receptor or apolipoprotein B, the proteinaceous component of LDL particles that binds the LDL receptor, elevate circulating LDL-cholesterol levels in an autosomal-dominant fashion, with heterozygotes displaying values between homozygous and normal individuals. Rarely, similar clinical phenotypes occur with a recessive pattern of inheritance, and several genetic lesions in the autosomal recessive hypercholesterolemia (ARH) gene on chromosome 1 have been mapped in this class of patients. ARH has an N-terminal phosphotyrosine-binding (PTB) domain evolutionarily related to that found in Disabled-2 and numb, two endocytic proteins. PTB domains bind to the consensus sequence FXNPXY, corresponding to the internalization motif of the LDL receptor. We show here that in addition to the FXNPXY sequence, ARH binds directly to soluble clathrin trimers and to clathrin adaptors by a mode involving the independently folded appendage domain of the beta subunit. At steady state, ARH colocalizes with endocytic proteins in HeLa cells, and the LDL receptor fluxes through peripheral ARH-positive sites before delivery to early endosomes. Because ARH also binds directly to phosphoinositides, which regulate clathrin bud assembly at the cell surface, our data suggest that in ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia.

  9. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes

    PubMed Central

    Pearson, Toni S.

    2016-01-01

    Background The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. Methods A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia–telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus). Results Involuntary movements occur in the majority of patients with ataxia–telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia–telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia). Discussion An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment. PMID:27536460

  10. Autosomal Recessive Dilated Cardiomyopathy due to DOLK Mutations Results from Abnormal Dystroglycan O-Mannosylation

    PubMed Central

    Morava, Eva; Riemersma, Moniek; Schuurs-Hoeijmakers, Janneke H. M.; Absmanner, Birgit; Verrijp, Kiek; van den Akker, Willem M. R.; Huijben, Karin; Steenbergen, Gerry; van Reeuwijk, Jeroen; Jozwiak, Adam; Zucker, Nili; Lorber, Avraham; Lammens, Martin; Knopf, Carlos; van Bokhoven, Hans; Grünewald, Stephanie; Lehle, Ludwig; Kapusta, Livia; Mandel, Hanna; Wevers, Ron A.

    2011-01-01

    Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5–13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations. PMID:22242004

  11. Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss.

    PubMed

    Atik, Tahir; Onay, Huseyin; Aykut, Ayca; Bademci, Guney; Kirazli, Tayfun; Tekin, Mustafa; Ozkinay, Ferda

    2015-01-01

    Comprehensive genetic testing has the potential to become the standard of care for individuals with hearing loss. In this study, we investigated the genetic etiology of autosomal recessive nonsyndromic hearing loss (ARNSHL) in a Turkish cohort including individuals with cochlear implant, who had a pedigree suggestive of an autosomal recessive inheritance. A workflow including prescreening of GJB2 and a targeted next generation sequencing panel (Illumına TruSightTM Exome) covering 2761 genes that we briefly called as mendelian exome sequencing was used. This panel includes 102 deafness genes and a number of genes causing Mendelian disorders. Using this approach, we identified causative variants in 21 of 29 families. Three different GJB2 variants were present in seven families. Remaining 14 families had 15 different variants in other known NSHL genes (MYO7A, MYO15A, MARVELD2, TMIE, DFNB31, LOXHD1, GPSM2, TMC1, USH1G, CDH23). Of these variants, eight are novel. Mutation detection rate of our workflow is 72.4%, confirming the usefulness of targeted sequencing approach in NSHL.

  12. Autosomal recessive congenital cataract, intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family.

    PubMed

    Chograni, M; Alkuraya, F S; Ourteni, I; Maazoul, F; Lariani, I; Chaabouni, H B

    2015-09-01

    The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability.

  13. A Defect in NIPAL4 Is Associated with Autosomal Recessive Congenital Ichthyosis in American Bulldogs

    PubMed Central

    Casal, Margret L.; Wang, Ping; Mauldin, Elizabeth A.; Lin, Gloria; Henthorn, Paula S.

    2017-01-01

    Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC_06586.3 g.52737379del), the 157th base (cytosine) in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin) protein of 248 amino acids instead of the wild-type length of 404. Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species. PMID:28122049

  14. Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia

    PubMed Central

    Gan-Or, Ziv; Bouslam, Naima; Birouk, Nazha; Lissouba, Alexandra; Chambers, Daniel B.; Vérièpe, Julie; Androschuck, Alaura; Laurent, Sandra B.; Rochefort, Daniel; Spiegelman, Dan; Dionne-Laporte, Alexandre; Szuto, Anna; Liao, Meijiang; Figlewicz, Denise A.; Bouhouche, Ahmed; Benomar, Ali; Yahyaoui, Mohamed; Ouazzani, Reda; Yoon, Grace; Dupré, Nicolas; Suchowersky, Oksana; Bolduc, Francois V.; Parker, J. Alex; Dion, Patrick A.; Drapeau, Pierre; Rouleau, Guy A.; Bencheikh, Bouchra Ouled Amar

    2016-01-01

    Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms. PMID:27153400

  15. Is autosomal recessive deafness associated with oculocutaneous albinism a "coincidence syndrome"?

    PubMed

    Lezirovitz, Karina; Nicastro, Fernanda Stávale; Pardono, Eliete; Abreu-Silva, Ronaldo Serafim; Batissoco, Ana Carla; Neustein, Isaac; Spinelli, Mauro; Mingroni-Netto, Regina Célia

    2006-01-01

    Hearing impairment is frequently found associated with pigmentary disorders in many syndromes. However, total oculocutaneous albinism (OCA) associated with deafness has been described only once, by Ziprkowski and Adam (Arch Dermatol 89:151-155, 1964) in an inbred family. A syndrome associating deafness and OCA was suggested by the authors, but two separate recessive genes segregating in this inbred group were also proposed later by Fraser (OMIM # 220900). Combined deafness and total OCA were also observed by us in a family originally reported to be nonconsanguineous but in which haplotyping showed evidence of a common ancestry: the proband was affected by both diseases, one of his sisters had only OCA and another sister had only deafness. Both the proband and his deaf sister were found to be homozygotes for the 35delG mutation (GJB2 gene), the most frequent cause of hereditary deafness. Linkage analysis with markers close to the four known OCA loci excluded linkage to OCA1, OCA2, and OCA3, and homozygosity in markers near OCA4 locus was observed. Sequencing of the corresponding gene (MATP) revealed a c.1121delT mutation, which leads to a stop codon at position 397 (L374fsX397). Clearly, the combined occurrence of deafness and albinism in this pedigree was due to mutations in two different genes, showing autosomal recessive inheritance. We speculate that the putative syndrome reported by Ziprkowski and Adam might have resulted from the co-occurrence of autosomal recessive deafness and albinism in the same pedigree, as suggested by Fraser.

  16. [Autosomal recessive polycystic kidney disease and complex nephronophtisis medullary cystic disease].

    PubMed

    2008-12-01

    Reseach during the past decade has led to the discovery that defects in some proteins that localize to primary cilia or the basal body are the main contributors to renal cyst development. Autosomal recessive polycystic disease and nephronophthisis- medullary cystic kidney disease are named ciliopathies. The cilium is a microtubule-based organelle that is found on most mammalian cells. Cilia-mediated hypothesis has evolved into the concept of cystogenesis, cilia bend by fluid initiate a calcium influx that prevents cyst formation. Cilia might sense stimuli in the cell enviroment and control cell polarity and mitosis. A new set of pathogenic mechanisms in renal cystic disease defined new therapeutic targets, control of intracellular calcium, inhibition of cAMP and down regulation cannonical Wnt signaling.

  17. Autosomal recessive chronic granulomatous disease presenting with cutaneous dermatoses and ocular infection.

    PubMed

    Low, L C M; Manson, A L; Hardman, C; Carton, J; Seneviratne, S L; Ninis, N

    2013-04-01

    Dermatoses such as eczematous dermatitis and cutaneous infection are recognized presentations of primary immunodeficiency (PID). However, atopic dermatitis affects approximately 10% of infants, and cutaneous infections are not uncommon in children, therefore the challenge for the dermatologist is to distinguish the few patients that have PID from the many that do not. We report on a 6-year-old girl who was ultimately diagnosed with autosomal recessive chronic granulomatous disease (AR-CGD) after presenting to various hospitals with dermatitis, scalp plaques recalcitrant to treatment, and recurrent infections over a 3-year period, and describe some aspects of her diagnosis and management. This report highlights the importance of considering rare disorders such as AR-CGD in the differential diagnosis of recurrent or recalcitrant dermatological infections in children.

  18. Root anomalies and dentin dysplasia in autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC)

    PubMed Central

    Vieira, Alexandre R.; Lee, Moses; Vairo, Filippo; Leite, Julio Cesar Loguercio; Munerato, Maria Cristina; Visioli, Fernanda; D’Ávila, Stéphanie Rodrigues; Wang, Shih-Kai; Choi, Murim; Simmer, James P.; Hu, Jan C-C.

    2015-01-01

    Hyperphosphatemic familial tumoral calcinosis (HFTC, OMIM #211900) is an autosomal recessive metabolic disorder characterized by hyperphosphatemia, tooth root defects, and the progressive deposition of calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone.1 In this HFTC case report, we document the dental phenotype associated with a homozygous missense mutation (g.29077 C>T; c.484 C>T; p.Arg162*) in GALNT3 (OMIM 6017563), a gene encoding UDP-GalNAc transferase 3 that catalyzes the first step of O-linked oligosaccharide biosynthesis in the Golgi. The medical and dental pathology is believed to be caused primarily by high serum phosphate levels (hyperphosphatemia), which, in turn, is caused by failure of GALNT3 to glycosylate the phosphate regulator protein FGF23, impairing its ability inhibit reabsorption of filtered phosphate in the kidneys. PMID:26337219

  19. Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations

    PubMed Central

    Jaureguiberry, Graciana; De la Dure-Molla, Muriel; Parry, David; Quentric, Mickael; Himmerkus, Nina; Koike, Toshiyasu; Poulter, James; Klootwijk, Enriko; Robinette, Steven L.; Howie, Alexander J.; Patel, Vaksha; Figueres, Marie-Lucile; Stanescu, Horia C.; Issler, Naomi; Nicholson, Jeremy K.; Bockenhauer, Detlef; Laing, Christopher; Walsh, Stephen B.; McCredie, David A.; Povey, Sue; Asselin, Audrey; Picard, Arnaud; Coulomb, Aurore; Medlar, Alan J.; Bailleul-Forestier, Isabelle; Verloes, Alain; Le Caignec, Cedric; Roussey, Gwenaelle; Guiol, Julien; Isidor, Bertrand; Logan, Clare; Shore, Roger; Johnson, Colin; Inglehearn, Christopher; Al-Bahlani, Suhaila; Schmittbuhl, Matthieu; Clauss, François; Huckert, Mathilde; Laugel, Virginie; Ginglinger, Emmanuelle; Pajarola, Sandra; Spartà, Giuseppina; Bartholdi, Deborah; Rauch, Anita; Addor, Marie-Claude; Yamaguti, Paulo M.; Safatle, Heloisa P.; Acevedo, Ana Carolina; Martelli-Júnior, Hercílio; dos Santos Netos, Pedro E.; Coletta, Ricardo D.; Gruessel, Sandra; Sandmann, Carolin; Ruehmann, Denise; Langman, Craig B.; Scheinman, Steven J.; Ozdemir-Ozenen, Didem; Hart, Thomas C.; Hart, P. Suzanne; Neugebauer, Ute; Schlatter, Eberhard; Houillier, Pascal; Gahl, William A.; Vikkula, Miikka; Bloch-Zupan, Agnès; Bleich, Markus; Kitagawa, Hiroshi; Unwin, Robert J.; Mighell, Alan; Berdal, Ariane; Kleta, Robert

    2013-01-01

    Background/Aims Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis. PMID:23434854

  20. The DFNB1 subtype of autosomal recessive non-syndromic hearing impairment.

    PubMed

    del Castillo, Francisco J; del Castillo, Ignacio

    2011-06-01

    Inherited hearing impairment is a frequent and highly heterogeneous condition. Among the different subtypes of autosomal recessive non-syndromic hearing impairment, DFNB1 is remarkable for its high frequency in most populations. It is caused by mutations in the coding region or splice-sites of the GJB2 gene, or by mutations affecting regulatory sequences that are essential for the expression of this gene. GJB2 encodes connexin-26, a protein component of intercellular gap junctions, which play crucial physiological roles in the cochlea. Because of its high frequency, DFNB1 hearing impairment has received continued attention from researchers along the years, resulting in a wealth of data that is unparalleled among these disorders. Here we review our current knowledge on the genetic, molecular, and phenotypic aspects of this subtype of hearing impairment.

  1. Autosomal recessive peripheral sensory neuropathy in 3 non-Ashkenazi Jewish families.

    PubMed Central

    Tamari, I; Goodman, R M; Sarova, I; Hertz, M; Adar, R; Zvibach, T

    1980-01-01

    Three unrelated Oriental Jewish families with a total of eight subjects with progressive hereditary sensory neuropathy are reported. The parents were all unaffected and because of parental consanguinity in each of the three families it is postulated that this rare neurological disorder is transmitted in an autosomal recessive manner. In one family both parents showed an abnormal response to pain stimulation with normal motor and sensory nerve conduction velocity. This response may be an expression of the carrier state for this hereditary disease. Only five other families (non-Jewish) have been reported as having this form of peripheral hereditary sensory neuropathy. These observations suggest that one type, the progressive form, of peripheral hereditary sensory neuropathy may be more common in Oriental Jews. Images PMID:6937618

  2. Missense mutation (E150K) of rhodopsin in autosomal recessive retinitis pigmentosa

    SciTech Connect

    Orth, U.; Oehlmann, R.; Gal, A.

    1994-09-01

    Missense or nonsense mutations of the rhodopsin gene have been implied in the pathogenesis of at least 3 different traits; autosomal dominant retinitis pigmentosa (adRP), congenital stationary night blindness (CSNB), and autosomal recessive retinitis pigmentosa (arRP). For the latter, a single patient has been reported with a nonsense mutation at codon 249 on both alleles. Heterozygous carriers of missense mutations of rhodopsin develop either adRP or CSNB depending on the particular amino acid substitution. Four of the 9 siblings from a consanguineous marriage in southern India were reported the have arRP. Mutational screening and sequencing of the rhodopsin gene revealed a G-to-A transition of the first nucleotide at codon 150 in exon II, which alters glutamate to lysine. The E150K mutation was present in the 4 patients in homozygous form, whereas the parents and 2 of the siblings were heterozygotes. Two-point analysis produced a Zmax=3.46 at theta=0.00. Two unaffected siblings who are heterozygotes for the E150K mutation underwent a thorough ophthalmological and psychophysical examination. No clinical abnormalities were found although these individuals were over forty, whereas the onset of RP in their affected siblings was in the second decade. Collectively, both the genetic and clinical findings strongly suggest that the E150K mutation of rhodopsin is recessive in this family. Glu150 forms part of the CD cytoplasmic loop of rhodopsin, which has been implicated in the binding and activation of transducin. We speculate that E150K leads to RP because the mutant protein may be incapable of activating transducin. It is tempting to speculate that, in addition to mutations in the genes for rhodopsin and the {beta}-subunit of PDE, mutations in the genes for transducin may also result in arRP.

  3. A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family.

    PubMed

    Singh, Nivedita; Kumble Bhat, Vishwanath; Tiwari, Ankana; Kodaganur, Srinivas G; Tontanahal, Sagar J; Sarda, Astha; Malini, K V; Kumar, Arun

    2017-01-13

    Anencephaly is characterized by the absence of brain tissues and cranium. During primary neurulation stage of the embryo, the rostral part of the neural pore fails to close, leading to anencephaly. Anencephaly shows a heterogeneous etiology, ranging from environmental to genetic causes. The autosomal recessive inheritance of anencephaly has been reported in several populations. In this study, we employed whole-exome sequencing and identified a homozygous missense mutation c.1522C>A (p.Pro508Thr) in the TRIM36 gene as the cause of autosomal recessive anencephaly (APH) in an Indian family. The TRIM36 gene is expressed in the developing brain, suggesting a role in neurogenesis. In silco analysis showed that proline at codon position 508 is highly conserved in 26 vertebrate species, and the mutation is predicted to affect the conformation of the B30.2/SPRY domain of TRIM36. Both in vitro and in vivo results showed that the mutation renders the TRIM36 protein less stable. TRIM36 is known to associate with microtubules. Transient expression of the mutant TRIM36 in HeLa and LN229 cells resulted in microtubule disruption, disorganized spindles, loosely arranged chromosomes, multiple spindles, abnormal cytokinesis, reduced cell proliferation and increased apoptosis as compared to cells transfected with its wild-type counterpart. The siRNA knock down of TRIM36 in HeLa and LN229 cells also led to reduced cell proliferation and increased apoptosis. We suggest that microtubule disruption and disorganized spindles mediated by mutant TRIM36 affect neural cell proliferation during neural tube formation, leading to anencephaly.

  4. Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23.

    PubMed

    Lee, John Y W; Hsu, Chao-Kai; Michael, Magdalene; Nanda, Arti; Liu, Lu; McMillan, James R; Pourreyron, Celine; Takeichi, Takuya; Tolar, Jakub; Reid, Evan; Hayday, Thomas; Blumen, Sergiu C; Abu-Mouch, Saif; Straussberg, Rachel; Basel-Vanagaite, Lina; Barhum, Yael; Zouabi, Yasmin; Al-Ajmi, Hejab; Huang, Hsin-Yu; Lin, Ting-Chien; Akiyama, Masashi; Lee, Julia Y Y; McLean, W H Irwin; Simpson, Michael A; Parsons, Maddy; McGrath, John A

    2017-02-02

    SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24-q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3' UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.

  5. Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis

    PubMed Central

    Keupp, Katharina; Li, Yun; Vargel, Ibrahim; Hoischen, Alexander; Richardson, Rebecca; Neveling, Kornelia; Alanay, Yasemin; Uz, Elif; Elcioğlu, Nursel; Rachwalski, Martin; Kamaci, Soner; Tunçbilek, Gökhan; Akin, Burcu; Grötzinger, Joachim; Konas, Ersoy; Mavili, Emin; Müller-Newen, Gerhard; Collmann, Hartmut; Roscioli, Tony; Buckley, Michael F; Yigit, Gökhan; Gilissen, Christian; Kress, Wolfram; Veltman, Joris; Hammerschmidt, Matthias; Akarsu, Nurten A; Wollnik, Bernd

    2013-01-01

    We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation; a family with pansynostosis with compound heterozygous missense mutations, p.Pro200Thr and p.Arg237Pro; and two further Turkish families with Crouzon-like syndrome carrying the homozygous nonsense mutations p.Tyr232* and p.Arg292*. Using transient coexpression in HEK293T and COS7 cells, we demonstrated dramatically reduced IL11-mediated STAT3 phosphorylation for all mutations. Immunofluorescence analysis of mouse Il11ra demonstrated specific protein expression in cranial mesenchyme which was localized around the coronal suture tips and in the lambdoidal suture. In situ hybridization analysis of adult zebrafish also detected zfil11ra expression in the coronal suture between the overlapping frontal and parietal plates. This study demonstrates that mutations in the IL11RA gene cause an autosomal recessive Crouzon-like craniosynostosis. PMID:24498618

  6. Genetic analysis of TMPRSS3 gene in the Korean population with autosomal recessive nonsyndromic hearing loss.

    PubMed

    Lee, Jinwook; Baek, Jeong-In; Choi, Jae Young; Kim, Un-Kyung; Lee, Sang-Heun; Lee, Kyu-Yup

    2013-12-15

    The TMPRSS3 gene (DFNB8/10), which encodes a transmembrane serine protease, is a common hearing loss gene in several populations. Accurate functions of TMPRSS3 in the hearing pathway are still unknown, but TMPRSS3 has been reported to play a crucial role in inner ear development or maintenance. To date, 16 pathogenic mutations have been identified in many countries, but no mutational studies of the TMPRSS3 gene have been conducted in the Korean hearing loss population. In this study, we performed genetic analysis of TMPRSS3 in 40 unrelated Korean patients with autosomal recessive hearing loss to identify the aspect and frequency of TMPRSS3 gene mutations in the Korean population. A total of 22 variations were detected, including a novel variant (p.V291L) and a previously reported pathogenic mutation (p.A306T). The p.A306T mutation which has been detected in only compound heterozygous state in previous studies was identified in homozygous state for the first time in this study. Moreover, the clinical evaluation identified bilateral dilated vestibules in the patient with p.A306T mutation, and it suggested that p.A306T mutation of the TMPRSS3 gene might be associated with vestibular anomalies. In conclusion, this study investigated that only 2.5% of patients with autosomal recessive hearing loss were related to TMPRSS3 mutations suggesting low prevalence of TMPRSS3 gene in Korean hearing loss population. Also, it will provide the information of genotype-phenotype correlation to understand definite role of TMPRSS3 in the auditory system.

  7. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome

    PubMed Central

    Marrone, Anna; Walne, Amanda; Tamary, Hannah; Masunari, Yuka; Kirwan, Michael; Beswick, Richard; Vulliamy, Tom; Dokal, Inderjeet

    2010-01-01

    Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and an increased predisposition to malignancy. X-linked DC is due to mutations in DKC1, while heterozygous mutations in TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase) have been found in autosomal dominant DC. Many patients with DC remain uncharacterized, particularly families displaying autosomal recessive (AR) inheritance. We have now identified novel homozygous TERT mutations in 2 unrelated consanguineous families, where the index cases presented with classical DC or the more severe variant, Hoyeraal-Hreidarsson (HH) syndrome. These TERT mutations resulted in reduced telomerase activity and extremely short telomeres. As these mutations are homozygous, these patients are predicted to have significantly reduced telomerase activity in vivo. Interestingly, in contrast to patients with heterozygous TERT mutations or hemizygous DKC1 mutations, these 2 homozygous TERT patients were observed to have higher-than-expected TERC levels compared with controls. Collectively, the findings from this study demonstrate that homozygous TERT mutations, resulting in a pure but severe telomerase deficiency, produce a phenotype of classical AR-DC and its severe variant, the HH syndrome. PMID:17785587

  8. Characterization of an Early-Onset, Autosomal Recessive, Progressive Retinal Degeneration in Bengal Cats

    PubMed Central

    Ofri, Ron; Reilly, Christopher M.; Maggs, David J.; Fitzgerald, Paul G.; Shilo-Benjamini, Yael; Good, Kathryn L.; Grahn, Robert A.; Splawski, Danielle D.; Lyons, Leslie A.

    2015-01-01

    Purpose A form of retinal degeneration suspected to be hereditary was discovered in a family of Bengal cats. A breeding colony was established to characterize disease progression clinically, electrophysiologically, and morphologically, and to investigate the mode of inheritance. Methods Affected and related cats were donated by owners for breeding trials and pedigree analysis. Kittens from test and complementation breedings underwent ophthalmic and neuro-ophthalmic examinations and ERG, and globes were evaluated using light microscopy. Results Pedigree analysis, along with test and complementation breedings, indicated autosomal recessive inheritance and suggested that this disease is nonallelic to a retinal degeneration found in Persian cats. Mutation analysis confirmed the disease is not caused by CEP290 or CRX variants found predominantly in Abyssinian and Siamese cats. Ophthalmoscopic signs of retinal degeneration were noted at 9 weeks of age and became more noticeable over the next 4 months. Visual deficits were behaviorally evident by 1 year of age. Electroretinogram demonstrated reduced rod and cone function at 7 and 9 weeks of age, respectively. Rod responses were mostly extinguished at 14 weeks of age; cone responses were minimal by 26 weeks. Histologic degeneration was first observed at 8 weeks, evidenced by reduced photoreceptor numbers, then rapid deterioration of the photoreceptor layer and, subsequently, severe outer retinal degeneration. Conclusions A recessively inherited primary photoreceptor degeneration was characterized in the Bengal cat. The disease is characterized by early onset, with histologic, ophthalmoscopic, and electrophysiological signs evident by 2 months of age, and rapid progression to blindness. PMID:26258614

  9. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia

    PubMed Central

    Stitziel, Nathan O.; Fouchier, Sigrid W.; Sjouke, Barbara; Peloso, Gina M.; Moscoso, Alessa M.; Auer, Paul L.; Goel, Anuj; Gigante, Bruna; Barnes, Timothy A.; Melander, Olle; Orho-Melander, Marju; Duga, Stefano; Sivapalaratnam, Suthesh; Nikpay, Majid; Martinelli, Nicola; Girelli, Domenico; Jackson, Rebecca D.; Kooperberg, Charles; Lange, Leslie A.; Ardissino, Diego; McPherson, Ruth; Farrall, Martin; Watkins, Hugh; Reilly, Muredach P.; Rader, Daniel J.; de Faire, Ulf; Schunkert, Heribert; Erdmann, Jeanette; Samani, Nilesh J.; Charnas, Lawrence; Altshuler, David; Gabriel, Stacey; Kastelein, John J.P.; Defesche, Joep C.; Nederveen, Aart J.; Kathiresan, Sekar; Hovingh, G. Kees

    2014-01-01

    Objective Autosomal recessive hypercholesterolemia (ARH) is a rare inherited disorder characterized by extremely high total and low-density lipoprotein cholesterol levels that has been previously linked to mutations in LDLRAP1. We identified a family with ARH not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular etiology of ARH in this family. Approach and Results We used exome sequencing to assess all protein coding regions of the genome in three family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Since homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease (CESD), we performed directed follow-up phenotyping by non-invasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of CESD. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27,000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance. Conclusions By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent CESD in the affected individuals from this kindred and addressed an outstanding question regarding risk of cardiovascular disease in LIPA E8SJM heterozygous carriers. PMID:24072694

  10. The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification.

    PubMed

    Fellin, Renato; Arca, Marcello; Zuliani, Giovanni; Calandra, Sebastiano; Bertolini, Stefano

    2015-01-15

    The most frequent form of monogenic hypercholesterolemia, also known as Familial Hypercholesterolemia (FH), is characterized by plasma accumulation of cholesterol transported in Low Density Lipoproteins (LDLs). FH has a co-dominant transmission with a gene-dosage effect. FH heterozygotes have levels of plasma LDL-cholesterol (LDL-C) twice normal and present xanthomas and coronary heart disease (CHD) in adulthood. In rare FH homozygotes plasma LDL-C level is four times normal, while xanthomas and CHD are present from infancy. Most FH patients are carriers of mutations of the LDL receptor (LDLR); a minority of them carry either mutations in the Apolipoprotein B (ApoB), the protein constituent of LDLs which is the ligand for LDLR, or gain of function mutations of PCSK9, the protein responsible for the intracellular degradation of the LDLR. From 1970 to the mid 90s some publications described children with the clinical features of homozygous FH, who were born from normocholesterolemic parents, strongly suggesting a recessive transmission of FH. In these patients the involvement of LDLR and APOB genes was excluded. Interestingly, several patients were identified in the island of Sardinia (Italy), whose population has a peculiar genetic background due to geographical isolation. In this review, starting from the early descriptions of patients with putative recessive hypercholesterolemia, we highlight the milestones that led to the identification of a novel gene involved in LDL metabolism and the characterization of its encoded protein. The latter turned out to be an adaptor protein required for the LDLR-mediated endocytosis of LDLs in hepatocytes. The loss of function of this protein is the cause of Autosomal Recessive Hypercholesterolemia (ARH).

  11. Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts

    PubMed Central

    Irum, Bushra; Khan, Shahid Y.; Ali, Muhammad; Kaul, Haiba; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Nadeem, Raheela; Khan, Arif O.; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A.; Khan, Shaheen N.; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O.; Riazuddin, S. Amer

    2016-01-01

    Purpose To identify the molecular basis of non-syndromic autosomal recessive congenital cataracts (arCC) in a consanguineous family. Methods All family members participating in the study received a comprehensive ophthalmic examination to determine their ocular phenotype and contributed a blood sample, from which genomic DNA was extracted. Available medical records and interviews with the family were used to compile the medical history of the family. The symptomatic history of the individuals exhibiting cataracts was confirmed by slit-lamp biomicroscopy. A genome-wide linkage analysis was performed to localize the disease interval. The candidate gene, LIM2 (lens intrinsic membrane protein 2), was sequenced bi-directionally to identify the disease-causing mutation. The physical changes caused by the mutation were analyzed in silico through homology modeling, mutation and bioinformatic algorithms, and evolutionary conservation databases. The physiological importance of LIM2 to ocular development was assessed in vivo by real-time expression analysis of Lim2 in a mouse model. Results Ophthalmic examination confirmed the diagnosis of nuclear cataracts in the affected members of the family; the inheritance pattern and cataract development in early infancy indicated arCC. Genome-wide linkage analysis localized the critical interval to chromosome 19q with a two-point logarithm of odds (LOD) score of 3.25. Bidirectional sequencing identified a novel missense mutation, c.233G>A (p.G78D) in LIM2. This mutation segregated with the disease phenotype and was absent in 192 ethnically matched control chromosomes. In silico analysis predicted lower hydropathicity and hydrophobicity but higher polarity of the mutant LIM2-encoded protein (MP19) compared to the wild-type. Moreover, these analyses predicted that the mutation would disrupt the secondary structure of a transmembrane domain of MP19. The expression of Lim2, which was detected in the mouse lens as early as embryonic day 15

  12. Next-generation sequencing for molecular diagnosis of autosomal recessive polycystic kidney disease.

    PubMed

    Edrees, Burhan M; Athar, Mohammad; Al-Allaf, Faisal A; Taher, Mohiuddin M; Khan, Wajahatullah; Bouazzaoui, Abdellatif; Al-Harbi, Naffaa; Safar, Ramzia; Al-Edressi, Howaida; Alansary, Khawala; Anazi, Abulkareem; Altayeb, Naji; Ahmed, Muawia A; Abduljaleel, Zainularifeen

    2016-10-10

    Autosomal recessive polycystic kidney disease (ARPKD) a rare genetic disorder, described by formation of cysts in the kidney. A targeted customized sequencing of genes implicated in ARPKD phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified likely pathogenic disease causing variants during the validation process. Four potential pathogenic variants [c.4870C>T, p.(Arg1624Trp)], [c.5725C>T, p.(Arg1909Trp)], c.1736C>T, p.(Thr579Met)] and [(c.10628T>G), p.(Leu3543Trp)] were observed in PKHD1 gene among 12 out of 18 samples. The rest of the patient samples also showed few variants in ADPKD (Autosomal Dominant Polycystic Kidney Disease) disease causing genes PKD1 and PKD2 i.e. [c.12433G>A, p.(Val4145Ile)] and [c.1445T>G, p.(Phe482Cys)], respectively. All causative variants were validated by capillary sequencing, confirming the presence of a novel homozygous variants [c.10628T>G, p.(Leu3543Trp)] found in exon 61 of a male proband. All potentially deleterious variants identified in PKHD1, PKD1, and PKD2 gene, also exhibited pathologically or clinically significance based on the computational predictions involved in predicting the impact of non-synonymous SNPs (nsSNPs) on protein function such as Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen2). SIFT classified 50% of our nsSNPs as "deleterious", while PolyPhen2 identified 45% of our nsSNPs as "Probably damaged" and the results from both programs were largely complementary. Taken together, these results suggest that the NGS strategies provide a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in targeted genes sequence analysis.

  13. Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population.

    PubMed Central

    Laiho, E; Ignatius, J; Mikkola, H; Yee, V C; Teller, D C; Niemi, K M; Saarialho-Kere, U; Kere, J; Palotie, A

    1997-01-01

    Autosomal recessive congenital ichthyosis (ARCI) is a rare, heterogenous keratinization disorder of the skin, classically divided into two clinical subtypes, lamellar ichthyosis (LI) and nonbullous congenital ichthyosiformis erythroderma (CIE). Recently, strong evidence for the involvement of the transglutaminase 1 gene (TGM1) in LI has evolved. We have studied ARCI in the isolated Finnish population, in which recessive disorders are often caused by single mutations enriched by a founder effect. Surprisingly, five different mutations of TGM1 (Arg141His, Arg142Cys, Gly217Ser, Val378Leu, and Arg395Leu) were found in Finnish ARCI patients. In addition to affected LI patients, we also identified TGM1 mutations in CIE patients. Moreover, haplotype analysis of the chromosomes carrying the most common mutation, a C-->T transition changing Arg142 to Cys, revealed that the same mutation has been introduced twice in the Finnish population. In addition to this Arg142Cys mutation, three other mutations, in Arg141 and Arg142, have been described elsewhere, in other populations. These findings suggest that this region of TGM1 is more susceptible to mutation. The corresponding amino acid sequence is conserved in other transglutaminases, but, for example, coagulation factor XIII (FXIII) mutations do not cluster in this region. Protein modeling of the Arg142Cys mutation suggested disruption or destabilization of the protein. In transfection studies, the closely related transglutaminase FXIII protein with the corresponding mutation was shown to be susceptible to degradation in COS cells, further supporting evidence of the destabilizing effect of the Arg142Cys mutation in TGM1. Images Figure 3 Figure 4 PMID:9326318

  14. Elevated c-myc protooncogene expression in autosomal recessive polycystic kidney disease

    SciTech Connect

    Cowley, B.D. Jr.; Smardo, F.L. Jr.; Grantham, J.J.; Calvet, J.P.

    1987-12-01

    The polycystic kidney diseases (PKDs) are a group of disorders characterized by the growth of epithelial cysts from the nephrons and collecting ducts of kidney tubules. The diseases can be inherited or can be provoked by environmental factors. To investigate the molecular basis of the abnormal cell growth associated with PKD, c-myc protooncogene expression was studied in a mouse model for autosomal recessive PKD. Homozygous recessive C57BL/6J (cpk/cpk) mice develop massively enlarged cystic kidneys and die from renal failure shortly after 3 weeks of age. Quantitative dot blot and RNA blot hybridization experiments in which whole kidney poly(A)/sup +/ RNA was hybridized with a c-myc RNA probe showed a 2- to 6-fold increase in c-myc mRNA at 2 weeks, and a 25- to 30-fold increase in c-myc mRNA at 3 weeks of age in polycystic mice, as compared to normal littermates. c-myc expression was also examined under two conditions in which kidney cell growth was experimentally induced in normal adult mice: compensatory renal hypertrophy and tubule regeneration following folic acid-induced renal cell injury. While compensatory hypertrophy resulted in only a small increase in c-myc, folic acid treatment gave rise after 24 hr to a 12-fold increase in c-myc RNA. The induction of c-myc by folic acid is consistent with increased cellular proliferation regenerating tubules. In contrast, polycystic kidneys show only a minimal increase in cellular proliferation over that seen in normal kidneys, while c-myc levels were found to be markedly elevated. Thus, the level of c-myc expression in cystic kidneys appears to be out of proportion to the rate of cell division, suggesting that elevated and potentially abnormal c-myc expression may be involved in the pathogenesis of PKD.

  15. Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families

    PubMed Central

    Moldenhauer Minillo, Renata; Sobreira, Nara; de Fatima de Faria Soares, Maria; Jurgens, Julie; Ling, Hua; Hetrick, Kurt N.; Doheny, Kimberly F.; Valle, David; Brunoni, Decio; Alvarez Perez, Ana B.

    2014-01-01

    Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed. PMID:25565926

  16. Development of novel noninvasive prenatal testing protocol for whole autosomal recessive disease using picodroplet digital PCR

    PubMed Central

    Chang, Mun Young; Kim, Ah Reum; Kim, Min Young; Kim, Soyoung; Yoon, Jinsun; Han, Jae Joon; Ahn, Soyeon; Kang, Changsoo; Choi, Byung Yoon

    2016-01-01

    We developed a protocol of noninvasive prenatal testing (NIPT), employing a higher-resolution picodroplet digital PCR, to detect genetic imbalance in maternal plasma DNA (mpDNA) caused by cell-free fetal DNA (cffDNA). In the present study, this approach was applied to four families with autosomal recessive (AR) congenital sensorineural hearing loss. First, a fraction of the fetal DNA in mpDNA was calculated. Then, we made artificial DNA mixtures (positive and negative controls) to simulate mpDNA containing the fraction of cffDNA with or without mutations. Next, a fraction of mutant cluster signals over the total signals was measured from mpDNA, positive controls, and negative controls. We determined whether fetal DNA carried any paternal or maternal mutations by calculating and comparing the sum of the log-likelihood of the study samples. Of the four families, we made a successful prediction of the complete fetal genotype in two cases where a distinct cluster was identified for each genotype and the fraction of cffDNA in mpDNA was at least 6.4%. Genotyping of only paternal mutation was possible in one of the other two families. This is the first NIPT protocol potentially applicable to any AR monogenic disease with various genotypes, including point mutations. PMID:27924908

  17. Fetal brain disruption sequence versus fetal brain arrest: A distinct autosomal recessive developmental brain malformation phenotype.

    PubMed

    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; El-Khayat, Hamed A; Eid, Ola M; Saba, Soliman; Farag, Mona K; Saleem, Sahar N; Gaber, Khaled R

    2015-05-01

    The term fetal brain disruption sequence (FBDS) was coined to describe a number of sporadic conditions caused by numerous external disruptive events presenting with variable imaging findings. However, rare familial occurrences have been reported. We describe five patients (two sib pairs and one sporadic) with congenital severe microcephaly, seizures, and profound intellectual disability. Brain magnetic resonance imaging (MRI) revealed unique and uniform picture of underdeveloped cerebral hemispheres with increased extraxial CSF, abnormal gyral pattern (polymicrogyria-like lesions in two sibs and lissencephaly in the others), loss of white matter, dysplastic ventricles, hypogenesis of corpus callosum, and hypoplasia of the brainstem, but hypoplastic cerebellum in one. Fetal magnetic resonance imaging (FMRI) of two patients showed the same developmental brain malformations in utero. These imaging findings are in accordance with arrested brain development rather than disruption. Molecular analysis excluded mutations in potentially related genes such as NDE1, MKL2, OCLN, and JAM3. These unique clinical and imaging findings were described before among familial reports with FBDS. However, our patients represent a recognizable phenotype of developmental brain malformations, that is, apparently distinguishable from either familial microhydranencephaly or microlissencephaly that were collectively termed FBDS. Thus, the use of the umbrella term FBDS is no longer helpful. Accordingly, we propose the term fetal brain arrest to distinguish them from other familial patients diagnosed as FBDS. The presence of five affected patients from three unrelated consanguineous families suggests an autosomal-recessive mode of inheritance. The spectrum of fetal brain disruption sequence is reviewed.

  18. Recent Progress of the ARegPKD Registry Study on Autosomal Recessive Polycystic Kidney Disease

    PubMed Central

    Ebner, Kathrin; Schaefer, Franz; Liebau, Max Christoph; Eid, L. A.

    2017-01-01

    Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disease with a severe phenotype often presenting prenatally or in early childhood. With its obligate renal and hepatic involvement, ARPKD is one of the most important indications for liver and/or kidney transplantation in childhood. Marked phenotypic variability is observed, the genetic basis of which is largely unknown. Treatment is symptomatic and largely empiric as evidence-based guidelines are lacking. Therapeutic initiatives for ARPKD face the problem of highly variable cohorts and lack of clinical or biochemical risk markers without clear-cut clinical end points. ARegPKD is an international, multicenter, retro- and prospective, observational study to deeply phenotype patients with the clinical diagnosis of ARPKD. Initiated in 2013 as a web-based registry (www.aregpkd.org), ARegPKD enrolls patients across large parts of Europe and neighboring countries. By January 2017, more than 400 patients from 17 mostly European countries have been registered in the ARPKD registry study with significant follow-up data. Due to comprehensive retro- and prospective data collection and associated biobanking, ARegPKD will generate a unique ARPKD cohort with detailed longitudinal clinical characterization providing a basis for future clinical trials as well as translational research. Hence, ARegPKD is hoped to contribute to the pathophysiological understanding of the disease and to the improvement of clinical management. PMID:28296980

  19. Genetic dissection of two Pakistani families with consanguineous localized autosomal recessive hypotrichosis (LAH)

    PubMed Central

    Abbas, Seyyedha; Naveed, Abdul Khaliq; Khan, Shakir; Yousaf, Muhammad Jawad; Azeem, Zahid; Razak, Suhail; Qaiser, Fatima

    2014-01-01

    Objective(s): Genetic analysis of two consanguineous Pakistani families with localized autosomal recessive hypotrichosis was performed with the goal to establish genotype-phenotype correlation. Materials and Methods: Genomic DNA extraction had been done from peripheral blood samples. Extracted DNA was then subjected to PCR (polymerase chain reaction) for amplification. Linkage analysis was performed using 8% polyacrylamide gel. Candidate gene was sequenced after gene linkage supported at highly polymorphic microsatellite markers of the diseased region. Results: Both families were initially tested for linkage to known genes, which were involved in human hereditary hypotrichosis, by genotyping Highly polymorphic microsatellite markers. Family B showed partial linkage at P2RY5 gene on chromosome 13q14.11-q21.32; hence, all exonic regions and their introns boundaries were subjected to DNA sequencing for any pathogenic mutation. Conclusion: Both families were tested for linkage by genotyping polymorphic microsatellite markers linked to known alopecia loci. Family A excluded all known diseased regions that is suggestive of some novel chromosomal disorder. However, sequencing of P2RY5 gene in family B showed no pathogenic mutation. PMID:25429336

  20. Mutation Screening of Multiple Genes in Spanish Patients with Autosomal Recessive Retinitis Pigmentosa by Targeted Resequencing

    PubMed Central

    González-del Pozo, María; Borrego, Salud; Barragán, Isabel; Pieras, Juan I.; Santoyo, Javier; Matamala, Nerea; Naranjo, Belén; Dopazo, Joaquín; Antiñolo, Guillermo

    2011-01-01

    Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing. PMID:22164218

  1. Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia

    PubMed Central

    Jones, Christopher; Garuti, Rita; Michaely, Peter; Li, Wei-Ping; Maeda, Nobuyo; Cohen, Jonathan C.; Herz, Joachim; Hobbs, Helen H.

    2007-01-01

    Genetic defects in LDL clearance result in severe hypercholesterolemia and premature atherosclerosis. Mutations in the LDL receptor (LDLR) cause familial hypercholesterolemia (FH), the most severe form of genetic hypercholesterolemia. A phenocopy of FH, autosomal recessive hypercholesterolemia (ARH), is due to mutations in an adaptor protein involved in LDLR internalization. Despite comparable reductions in LDL clearance rates, plasma LDL levels are substantially lower in ARH than in FH. To determine the metabolic basis for this difference, we examined the synthesis and catabolism of VLDL in murine models of FH (Ldlr–/–) and ARH (Arh–/–). The hyperlipidemic response to a high-sucrose diet was greatly attenuated in Arh–/– mice compared with Ldlr–/– mice despite similar rates of VLDL secretion. The rate of VLDL clearance was significantly higher in Arh–/– mice than in Ldlr–/– mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Consistent with these findings, hepatocytes from Arh–/– mice (but not Ldlr–/– mice) internalized β-migrating VLDL (β-VLDL). These results demonstrate that ARH is not required for LDLR-dependent uptake of VLDL by the liver. The preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH. PMID:17200716

  2. Cranial imaging in autosomal recessive osteopetrosis. Part I. Facial bones and calvarium.

    PubMed

    Elster, A D; Theros, E G; Key, L L; Chen, M Y

    1992-04-01

    Cranial imaging studies (radiographs, computed tomographic [CT] scans, magnetic resonance [MR] images, and bone marrow scintigrams) in 13 infants and children with autosomally recessive osteopetrosis were reviewed to characterize patterns of facial and calvarial involvement at presentation and with progression of disease. In the mandible, a characteristic triangular opacity representing calcification within the secondary condylar cartilage ossification center was seen in 10 of the 13 patients. Defective dentition with incomplete enamel formation and/or caries was encountered in all patients. The paranasal sinuses were poorly pneumatized in all patients, but the ethmoid sinuses tended to be the least severely affected. Hypertelorism was present in five of the 13 patients, with a characteristic "space-alien" appearance on frontal radiographs. In younger patients, the calvarium demonstrated a high-attenuation inner table, a broad, low-attenuation diploic space, and a less high-attenuation outer table at CT. In three older children, a "hair-on-end" appearance was seen, which, at bone marrow scintigraphy, corresponded to areas of marked hematopoietic activity. Regions of sclerotic bone demonstrated low signal intensity on both T1- and T2-weighted MR images; areas containing marrow had intermediate signal intensity. These many new radiologic features of osteopetrosis are related to its pathophysiologic characteristics.

  3. A pedigree-analysis approach to the descriptive epidemiology of autosomal-recessive disorders.

    PubMed

    Man, W Y N; Nicholas, F W; James, J W

    2007-03-17

    We describe a pedigree-analysis approach to estimating descriptive epidemiological parameters for autosomal-recessive disorders when the ancestral source of the disorder is known. We show that the expected frequency of carriers in a cohort equals the gene contribution of the ancestral source to that cohort, which is equivalent to the direct (additive) genetic relationship of that ancestor to the cohort. Also, the expected incidence of affected foetuses ranges from (1/2)F* to F*, where F* is the mean partial inbreeding coefficient (due to the ancestor) of the cohort. We applied this approach to complex vertebral malformation (CVM) in Holstein-Friesians in Australia, for which the ancestral source is a USA-born bull, Carlin-M Ivanhoe Bell. The estimated frequency of carriers was 2.47% for the 1992-born and 4.44% for the 1997-born cohort of Holstein-Friesian cows in Australia. The estimated incidence of affected foetuses/calves was considerably less than one per thousand, ranging from 0.0024 to 0.0048% for the 1992-born cohort, and from 0.0288 to 0.0576% for the 1997-born cohort. These incidences correspond to expected numbers of affected female foetuses/calves ranging from 2 to 4 for the 1992-born cohort and from 28 to 56 for the 1997-born cohort. This approach is easy to implement using software that is readily available.

  4. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration

    PubMed Central

    Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka ELM; de Brouwer, Arjan PM; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

    2016-01-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far. PMID:26173967

  5. An autosomal recessive mutation of DSG4 causes monilethrix through the ER stress response.

    PubMed

    Kato, Madoka; Shimizu, Akira; Yokoyama, Yoko; Kaira, Kyoichi; Shimomura, Yutaka; Ishida-Yamamoto, Akemi; Kamei, Kiyoko; Tokunaga, Fuminori; Ishikawa, Osamu

    2015-05-01

    Monilethrix is a hair shaft anomaly characterized by beaded hair with periodic changes in hair thickness. Mutations in the desmoglein 4 (DSG4) gene reportedly underlie the autosomal recessive form of the disease. However, the pathogenesis and cellular basis for the DSG4 mutation-induced monilethrix remained largely unknown. We report a Japanese female patient with monilethrix. Observation of her hair shaft by means of transmission electron microscopy showed fewer desmosomes and abnormal keratinization. Genetic analysis revealed a homozygous mutation, c.2119delG (p.Asp707Ilefs*109), in the DSG4 gene, which was predicted to cause a frameshift and premature termination in the intracellular region of the DSG4 protein. The mutation has not been reported previously. In the patient's hair shaft, we detected reduced but partial expression of the mutant DSG4 protein. Cellular analyses demonstrated that the mutant DSG4 lost its affinity to plakoglobin and accumulated in the endoplasmic reticulum (ER). The amounts of mutant DSG4 were increased by proteasome inhibitor treatment, and the expression of an ER chaperone, GRP78/BiP, was elevated in the patient's skin. Collectively, these results suggest that the dysfunctional mutated DSG4, tethered in the ER, undergoes ER-associated degradation, leading to unfolded protein response induction, and thus ER stress may have a role in the pathogenesis of monilethrix.

  6. COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia.

    PubMed

    Goldstein, Orly; Guyon, Richard; Kukekova, Anna; Kuznetsova, Tatyana N; Pearce-Kelling, Susan E; Johnson, Jennifer; Aguirre, Gustavo D; Acland, Gregory M

    2010-08-01

    Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the 5' end of COL9A2 that cosegregates with drd2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed that RNA expression of the respective genes was reduced in affected retinas. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family, regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.

  7. A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.

    PubMed

    Canizales-Quinteros, Samuel; Aguilar-Salinas, Carlos A; Huertas-Vázquez, Adriana; Ordóñez-Sánchez, María L; Rodríguez-Torres, Maribel; Venturas-Gallegos, José L; Riba, Laura; Ramírez-Jimenez, Salvador; Salas-Montiel, Rocío; Medina-Palacios, Giovani; Robles-Osorio, Ludivina; Miliar-García, Angel; Rosales-León, Luis; Ruiz-Ordaz, Blanca H; Zentella-Dehesa, Alejandro; Ferré-D'Amare, Adrian; Gómez-Pérez, Francisco J; Tusié-Luna, Ma Teresa

    2005-01-01

    Autosomal recessive hypercholesterolemia (ARH) is characterized by elevated LDL serum levels, xanthomatosis, and premature coronary artery disease. Three loci have been described for this condition (1p35, 15q25-q26 and 13q). Recently, the responsible gene at the 1p35 locus, encoding an LDL receptor adaptor protein (ARH) has been identified. We studied a Mexican ARH family with two affected siblings. Sequence analysis of the ARH gene (1p35 locus) revealed that the affected siblings are homozygous for a novel mutation (IVS4+2T>G) affecting the donor splice site in intron 4, whereas both the parents and an unaffected sister are heterozygous for this mutation. The IVS4+2T>G mutation results in a major alternative transcript derived from a cryptic splice site, which carries an in-frame deletion of 78 nucleotides in the mature mRNA. The translation of this mRNA yields a mutant protein product (ARH-26) lacking 26 amino acids, resulting in the loss of beta-strands beta6 and beta7 from the PTB domain. This is the first case where a naturally occurring mutant with an altered PTB domain has been identified.

  8. Autosomal recessive hypercholesterolemia in Spanish kindred due to a large deletion in the ARH gene.

    PubMed

    Quagliarini, Fabiana; Vallvé, Joan-Carles; Campagna, Filomena; Alvaro, Adriana; Fuentes-Jimenez, Francisco José; Sirinian, Maria Isabella; Meloni, Francesca; Masana, Luis; Arca, Marcello

    2007-11-01

    Autosomal recessive hypercholesterolemia (ARH) is a rare genetic defect that causes marked elevation of plasma low-density lipoprotein cholesterol (LDL-C) and premature atherosclerosis. It is due to mutations in the ARH gene that plays a critical role in the internalization of LDL receptor (LDLR) in liver cells. We describe a Spanish family where a 24-year-old proband and his 13-year-old sister showed the typical characteristics of ARH. The proband's LDLR activity in peripheral lymphocytes was 14% of normal and his in vivo LDL catabolism was reduced by 64% compared to normal. Notably, the sister showed normal lipid levels when her umbilical cord blood was tested. In this family, ARH was due to homozygosity for a large approximately 1.6kb deletion that eliminates exon 4 of ARH gene. Analysis of ARH mRNA demonstrated that the fusion of exon 3 to exon 5 during the splicing of the primary transcript changes the reading frame leading to stop codon 7 amino acids downstream in exon 5. No protein product was detected in affected individuals by immunoblot analysis. This novel mutation adds new support to the molecular heterogeneity of ARH in the Mediterranean basin.

  9. Where do we stand in trial readiness for autosomal recessive limb girdle muscular dystrophies?

    PubMed

    Straub, Volker; Bertoli, Marta

    2016-02-01

    Autosomal recessive limb girdle muscular dystrophies (LGMD2) are a group of genetically heterogeneous diseases that are typically characterised by progressive weakness and wasting of the shoulder and pelvic girdle muscles. Many of the more than 20 different conditions show overlapping clinical features with other forms of muscular dystrophy, congenital, myofibrillar or even distal myopathies and also with acquired muscle diseases. Although individually extremely rare, all types of LGMD2 together form an important differential diagnostic group among neuromuscular diseases. Despite improved diagnostics and pathomechanistic insight, a curative therapy is currently lacking for any of these diseases. Medical care consists of the symptomatic treatment of complications, aiming to improve life expectancy and quality of life. Besides well characterised pre-clinical tools like animal models and cell culture assays, the determinants of successful drug development programmes for rare diseases include a good understanding of the phenotype and natural history of the disease, the existence of clinically relevant outcome measures, guidance on care standards, up to date patient registries, and, ideally, biomarkers that can help assess disease severity or drug response. Strong patient organisations driving research and successful partnerships between academia, advocacy, industry and regulatory authorities can also help accelerate the elaboration of clinical trials. All these determinants constitute aspects of translational research efforts and influence patient access to therapies. Here we review the current status of determinants of successful drug development programmes for LGMD2, and the challenges of translating promising therapeutic strategies into effective and accessible treatments for patients.

  10. Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation.

    PubMed

    Gatz, S A; Benninghoff, U; Schütz, C; Schulz, A; Hönig, M; Pannicke, U; Holzmann, K-H; Schwarz, K; Friedrich, W

    2011-04-01

    Autosomal-recessive hyper-IgE syndrome (AR-HIES) is a combined immunodeficiency recently found to be associated with mutations of DOCK8. Clinically, this disorder is characterized beside recurrent bacterial complications, in particular by an unusual susceptibility to extensive cutaneous viral complications and by a high risk for squamous cell carcinoma. Here, we report on lasting control over the disorder in two patients by hematopoietic cell transplantation (HCT). Both patients were suffering from extensive long-lasting cutaneous viral complications, in particular from disfiguring molluscum contagiosum infections, when treated at the age of 10 and 17 years. Donors were matched unrelated, and conditioning was carried out with a combination of fludarabine, melphalan and BM-targeted radioimmunotherapy. Both patients developed stable, full donor cell chimerism, with the exception of persistent low-IgA serum levels and the exception of normal immune functions. Over the course of several months, cutaneous manifestations of viral disease resolved completely and both patients remain clinically well and free of infectious complications at 4 and 2 years, respectively, after transplantation. This represents the first report indicating HCT to be curative in patients with AR-HIES, which should be considered early before life-threatening complications develop, which include malignancies.

  11. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy

    SciTech Connect

    Roberds, S.L.; Anderson, R.D.; Lim, L.E.

    1994-09-01

    Adhalin, the 50-kDa dystrophin-associated glycoprotein, is deficient in skeletal muscle of patients having severe childhood autosomal recessive muscular dystrophy (SCARMD). In several North African families, SCARMD has been linked to markers in the pericentromeric region of chromosome l3q, but SCARMD has been excluded from linkage to this locus in other families. To determine whether the adhalin gene might be involved in SCARMD, human adhalin cDNA and large portions of the adhalin gene were cloned. Adhalin is a transmembrane glycoprotein with an extracellular domain bearing limited homology to domains of entactin and nerve growth factor receptor, suggesting that adhalin may serve as a receptor for an extracellular matrix protein. The adhalin gene was mapped to chromosome 17q12-q21.33, excluding the gene from involvement in 13q-linked SCARMD. A polymorphic microsatellite was identified within intron 6 of the adhalin gene, and one allelic variant of this marker cosegregated with the disease phenotype in a large French family with a lod score of 3.61 at 0 recombination. Adhalin is undetectable in skeletal muscle from affected members of this family. Missense mutations were identified within the adhalin gene that might cause SCARMD in this family. Thus, genetic defects in at least two components, dystrophin and adhalin, of the dystrophin-glycoprotein complex can independently cause muscular dystrophies.

  12. Naturally- and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism.

    PubMed

    Asai, Hirohide; Hirano, Makito; Kiriyama, Takao; Ikeda, Masanori; Ueno, Satoshi

    2010-01-01

    Intranuclear events due to mutations in the Parkin gene remain elusive in autosomal recessive juvenile parkinsonism (ARJP). We identified a mutant PARKIN protein in fibroblast cultures from a pair of siblings with ARJP who were homozygous for the exon 4-deleted Parkin gene. Disease was mild in one patient and debilitating in the other. The detected mutant, encoded by a transcript lacking exon 3 as well as exon 4, is an in-frame deletion that removes 121 aa, resulting in a 344-aa protein (PaDel3,4). Cell culture and transfection studies revealed negative correlations between expression levels of PaDel3,4 and those of cell cycle proteins, including cyclin E, CDK2, ppRb, and E2F-1, and demonstrated that GFP-PaDel3,4 entered nucleus and ubiquitinated cyclin E as a part of SCF(hSel-10) ligase complex in the patient cells. In addition, nuclear localization signal-tagged PaDel3,4 expressed in the transfected patient cells most effectively ubiquitinated cyclin E and reduced DNA damage, protecting cells from oxidative stress. Antisense-oligonucleotide treatment promoted skipping of exon 3 and thus generated PaDel3,4, increasing cell survival. Collectively, we propose that naturally- and experimentally-induced exon skipping at least partly restores the mutant Parkin gene deficit, providing a molecular basis for the development of therapeutic exon skipping.

  13. Sample-size considerations and strategies for linkage analysis in autosomal recessive disorders.

    PubMed Central

    Wong, F L; Cantor, R M; Rotter, J I

    1986-01-01

    The opportunity raised by recombinant DNA technology to develop a linkage marker panel that spans the human genome requires cost-efficient strategies for its optimal utilization. Questions arise as to whether it is more cost-effective to convert a dimorphic restriction enzyme marker system into a highly polymorphic system or, instead, to increase the number of families studied, simply using the available marker alleles. The choice is highly dependent on the population available for study, and, therefore, an examination of the informational content of the various family structures is important to obtain the most informative data. To guide such decisions, we have developed tables of the average sample number of families required to detect linkage for autosomal recessive disorders under single backcross and under "fully informative" matings. The latter cross consists of a marker locus with highly polymorphic codominant alleles such that the parental marker genotypes can be uniquely distinguished. The sampling scheme considers families with unaffected parents of known mating types ascertained via affected offspring, for sibship sizes ranging from two to four and various numbers of affected individuals. The sample-size tables, calculated for various values of the recombination fractions and lod scores, may serve as a guide to a more efficient application of the restriction fragment length polymorphism technology to sequential linkage analysis. PMID:3019130

  14. Naturally- and experimentally-designed restorations of the Parkin gene deficit in autosomal recessive juvenile parkinsonism

    SciTech Connect

    Asai, Hirohide; Hirano, Makito; Kiriyama, Takao; Ikeda, Masanori; Ueno, Satoshi

    2010-01-01

    Intranuclear events due to mutations in the Parkin gene remain elusive in autosomal recessive juvenile parkinsonism (ARJP). We identified a mutant PARKIN protein in fibroblast cultures from a pair of siblings with ARJP who were homozygous for the exon 4-deleted Parkin gene. Disease was mild in one patient and debilitating in the other. The detected mutant, encoded by a transcript lacking exon 3 as well as exon 4, is an in-frame deletion that removes 121 aa, resulting in a 344-aa protein (PaDel3,4). Cell culture and transfection studies revealed negative correlations between expression levels of PaDel3,4 and those of cell cycle proteins, including cyclin E, CDK2, ppRb, and E2F-1, and demonstrated that GFP-PaDel3,4 entered nucleus and ubiquitinated cyclin E as a part of SCF{sup hSel-10} ligase complex in the patient cells. In addition, nuclear localization signal-tagged PaDel3,4 expressed in the transfected patient cells most effectively ubiquitinated cyclin E and reduced DNA damage, protecting cells from oxidative stress. Antisense-oligonucleotide treatment promoted skipping of exon 3 and thus generated PaDel3,4, increasing cell survival. Collectively, we propose that naturally- and experimentally-induced exon skipping at least partly restores the mutant Parkin gene deficit, providing a molecular basis for the development of therapeutic exon skipping.

  15. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration.

    PubMed

    Iqbal, Zafar; Püttmann, Lucia; Musante, Luciana; Razzaq, Attia; Zahoor, Muhammad Yasir; Hu, Hao; Wienker, Thomas F; Garshasbi, Masoud; Fattahi, Zohreh; Gilissen, Christian; Vissers, Lisenka E L M; de Brouwer, Arjan P M; Veltman, Joris A; Pfundt, Rolph; Najmabadi, Hossein; Ropers, Hans-Hilger; Riazuddin, Sheikh; Kahrizi, Kimia; van Bokhoven, Hans

    2016-03-01

    AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.

  16. Autosomal recessive Wolfram syndrome associated with an 8.5 kb mtDNA single deletion

    SciTech Connect

    Barrientos, A.; Casademont, J.; Cardellach, F.

    1996-05-01

    Wolfram syndrome (MIM 222300) is characterized by optic atrophy, diabetes mellitus, diabetes insipidus, neurosensory hearing loss, urinary tract abnormalities, and neurological dysfunction. The association of clinical manifestations in tissues and organs unrelated functionally or embryologically suggested the possibility of a mitochondrial implication in the disease, which has been demonstrated in two sporadic cases. Nonetheless, familial studies suggested an autosomal recessive mode of transmission, and recent data demonstrated linkage with markers on the short arm of human chromosome 4. The patient reported here, as well as her parents and unaffected sister, carried a heteroplasmic 8.5-kb deletion in mtDNA. The deletion accounted for 23% of mitochondrial genomes in lymphocytes from the patient and {approximately}5% in the tissues studied from members of her family. The presence of the deletion in the patient in a proportion higher than in her unaffected parents suggests a putative defect in a nuclear gene that acts at the mitochondrial level. 39 refs., 6 figs., 3 tabs.

  17. Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa

    SciTech Connect

    Danciger, M.; Blaney, J.; Gao, Y.Q.; Zhao, D.Y.

    1995-11-01

    We have studied 24 small families with presumed autosomal recessive inheritance of retinitis pigmentosa by a combination of haplotype analysis and exon screening. Initial analysis of the families was made with a dinucleotide repeat polymorphism adjacent to the gene for rod cGMP-phosphodiesterase (PDE6B). This was followed by denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism electrophoresis (SSCPE) of the 22 exons and a portion of the 5{prime} untranslated region of the PDE6B gene in the probands of each family in which the PDE6B locus could not be ruled out from segregating with disease. Two probands were found with compound heterozygous mutations: Gly576Asp and His620(1-bp del) mutations were present in one proband, and a Lys706X null mutation and an AG to AT splice acceptor site mutation in intron 2 were present in the other. Only the affecteds of each of the two families carried both corresponding mutations. 29 refs., 3 figs., 1 tab.

  18. Mutation Spectrum of EYS in Spanish Patients with Autosomal Recessive Retinitis Pigmentosa

    PubMed Central

    Barragán, Isabel; Borrego, Salud; Pieras, Juan Ignacio; Pozo, María González-del; Santoyo, Javier; Ayuso, Carmen; Baiget, Montserrat; Millan, José M; Mena, Marcela; El-Aziz, Mai M Abd; Audo, Isabelle; Zeitz, Christina; Littink, Karin W; Dopazo, Joaquín; Bhattacharya, Shomi S; Antiñolo, Guillermo

    2010-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene (EYS) encoding an ortholog of Drosophila spacemaker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28) are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain. Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study. © 2010 Wiley-Liss, Inc. PMID:21069908

  19. A homozygous missense variant in type I keratin KRT25 causes autosomal recessive woolly hair

    PubMed Central

    Ansar, Muhammad; Raza, Syed Irfan; Lee, Kwanghyuk; Irfanullah; Shahi, Shamim; Acharya, Anushree; Dai, Hang; Smith, Joshua D; Shendure, Jay; Bamshad, Michael J; Nickerson, Deborah A; Santos-Cortez, Regie Lyn P; Ahmad, Wasim; Leal, Suzanne M

    2016-01-01

    Background Woolly hair (WH) is a hair abnormality that is primarily characterised by tightly curled hair with abnormal growth. Methods In two unrelated consanguineous Pakistani families with non-syndromic autosomal recessive (AR) WH, homozygosity mapping and linkage analysis identified a locus within 17q21.1–q22, which contains the type I keratin gene cluster. A DNA sample from an affected individual from each family underwent exome sequencing. Results A homozygous missense variant c.950T>C (p.(Leu317Pro)) within KRT25 segregated with ARWH in both families, and has a combined maximum two-point LOD score of 7.9 at ϴ=0. The KRT25 variant is predicted to result in disruption of the second α-helical rod domain and the entire protein structure, thus possibly interfering with heterodimerisation of K25 with type II keratins within the inner root sheath (IRS) of the hair follicle and the medulla of the hair shaft. Conclusions Our findings implicate a novel gene involved in human hair abnormality, and are consistent with the curled, fragile hair found in mice with Krt25 mutations, and further support the role of IRS-specific type I keratins in hair follicle development and maintenance of hair texture. PMID:26160856

  20. Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance.

    PubMed

    Finsterer, Josef; Löscher, Wolfgang; Quasthoff, Stefan; Wanschitz, Julia; Auer-Grumbach, Michaela; Stevanin, Giovanni

    2012-07-15

    Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impairment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of corticospinal tract neurons. Among the AD-SPGs, 40-45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, debated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investigations. Treatment is exclusively symptomatic.

  1. Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum

    PubMed Central

    2013-01-01

    Background Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype. Methods Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers. Results We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name “spastic ataxia”, neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified

  2. A newly described mutation of the CLCN7 gene causes neuropathic autosomal recessive osteopetrosis in an Arab family.

    PubMed

    Al-Aama, Jumana Y; Dabbagh, Amal A; Edrees, Alaa Y

    2012-01-01

    Neurologic manifestations in osteopetrosis are usually secondary to sclerosis of the skull bones. However, a rare neuropathic subtype of osteopetrosis exists that resembles neurodegenerative storage disorders. Unlike other forms of osteopetrosis, this latter form does not respond to hematopoietic stem cell transplantation. Preliminary studies suggest that this neuropathic form is more likely to be caused by mutations in the CLCN7 gene in an autosomal recessive manner. This study provides further evidence for this phenotype-genotype correlation by presenting a previously unreported mutation in the CLCN7 gene in a Yemeni family with the neuropathic form. This is also the first study of any mutation in patients with osteopetrosis of Arabic ethnicity. As literature review suggests that this type may be more common in Arabs, cascade genetic screening of early onset of autosomal recessive-osteopetrosis in patients of Arabic ancestry may preferably start with the CLCN7 gene rather than the TCIRG gene as is routinely done in clinical laboratories. Identifying a mutation in the CLCN7 gene in a patient with early onset of autosomal recessive-osteopetrosis may also guide therapeutic decisions including the option of hematopoietic stem cell transplantation.

  3. UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia

    PubMed Central

    Yu, Li; Zhang, Gehan; Li, Jia; Lin, Yunting; Guo, Jifeng; Wang, Junling; Shen, Lu; Jiang, Hong; Wang, Guanghui; Tang, Beisha

    2016-01-01

    Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. Moreover, copy number variations in UBA5 or ubiquitin-fold modifier 1 gene (UFM1) were documented with the phenotypes of global developmental delays and gait disturbances in the ClinVar database. UBA5 encodes UBA5, the ubiquitin-activating enzyme of UFM1. However, a crucial role for UBA5 in human neurological disease remains to be reported. Our molecular study of UBA5-R246X revealed a dramatically decreased half-life and loss of UFM1 activation due to the absence of the catalytic cysteine Cys250. UBA5-K310E maintained its interaction with UFM1, although with less stability, which may affect the ability of this UBA5 mutant to activate UFM1. Drosophila modeling revealed that UBA5 knockdown induced locomotive defects and a shortened lifespan accompanied by aberrant neuromuscular junctions (NMJs). Strikingly, we found that UFM1 and E2 cofactor knockdown induced markedly similar phenotypes. Wild-type UBA5, but not mutant UBA5, significantly restored neural lesions caused by the absence of UBA5. The finding of a UBA5 mutation in cerebellar ataxia suggests that impairment of the UFM1 pathway may contribute to the neurological phenotypes of ARCA. PMID:26872069

  4. Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations

    PubMed Central

    Zeevi, David A.; Altarescu, Gheona; Weinberg-Shukron, Ariella; Zahdeh, Fouad; Dinur, Tama; Chicco, Gaya; Herskovitz, Yair; Renbaum, Paul; Elstein, Deborah; Levy-Lahad, Ephrat; Rolfs, Arndt; Zimran, Ari

    2015-01-01

    BACKGROUND. Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population. METHODS. Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid β-glucosidase, were recruited at the SZMC Gaucher Clinic. Targeted next-generation sequencing of GBA-flanking SNPs was performed on peripheral blood samples from each couple, relevant mutation carrier family members, and unrelated individuals who are homozygotes for an AJ founder mutation. Allele-specific haplotypes were constructed based on linkage, and a consensus Gaucher disease–associated founder mutation–flanking haplotype was fine mapped. Together, these haplotypes were used for NIPD. All test results were validated by conventional prenatal or postnatal diagnostic methods. RESULTS. Ten parental alleles in eight unrelated fetuses were diagnosed successfully based on the noninvasive method developed in this study. The consensus mutation–flanking haplotype aided diagnosis for 6 of 9 founder mutation alleles. CONCLUSIONS. The founder NIPD method developed and described here is rapid, economical, and readily adaptable for prenatal testing of prevalent autosomal recessive disease-causing mutations in an assortment of worldwide populations. FUNDING. SZMC, Protalix Biotherapeutics Inc., and Centogene AG. PMID:26426075

  5. A rare case of respiratory disorders associated with two autosomal recessive diseases and male infertility

    PubMed Central

    Costa, Sergio López; Scigliano, Sergio; Menga, Guillermo; Demiceu, Sergio; Palaoro, Luis Alberto

    2013-01-01

    The study of nasal ciliary beat frequency (CBF) and ultrastructure may contribute to the understanding of pathognomonic cases of male infertility associated with defects in sperm motility. This study was designed to report a particular case of male infertility, characterized by the association of two respiratory autosomal recessive genetic diseases (alpha-1-antitrypsin deficiency [AAT-D] and primary ciliary dyskinesia [PCD]). A 39-year-old patient with complete sperm immotility, AAT-D, and bronchiectasis was studied in the Laboratory of Male Fertility, the Department of Urology, the Respiratory Center of a Pediatric Hospital, and in the Department of Clinical Medicine of a Rehabilitation Respiratory Hospital. Family history, physical examination, hormonal analysis, microbial assays, semen analysis, nasal ciliary function, and structure study by digital high-speed video photography and transmission electron microscopy are described. A noninvasive nasal biopsy to retrieve ciliated epithelium lining the inferior surface of the inferior nasal turbinates was performed and CBF was determined. Beat pattern was slightly curved and rigid, not wide, and metacronic in all the observed fields analyzed. CBF was 8.2 Hz in average (reference value, 10–15 Hz) Ultrastructural assay revealed absence of the inner dynein arms in 97% of the cilia observed. The final infertility accurate diagnosis was achieved by the study of nasal CBF and ultrastructure contributing to the patient health management and genetic counseling while deciding fatherhood. Beyond this particular case, the present report may open a new field of studies in male infertility, mainly in cases of asthenozoospermia. PMID:23772318

  6. Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III

    PubMed Central

    Kölbel, Heike; Hauffa, Berthold P.; Wudy, Stefan A.; Bouikidis, Anastasios; Della Marina, Adela; Schara, Ulrike

    2017-01-01

    Background Autosomal-recessive proximal spinal muscular atrophies (SMA) are disorders characterized by a ubiquitous deficiency of the survival of motor neuron protein that leads to a multisystemic disorder, which mostly affects alpha motor neurons. Disease progression is clinically associated with failure to thrive or weight loss, mainly caused by chewing and swallowing difficulties. Although pancreatic involvement has been described in animal models, systematic endocrinological evaluation of the energy metabolism in humans is lacking. Methods In 43 patients with SMA type I-III (8 type I; 22 type II; 13 type III), aged 0.6–21.8 years, auxological parameters, pubertal stage, motor function (Motor Function Measurement 32 –MFM32) as well as levels of leptin, insulin glucose, hemoglobin A1c, Homeostasis Model Assessment index and an urinary steroid profile were determined. Results Hyperleptinemia was found in 15/35 (43%) of our patients; 9/15 (60%) of the hyperleptinemic patients were underweight, whereas 1/15 (7%) was obese. Hyperleptinemia was associated with SMA type (p = 0.018). There was a significant association with decreased motor function (MFM32 total score in hyperleptinemia 28.5%, in normoleptinemia 54.7% p = 0.008, OR 0.969; 95%-CI: 0.946–0.992). In addition, a higher occurrence of hirsutism, premature pubarche and a higher variability of the urinary steroid pattern were found. Conclusion Hyperleptinemia is highly prevalent in underweight children with SMA and is associated with disease severity and decreased motor function. Neuronal degradation of hypothalamic cells or an increase in fat content by muscle remodeling could be the cause of hyperleptinemia. PMID:28278160

  7. Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts

    PubMed Central

    Irum, Bushra; Khan, Shahid Y.; Ali, Muhammad; Daud, Muhammad; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Iqbal, Hira; Khan, Arif O.; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A.; Khan, Shaheen N.; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O.; Riazuddin, S. Amer

    2016-01-01

    Purpose The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. Methods All participating individuals underwent a detailed ophthalmic examination. Each patient’s medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. Results Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. Conclusion Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family. PMID:27936067

  8. Disruption of autosomal recessive hypercholesterolemia gene shows different phenotype in vitro and in vivo.

    PubMed

    Harada-Shiba, Mariko; Takagi, Atsuko; Marutsuka, Kousuke; Moriguchi, Sayaka; Yagyu, Hiroaki; Ishibashi, Shun; Asada, Yujiro; Yokoyama, Shinji

    2004-10-29

    We previously characterized the patients with autosomal recessive hypercholesterolemia (ARH) as having severe hypercholesterolemia and retarded plasma low-density lipoprotein (LDL) clearance despite normal LDL receptor (LDLR) function in their cultured fibroblasts, and we identified a mutation in the ARH locus in these patients. ARH protein is an adaptor protein of the LDL and reportedly modulates its internalization. We developed ARH knockout mice (ARH-/-) to study the function of this protein. Plasma total cholesterol level was higher in ARH-/- mice than that in wild-type mice (ARH+/+), being attributed to a 6-fold increase of LDL, whereas plasma lipoprotein was normal in the heterozygotes (ARH+/-). Clearance of 125I-LDL from plasma was retarded in ARH-/- mice, as much as that found in LDLR-/- mice. Fluorescence activity of the intravenously injected 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-LDL was recovered in the cytosol of the hepatocytes of ARH+/+ mice, but not in those of ARH-/- or LDLR-/- mice. Also, less radioactivity was recovered in the liver of ARH-/- or LDLR-/- mice when [3H]cholesteryl oleyl ether (CE)-labeled LDL was injected. In contrast, uptakes of [3H]CE-labeled LDL, 125I-LDL, and DiI-LDL were all normal or slightly subnormal when the ARH-/- hepatocytes were cultured. We thus concluded that the function of the hepatic LDLR is impaired in the ARH-/- mice in vivo, despite its normal function in vitro. These findings were consistent with the observations with the ARH homozygous patients and suggested that certain cellular environmental factors modulate the requirement of ARH for the LDLR function.

  9. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects

    PubMed Central

    Schaffner, Adam; Fedick, Anastasia; Kaye, Lauren E.; Liao, Jun; Yachelevich, Naomi; Chu, Mary-Lynn; Boles, Richard G.; Moran, Ellen; Tokita, Mari; Gorman, Elizabeth; Zhang, Wei; Xia, Fan; Leduc, Magalie; Yang, Yaping; Eng, Christine; Wong, Lee-Jun; Schiffmann, Raphael; Diaz, George A.; Kornreich, Ruth; Thummel, Ryan; Wasserstein, Melissa; Yue, Zhenyu; Edelmann, Lisa

    2016-01-01

    Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway. PMID:27120463

  10. Brain Connectivity Changes in Autosomal Recessive Parkinson Disease: A Model for the Sporadic Form

    PubMed Central

    Makovac, Elena; Cercignani, Mara; Serra, Laura; Torso, Mario; Spanò, Barbara; Petrucci, Simona; Ricciardi, Lucia; Ginevrino, Monia; Caltagirone, Carlo; Bentivoglio, Anna Rita; Valente, Enza Maria; Bozzali, Marco

    2016-01-01

    Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients’ cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptoms. PMID:27788143

  11. Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1

    PubMed Central

    Guergueltcheva, Velina; Azmanov, Dimitar N.; Angelicheva, Dora; Smith, Katherine R.; Chamova, Teodora; Florez, Laura; Bynevelt, Michael; Nguyen, Thai; Cherninkova, Sylvia; Bojinova, Veneta; Kaprelyan, Ara; Angelova, Lyudmila; Morar, Bharti; Chandler, David; Kaneva, Radka; Bahlo, Melanie; Tournev, Ivailo; Kalaydjieva, Luba

    2012-01-01

    Autosomal-recessive congenital cerebellar ataxia was identified in Roma patients originating from a small subisolate with a known strong founder effect. Patients presented with global developmental delay, moderate to severe stance and gait ataxia, dysarthria, mild dysdiadochokinesia, dysmetria and tremors, intellectual deficit, and mild pyramidal signs. Brain imaging revealed progressive generalized cerebellar atrophy, and inferior vermian hypoplasia and/or a constitutionally small brain were observed in some patients. Exome sequencing, used for linkage analysis on extracted SNP genotypes and for mutation detection, identified two novel (i.e., not found in any database) variants located 7 bp apart within a unique 6q24 linkage region. Both mutations cosegregated with the disease in five affected families, in which all ten patients were homozygous. The mutated gene, GRM1, encodes metabotropic glutamate receptor mGluR1, which is highly expressed in cerebellar Purkinje cells and plays an important role in cerebellar development and synaptic plasticity. The two mutations affect a gene region critical for alternative splicing and the generation of receptor isoforms; they are a 3 bp exon 8 deletion and an intron 8 splicing mutation (c.2652_2654del and c.2660+2T>G, respectively [RefSeq accession number NM_000838.3]). The functional impact of the deletion is unclear and is overshadowed by the splicing defect. Although ataxia lymphoblastoid cell lines expressed GRM1 at levels comparable to those of control cells, the aberrant transcripts skipped exon 8 or ended in intron 8 and encoded various species of nonfunctional receptors either lacking the transmembrane domain and containing abnormal intracellular tails or completely missing the tail. The study implicates mGluR1 in human hereditary ataxia. It also illustrates the potential of the Roma founder populations for mutation identification by exome sequencing. PMID:22901947

  12. Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic

    PubMed Central

    2014-01-01

    Background Autosomal recessive limb-girdle muscular dystrophies (LGMD2) include a number of disorders with heterogeneous etiology that cause predominantly weakness and wasting of the shoulder and pelvic girdle muscles. In this study, we determined the frequency of LGMD subtypes within a cohort of Czech LGMD2 patients using mutational analysis of the CAPN3, FKRP, SGCA, and ANO5 genes. Methods PCR-sequencing analysis; sequence capture and targeted resequencing. Results Mutations of the CAPN3 gene are the most common cause of LGMD2, and mutations in this gene were identified in 71 patients in a set of 218 Czech probands with a suspicion of LGMD2. Totally, we detected 37 different mutations of which 12 have been described only in Czech LGMD2A patients. The mutation c.550delA is the most frequent among our LGMD2A probands and was detected in 47.1% of CAPN3 mutant alleles. The frequency of particular forms of LGMD2 was 32.6% for LGMD2A (71 probands), 4.1% for LGMD2I (9 probands), 2.8% for LGMD2D (6 probands), and 1.4% for LGMD2L (3 probands). Further, we present the first results of a new approach established in the Czech Republic for diagnosis of neuromuscular diseases: sequence capture and targeted resequencing. Using this approach, we identified patients with mutations in the DYSF and SGCB genes. Conclusions We characterised a cohort of Czech LGMD2 patients on the basis of mutation analysis of genes associated with the most common forms of LGMD2 in the European population and subsequently compared the occurrence of particular forms of LGMD2 among countries on the basis of our results and published studies. PMID:25135358

  13. Mutations in the beta propeller WDR72 cause autosomal-recessive hypomaturation amelogenesis imperfecta.

    PubMed

    El-Sayed, Walid; Parry, David A; Shore, Roger C; Ahmed, Mushtaq; Jafri, Hussain; Rashid, Yasmin; Al-Bahlani, Suhaila; Al Harasi, Sharifa; Kirkham, Jennifer; Inglehearn, Chris F; Mighell, Alan J

    2009-11-01

    Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns. One subset, known as hypomaturation AI, is characterised by near-normal volumes of organic enamel matrix but with weak, creamy-brown opaque enamel that fails prematurely after tooth eruption. Mutations in genes critical to enamel matrix formation have been documented, but current understanding of other key events in enamel biomineralization is limited. We investigated autosomal-recessive hypomaturation AI in a consanguineous Pakistani family. A whole-genome SNP autozygosity screen identified a locus on chromosome 15q21.3. Sequencing candidate genes revealed a point mutation in the poorly characterized WDR72 gene. Screening of WDR72 in a panel of nine additional hypomaturation AI families revealed the same mutation in a second, apparently unrelated, Pakistani family and two further nonsense mutations in Omani families. Immunohistochemistry confirmed intracellular localization in maturation-stage ameloblasts. WDR72 function is unknown, but as a putative beta propeller is expected to be a scaffold for protein-protein interactions. The nearest homolog, WDR7, is involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Vesicle trafficking is important in maturation-stage ameloblasts with respect to secretion into immature enamel and removal of cleaved enamel matrix proteins via endocytosis. This raises the intriguing possibility that WDR72 is critical to ameloblast vesicle turnover during enamel maturation.

  14. Yeast model analysis of novel polymerase gamma variants found in patients with autosomal recessive mitochondrial disease.

    PubMed

    Kaliszewska, Magdalena; Kruszewski, Jakub; Kierdaszuk, Biruta; Kostera-Pruszczyk, Anna; Nojszewska, Monika; Łusakowska, Anna; Vizueta, Joel; Sabat, Dorota; Lutyk, Dorota; Lower, Michał; Piekutowska-Abramczuk, Dorota; Kaniak-Golik, Aneta; Pronicka, Ewa; Kamińska, Anna; Bartnik, Ewa; Golik, Paweł; Tońska, Katarzyna

    2015-09-01

    Replication of the mitochondrial genome depends on the single DNA polymerase (pol gamma). Mutations in the POLG gene, encoding the catalytic subunit of the human polymerase gamma, have been linked to a wide variety of mitochondrial disorders that show remarkable heterogeneity, with more than 200 sequence variants, often very rare, found in patients. The pathogenicity and dominance status of many such mutations remain, however, unclear. Remarkable structural and functional conservation of human POLG and its S. cerevisiae ortholog (Mip1p) led to the development of many successful yeast models, enabling to study the phenotype of putative pathogenic mutations. In a group of patients with suspicion of mitochondrial pathology, we identified five novel POLG sequence variants, four of which (p.Arg869Ter, p.Gln968Glu, p.Thr1053Argfs*6, and p.Val1106Ala), together with one previously known but uncharacterised variant (p.Arg309Cys), were amenable to modelling in yeast. Familial analysis indicated causal relationship of these variants with disease, consistent with autosomal recessive inheritance. To investigate the effect of these sequence changes on mtDNA replication, we obtained the corresponding yeast mip1 alleles (Arg265Cys, Arg672Ter, Arg770Glu, Thr809Ter, and Val863Ala, respectively) and tested their effect on mitochondrial genome stability and replication fidelity. For three of them (Arg265Cys, Arg672Ter, and Thr809Ter), we observed a strong, partially dominant phenotype of a complete loss of functional mtDNA, whereas the remaining two led to partial mtDNA depletion and significant increase in point mutation frequencies. These results show good correlation with the severity of symptoms observed in patients and allow to establish these variants as pathogenic mutations.

  15. Autosomal recessive polycystic kidney disease: the prototype of the hepato-renal fibrocystic diseases.

    PubMed

    Guay-Woodford, Lisa M

    Autosomal recessive polycystic kidney disease (ARPKD) is a severe, typically early onset form of renal cystic disease. The care of ARPKD patients has traditionally been the purview of pediatric nephrologists for management of systemic hypertension and progressive renal insufficiency. However, the disease has multisystem manifestations and a comprehensive care strategy frequently requires a multidisciplinary team. In severely affected infants, the diagnosis often is first suspected by obstetricians when enlarged, echogenic kidneys and oligohydramnios are detected on prenatal ultrasounds. Neonatologists are central to the care of these infants, who may have respiratory compromise due to pulmonary hypoplasia and massively enlarged kidneys. Among neonatal survivors, a subset of ARPKD patients has clinically significant congenital hepatic fibrosis, which can lead to portal hypertension, requiring close monitoring by pediatric hepatologists. Surgical consultation may be sought to access pre-emptive nephrectomy to relieve mass effect, placement of dialysis access, surgical shunting procedures, and kidney and/or liver transplantation. Recent data suggest that children with ARPKD may be at risk of neurocognitive dysfunction, and may require neuropsychological referral. In addition to these morbidities, families of patients with ARPKD face decisions regarding genetic testing of affected children, testing of asymptomatic siblings, or consideration of preimplantation genetic diagnosis for future pregnancies. These issues require the input of genetic counselors, geneticists, and reproductive endocrinologists. As a result, the management of ARPKD requires the involvement of multiple subspecialists, as well as the general pediatrician, in a complex care network. In this review, we discuss the genetics of this disorder and provide an overview of the associated pathobiology; outline the spectrum of clinical manifestations of ARPKD and the management of organ-specific complications

  16. Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2

    PubMed Central

    Santos-Cortez, Regie Lyn P.; Faridi, Rabia; Rehman, Atteeq U.; Lee, Kwanghyuk; Ansar, Muhammad; Wang, Xin; Morell, Robert J.; Isaacson, Rivka; Belyantseva, Inna A.; Dai, Hang; Acharya, Anushree; Qaiser, Tanveer A.; Muhammad, Dost; Ali, Rana Amjad; Shams, Sulaiman; Hassan, Muhammad Jawad; Shahzad, Shaheen; Raza, Syed Irfan; Bashir, Zil-e-Huma; Smith, Joshua D.; Nickerson, Deborah A.; Bamshad, Michael J.; Riazuddin, Sheikh; Ahmad, Wasim; Friedman, Thomas B.; Leal, Suzanne M.

    2016-01-01

    The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among ∼120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2−/− mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2−/− mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2. PMID:26805784

  17. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects.

    PubMed

    Zhang, Jinglan; Lachance, Véronik; Schaffner, Adam; Li, Xianting; Fedick, Anastasia; Kaye, Lauren E; Liao, Jun; Rosenfeld, Jill; Yachelevich, Naomi; Chu, Mary-Lynn; Mitchell, Wendy G; Boles, Richard G; Moran, Ellen; Tokita, Mari; Gorman, Elizabeth; Bagley, Kaytee; Zhang, Wei; Xia, Fan; Leduc, Magalie; Yang, Yaping; Eng, Christine; Wong, Lee-Jun; Schiffmann, Raphael; Diaz, George A; Kornreich, Ruth; Thummel, Ryan; Wasserstein, Melissa; Yue, Zhenyu; Edelmann, Lisa

    2016-04-01

    Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.

  18. Additional case of Marden-Walker syndrome: support for the autosomal-recessive inheritance adn refinement of phenotype in a surviving patient.

    PubMed

    Orrico, A; Galli, L; Zappella, M; Orsi, A; Hayek, G

    2001-02-01

    In this report, we present a 14-year-old girl, born to consanguineous parents, who presented with severe mental retardation, hypotonia, short stature, and congenital joint contractures. The craniofacial features were scaphocephaly, thin/long and immobile face, marked hypoplasia of the midface, temporal narrowness, blepharophimosis, palpebral ptosis, and strabismus. The combination of such a distinctive craniofacial appearance and psychomotor retardation allows us to recognize a new case of the Marden-Walker syndrome. Our patient represents one of the rare cases in which consanguineous mating supports the autosomal-recessive pattern of inheritance of this condition. Furthermore, through refining the phenotype of a surviving patient, this report may contribute to a better recognition of this disorder in older affected children.

  19. Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia

    PubMed Central

    Kannengiesser, Caroline; Sanchez, Mayka; Sweeney, Marion; Hetet, Gilles; Kerr, Briedgeen; Moran, Erica; Fuster Soler, Jose L.; Maloum, Karim; Matthes, Thomas; Oudot, Caroline; Lascaux, Axelle; Pondarré, Corinne; Sevilla Navarro, Julian; Vidyatilake, Sudharma; Beaumont, Carole; Grandchamp, Bernard; May, Alison

    2011-01-01

    Background Congenital sideroblastic anemias are rare disorders with several genetic causes; they are characterized by erythroblast mitochondrial iron overload, differ greatly in severity and some occur within a syndrome. The most common cause of non-syndromic, microcytic sideroblastic anemia is a defect in the X-linked 5-aminolevulinate synthase 2 gene but this is not always present. Recently, variations in the gene for the mitochondrial carrier SLC25A38 were reported to cause a non-syndromic, severe type of autosomal-recessive sideroblastic anemia. Further evaluation of the importance of this gene was required to estimate the proportion of patients affected and to gain further insight into the range and types of variations involved. Design and Methods In three European diagnostic laboratories sequence analysis of SLC25A38 was performed on DNA from patients affected by congenital sideroblastic anemia of a non-syndromic nature not caused by variations in the 5-aminolevulinate synthase 2 gene. Results Eleven patients whose ancestral origins spread across several continents were homozygous or compound heterozygous for ten different SLC25A38 variations causing premature termination of translation (p.Arg117X, p.Tyr109LeufsX43), predicted splicing alteration (c.625G>C; p.Asp209His) or missense substitution (p.Gln56Lys, p.Arg134Cys, p.Ile147Asn, p.Arg187Gln, p.Pro190Arg, p.Gly228Val, p.Arg278Gly). Only three of these variations have been described previously (p.Arg117X, p.Tyr109LeufsX43 and p.Asp209His). All new variants reported here are missense and affect conserved amino acids. Structure modeling suggests that these variants may influence different aspects of transport as described for mutations in other mitochondrial carrier disorders. Conclusions Mutations in the SLC25A38 gene cause severe, non-syndromic, microcytic/hypochromic sideroblastic anemia in many populations. Missense mutations are shown to be of importance as are mutations that affect protein production

  20. A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness.

    PubMed

    Kondo, Mineo; Das, Gautami; Imai, Ryoetsu; Santana, Evelyn; Nakashita, Tomio; Imawaka, Miho; Ueda, Kosuke; Ohtsuka, Hirohiko; Sakai, Kazuhiko; Aihara, Takehiro; Kato, Kumiko; Sugimoto, Masahiko; Ueno, Shinji; Nishizawa, Yuji; Aguirre, Gustavo D; Miyadera, Keiko

    2015-01-01

    Congenital stationary night blindness (CSNB) is a non-progressive, clinically and genetically heterogeneous disease of impaired night vision. We report a naturally-occurring, stationary, autosomal recessive phenotype in beagle dogs with normal daylight vision but absent night vision. Affected dogs had normal retinas on clinical examination, but showed no detectable rod responses. They had "negative-type" mixed rod and cone responses in full-field ERGs. Their photopic long-flash ERGs had normal OFF-responses associated with severely reduced ON-responses. The phenotype is similar to the Schubert-Bornschein form of complete CSNB in humans. Homozygosity mapping ruled out most known CSNB candidates as well as CACNA2D4 and GNB3. Three remaining genes were excluded based on sequencing the open reading frame and intron-exon boundaries (RHO, NYX), causal to a different form of CSNB (RHO) or X-chromosome (NYX, CACNA1F) location. Among the genes expressed in the photoreceptors and their synaptic terminals, and mGluR6 cascade and modulators, reduced expression of GNAT1, CACNA2D4 and NYX was observed by qRT-PCR in both carrier (n = 2) and affected (n = 2) retinas whereas CACNA1F was down-regulated only in the affecteds. Retinal morphology revealed normal cellular layers and structure, and electron microscopy showed normal rod spherules and synaptic ribbons. No difference from normal was observed by immunohistochemistry (IHC) for antibodies labeling rods, cones and their presynaptic terminals. None of the retinas showed any sign of stress. Selected proteins of mGluR6 cascade and its modulators were examined by IHC and showed that PKCα weakly labeled the rod bipolar somata in the affected, but intensely labeled axonal terminals that appeared thickened and irregular. Dendritic terminals of ON-bipolar cells showed increased Goα labeling. Both PKCα and Goα labeled the more prominent bipolar dendrites that extended into the OPL in affected but not normal retinas. Interestingly

  1. Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica

    PubMed Central

    Kariminejad, Ariana; Afroozan, Fariba; Bozorgmehr, Bita; Ghanadan, Alireza; Akbaroghli, Susan; Khorram Khorshid, Hamid Reza; Mojahedi, Faezeh; Setoodeh, Aria; Loh, Abigail; Tan, Yu Xuan; Escande-Beillard, Nathalie; Malfait, Fransiska; Reversade, Bruno; Gardeitchik, Thatjana; Morava, Eva

    2017-01-01

    Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A), cutis laxa IIB (ARCL2B), and geroderma osteodysplastica (GO), have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient’s clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions. PMID:28294978

  2. Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.

    PubMed

    Karaca, Ender; Yuregir, Ozge O; Bozdogan, Sevcan T; Aslan, Huseyin; Pehlivan, Davut; Jhangiani, Shalini N; Akdemir, Zeynep C; Gambin, Tomasz; Bayram, Yavuz; Atik, Mehmed M; Erdin, Serkan; Muzny, Donna; Gibbs, Richard A; Lupski, James R

    2015-11-01

    Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel-Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel-Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left-right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel-Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel's deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel-Feil syndrome, and in addition-from a mechanistic standpoint-suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. © 2015 Wiley Periodicals, Inc.

  3. Rare Variants in the Notch Signaling Pathway Describe a Novel Type of Autosomal Recessive Klippel–Feil Syndrome

    PubMed Central

    Karaca, Ender; Yuregir, Ozge O.; Bozdogan, Sevcan T.; Aslan, Huseyin; Pehlivan, Davut; Jhangiani, Shalini N.; Akdemir, Zeynep C.; Gambin, Tomasz; Bayram, Yavuz; Atik, Mehmed M.; Erdin, Serkan; Muzny, Donna; Gibbs, Richard A.; Lupski, James R.

    2016-01-01

    Klippel–Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel–Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel–Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left–right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel–Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel’s deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel–Feil syndrome, and in addition—from a mechanistic standpoint—suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. PMID:26238661

  4. Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene.

    PubMed

    Faletra, Flavio; D'Adamo, Adamo P; Bruno, Irene; Athanasakis, Emmanouil; Biskup, Saskia; Esposito, Laura; Gasparini, Paolo

    2014-01-01

    Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis.

  5. Screening for MYO15A Gene Mutations in Autosomal Recessive Nonsyndromic, GJB2 Negative Iranian Deaf Population

    PubMed Central

    Fattahi, Zohreh; Shearer, A. Eliot; Babanejad, Mojgan; Bazazzadegan, Niloofar; Almadani, Seyed Navid; Nikzat, Nooshin; Jalalvand, Khadijeh; Arzhangi, Sanaz; Esteghamat, Fatemehsadat; Abtahi, Rezvan; Azadeh, Batool; Smith, Richard J.H.; Kahrizi, Kimia; Najmabadi, Hossein

    2013-01-01

    MYO15A is located at the DFNB3 locus on chromosome 17p11.2, and encodes myosin-XV, an unconventional myosin critical for the formation of stereocilia in hair cells of cochlea. Recessive mutations in this gene lead to profound autosomal recessive nonsyndromic hearing loss (ARNSHL) in humans and the shaker2 (sh2) phenotype in mice. Here, we performed a study on 140 Iranian families in order to determine mutations causing ARNSHL. The families, who were negative for mutations in GJB2, were subjected to linkage analysis. Eight of these families showed linkage to the DFNB3 locus, suggesting a MYO15A mutation frequency of 5.71% in our cohort of Iranian population. Subsequent sequencing of the MYO15A gene led to identification of 7 previously unreported mutations, including 4 missense mutations, 1 nonsense mutation, and 2 deletions in different regions of the myosin-XV protein. PMID:22736430

  6. Bilateral sensorineural deafness and hydrocephalus due to foramen of Monro obstruction in sibs: A newly described autosomal recessive disorder

    SciTech Connect

    Chudley, A.E.; McCullough, C.; McCullough, D.W.

    1997-01-31

    We identified a Canadian-Mennonite family in which a brother and sister have hydrocephalus due to obstruction at the foramen of Monro and profound bilateral sensorineural deafness. This appears to be a unique combination of anomalies and, to our knowledge, has not been reported previously. Both parents and a brother are phenotypically normal. The parents are second cousins. Thus, on the basis of consanguinity, affected sibs of both sexes, and in the absence of evidence for intrauterine infections or other adverse perinatal events, this syndrome is likely inherited in an autosomal recessive fashion. 37 refs., 5 figs.

  7. Spastic paraplegia, optic atrophy, microcephaly with normal intelligence, and XY sex reversal: a new autosomal recessive syndrome?

    PubMed Central

    Teebi, A S; Miller, S; Ostrer, H; Eydoux, P; Colomb-Brockmann, C; Oudjhane, K; Watters, G

    1998-01-01

    Two female sibs of first cousin Iranian parents were found to have the syndrome of spastic paraplegia, optic atrophy with poor vision, microcephaly, and normal cognitive development. Karyotype analysis showed a normal female constitution in one and a male constitution (46,XY) in the other. The XY female showed normal female external genitalia, normal uterus and tubes, and streak gonads. SRY gene sequencing was normal. We conclude that the present family probably represents a new autosomal recessive trait of pleiotropic effects including XY sex reversal and adds further evidence for the heterogeneity of spastic paraplegia syndromes as well as sex reversal syndromes. Images PMID:9733035

  8. G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis

    PubMed Central

    Azimov, Rustam; Abuladze, Natalia; Sassani, Pakan; Newman, Debra; Kao, Liyo; Liu, Weixin; Orozco, Nicholas; Ruchala, Piotr; Pushkin, Alexander; Kurtz, Ira

    2008-01-01

    Autosomal recessive proximal renal tubular acidosis is caused by mutations in the SLC4A4 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe1-A. The mutations that have been characterized thus far result in premature truncation, mistargeting, or decreased function of the cotransporter. Despite bicarbonate treatment to correct the metabolic acidosis, extrarenal manifestations persist, including glaucoma, cataracts, corneal opacification, and mental retardation. Currently, there are no known therapeutic approaches that can specifically target mutant NBCe1-A proteins. In the present study, we tested the hypothesis that the NBCe1-A-Q29X mutation can be rescued in vitro by treatment with aminoglycoside antibiotics, which are known for their ability to suppress premature stop codons. As a model system, we cloned the NBCe1-A-Q29X mutant into a vector lacking an aminoglycoside resistance gene and transfected the mutant cotransporter in HEK293-H cells. Cells transfected with the NBCe1-A-Q29X mutant failed to express the cotransporter because of the premature stop codon. Treatment of the cells with G418 significantly increased the expression of the full-length cotransporter, as assessed by immunoblot analysis. Furthermore, immunocytochemical studies demonstrated that G418 treatment induced cotransporter expression on the plasma membrane whereas in the absence of G418, NBCe1-A-Q29X was not expressed. In HEK293-H cells transfected with the NBCe1-A-Q29X mutant not treated with G418, NBCe1-A-mediated flux was not detectable. In contrast, in cells transfected with the NBCe1-A-Q29X mutant, G418 treatment induced Na+- and HCO3−-dependent transport that did not differ from wild-type NBCe1-A function. G418 treatment in mock-transfected cells was without effect. In conclusion, G418 induces ribosomal read-through of the NBCe1-A-Q29X mutation in HEK293-H cells. These findings represent the first evidence that in the presence of the NBCe1-A-Q29X mutation that causes

  9. G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis.

    PubMed

    Azimov, Rustam; Abuladze, Natalia; Sassani, Pakan; Newman, Debra; Kao, Liyo; Liu, Weixin; Orozco, Nicholas; Ruchala, Piotr; Pushkin, Alexander; Kurtz, Ira

    2008-09-01

    Autosomal recessive proximal renal tubular acidosis is caused by mutations in the SLC4A4 gene encoding the electrogenic sodium bicarbonate cotransporter NBCe1-A. The mutations that have been characterized thus far result in premature truncation, mistargeting, or decreased function of the cotransporter. Despite bicarbonate treatment to correct the metabolic acidosis, extrarenal manifestations persist, including glaucoma, cataracts, corneal opacification, and mental retardation. Currently, there are no known therapeutic approaches that can specifically target mutant NBCe1-A proteins. In the present study, we tested the hypothesis that the NBCe1-A-Q29X mutation can be rescued in vitro by treatment with aminoglycoside antibiotics, which are known for their ability to suppress premature stop codons. As a model system, we cloned the NBCe1-A-Q29X mutant into a vector lacking an aminoglycoside resistance gene and transfected the mutant cotransporter in HEK293-H cells. Cells transfected with the NBCe1-A-Q29X mutant failed to express the cotransporter because of the premature stop codon. Treatment of the cells with G418 significantly increased the expression of the full-length cotransporter, as assessed by immunoblot analysis. Furthermore, immunocytochemical studies demonstrated that G418 treatment induced cotransporter expression on the plasma membrane whereas in the absence of G418, NBCe1-A-Q29X was not expressed. In HEK293-H cells transfected with the NBCe1-A-Q29X mutant not treated with G418, NBCe1-A-mediated flux was not detectable. In contrast, in cells transfected with the NBCe1-A-Q29X mutant, G418 treatment induced Na(+)- and HCO(3)(-)-dependent transport that did not differ from wild-type NBCe1-A function. G418 treatment in mock-transfected cells was without effect. In conclusion, G418 induces ribosomal read-through of the NBCe1-A-Q29X mutation in HEK293-H cells. These findings represent the first evidence that in the presence of the NBCe1-A-Q29X mutation that

  10. Autosomal dominant

    MedlinePlus

    ... whether the trait is dominant or recessive. A single abnormal gene on one of the first 22 nonsex ( autosomal ) chromosomes from either parent can cause an autosomal disorder. Dominant inheritance means ...

  11. Whole Genome Sequencing Identifies Novel Compound Heterozygous Lysosomal Trafficking Regulator Gene Mutations Associated with Autosomal Recessive Chediak-Higashi Syndrome

    PubMed Central

    Jin, Yaqiong; Zhang, Li; Wang, Senfen; Chen, Feng; Gu, Yang; Hong, Enyu; Yu, Yongbo; Ni, Xin; Guo, Yongli; Shi, Tieliu; Xu, Zigang

    2017-01-01

    Chediak–Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by varying degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. This syndrome is molecularly characterized by pathognomonic mutations in the LYST (lysosomal trafficking regulator). Using whole genome sequencing (WGS) we attempted to identify novel mutations of CHS based on a family of CHS with atypical symptoms. The two patients demonstrated a phenotypic constellation including partial oculocutaneous albinism, frequency upper respiratory infection or a marginal intelligence, without bleeding tendency and severe immunodeficiency. WGS revealed two compound LYST mutations including a maternally inherited chr1:235969126G > A (rs80338652) and a novel paternally inherited chr1: 235915327A > AT, associated with autosomal recessive CHS. These two variants fall in the coding regions of LYST, resulting in premature truncation of LYST due to R1104X/N2535KfsX2 induced incomplete translation. Notably, the heterozygous carriers (i.e. parents) were unaffected. Our finding also reveals decreased plasma serotonin levels in patients with CHS compared with unaffected individuals for the first time. The present study contributes to improved understanding of the causes of this disease and provides new ideas for possible treatments. PMID:28145517

  12. Mitochondrial Hsp60 Chaperonopathy Causes an Autosomal-Recessive Neurodegenerative Disorder Linked to Brain Hypomyelination and Leukodystrophy

    PubMed Central

    Magen, Daniella; Georgopoulos, Costa; Bross, Peter; Ang, Debbie; Segev, Yardena; Goldsher, Dorit; Nemirovski, Alexandra; Shahar, Eli; Ravid, Sarit; Luder, Anthony; Heno, Bayan; Gershoni-Baruch, Ruth; Skorecki, Karl; Mandel, Hanna

    2008-01-01

    Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration. PMID:18571143

  13. A new autosomal recessive spastic ataxia associated with frequent white matter changes maps to 2q33-34.

    PubMed

    Thiffault, I; Rioux, M F; Tetreault, M; Jarry, J; Loiselle, L; Poirier, J; Gros-Louis, F; Mathieu, J; Vanasse, M; Rouleau, G A; Bouchard, J P; Lesage, J; Brais, B

    2006-09-01

    Recessive ataxias are a heterogeneous group of diseases. We identified a group of 23 French-Canadian cases belonging to 17 families affected by an autosomal recessive spastic ataxia associated with frequent white matter changes. The fact that 59% of these families have a genealogical relationship to the Portneuf County of Quebec suggests that this is a new form of ataxia with a regional founder effect. All cases present with cerebellar ataxia and spasticity. There is great intrafamilial and interfamilial variability, as illustrated by the spectrum of age of diagnosis (range: 2-59 years, mean: 15.0) and the presence of white matter changes on MRI in 52.4% of cases. The more severe cases have spasticity from birth, scoliosis, dystonia and cognitive impairment and were considered cases of cerebral palsy. Brain MRI constantly shows cerebellar atrophy, which in some cases may be associated with cortical atrophy, leucoencephalopathy and corpus callosum thinning. A genome wide scan uncovered linkage of three families to marker D2S2321 localized on chromosome 2q33-34. Linkage analysis confirmed that all families are linked to the same region [multipoint log of the odds (LOD) score of 5.95]. Haplotype analysis and allele sharing suggest that one common mutation may account for 97% of carrier chromosomes in Quebec. The uncovering of the mutated gene may point to a common pathway for pyramidal and cerebellar degeneration as both are often observed in recessive ataxias and complicated paraplegias.

  14. Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene.

    PubMed

    Barbagallo, C M; Emmanuele, G; Cefalù, A B; Fiore, B; Noto, D; Mazzarino, M C; Pace, A; Brogna, A; Rizzo, M; Corsini, A; Notarbartolo, A; Travali, S; Averna, M R

    2003-02-01

    We describe a Sicilian family presenting a recessive form of hypercholesterolemia harboring a mutation of the autosomal recessive hypercholesterolemia (ARH) gene. In two of the three sibs, a 26-year-old male and a 22-year-old female, a severe hypercholesterolemia was diagnosed with very high levels of plasma cholesterol (15.9 and 12.2 mmol/l, respectively); tendon xanthomatas and xanthelasms were present and in the male proband was documented a diffuse coronary atherosclerotic disease with a rapid and fatal progression. Both the parents had normal or slightly increased levels of plasma cholesterol. All causes of secondary hypercholesterolemia were ruled out as well as an involvement of the LDL receptor or apoB genes. Beta-Sitosterol plasma levels were in the normal range. Cultured fibroblasts from skin biopsy from parents and the two probands displayed a normal ability to bind and degrade 125I-LDL. Direct sequencing of ARH gene demonstrated the presence of a 432insA mutation in homozygosis in the two probands; parents were heterozygotes for the same mutation. This mutation is the first report of a mutation of the ARH gene responsible for recessive forms of hypercholesterolemia in Sicily.

  15. Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis

    SciTech Connect

    Chung, E.; Hanukoglu, A.; Rees, M.; Thompson, R.; Gardiner, R.M.

    1995-10-01

    Pseudohypoaldosteronism type 1 (PHA1) is an uncommon inherited disorder characterized by salt-wasting in infancy arising from target organ unresponsiveness to mineralocorticoids. Clinical expression of the disease varies from severely affected infants who may die to apparently asymptomatic individuals. Inheritance is Mendelian and may be either autosomal dominant or autosomal recessive. A defect in the mineralocortiocoid receptor has been implicated as a likely cause of PHA1. The gene for human mineralocorticoid receptor (MLR) has been cloned and physically mapped to human chromosome 4q31.1-31.2. The etiological role of MLR in autosomal recessive PHA1 was investigated by performing linkage analysis between PHA1 and three simple sequence length polymorphisms (D4S192, D4S1548, and D4S413) on chromosome 4q in 10 consanguineous families. Linkage analysis was carried out assuming autosomal recessive inheritance with full penetrance and zero phenocopy rate using the MLINK program for two-point analysis and the HOMOZ program for multipoint analysis. Lod scores of less than -2 were obtained over the whole region from D4S192 to D4S413 encompassing MLR. This provides evidence against MLR as the site of mutations causing PHA1 in the majority of autosomal recessive families. 34 refs., 3 figs., 2 tabs.

  16. Diabetes mellitus, diabetes insipidus, and optic atrophy. An autosomal recessive syndrome?

    PubMed Central

    Fraser, F C; Gunn, T

    1977-01-01

    Twenty-one families were selected from the published reports in which the propositus had the triad of juvenile diabetes mellitus, diabetes insipidus, and optic atrophy. The data were consistent with the hypothesis of an autosomal gene which, in the homozygote, causes juvenile diabetes mellitus and one or more of diabetes insipidus, optic atrophy, and nerve deafness. Heterozygotes appear to have an increased probability of developing juvenile diabetes mellitus. PMID:881709

  17. A Novel Homozygous Missense Mutation in HOXC13 Leads to Autosomal Recessive Pure Hair and Nail Ectodermal Dysplasia.

    PubMed

    Li, Xiaoxiao; Orseth, Meredith Lee; Smith, J Michael; Brehm, Mary Abigail; Agim, Nnenna Gebechi; Glass, Donald Alexander

    2017-03-01

    Pure hair and nail ectodermal dysplasia (PHNED) is a rare disorder that presents with hypotrichosis and nail dystrophy while sparing other ectodermal structures such as teeth and sweat glands. We describe a homozygous novel missense mutation in the HOXC13 gene that resulted in autosomal recessive PHNED in a Hispanic child. The mutation c.812A>G (p.Gln271Arg) is located within the DNA-binding domain of the HOXC13 gene, cosegregates within the family, and is predicted to be maximally damaging. This is the first reported case of a missense HOXC13 mutation resulting in PHNED and the first reported case of PHNED identified in a North American family. Our findings illustrate the critical role of HOXC13 in human hair and nail development.

  18. Acquired factor VIII deficiency associated with a novel primary immunodeficiency suggestive of autosomal recessive hyper IgE syndrome.

    PubMed

    Ozgur, Tuba Turul; Asal, Gulten Turkkan; Gurgey, Aytemiz; Tezcan, Ilhan; Ersoy, Fugen; Sanal, Ozden

    2007-05-01

    Primary immunodeficiency diseases (PID) are associated with various autoimmune complications and several manifestations of autoimmunity can be seen in the disorders of T cells, B cells, phagocytes, and complement components. Acquired hemophilia is a rare entity in childhood. Although autoantibodies may develop in various forms of PID, Factor VIII (FVIII) inhibitors have not been described before. Herein, we present a case of acquired hemophilia resulting from FVIII inhibitors who had underlying undefined PID features suggestive of autosomal recessive hyper IgE syndrome. Our patient responded to corticosteroid treatment rather well and quickly, with an increased FVIII level and decreased FVIII inhibitors. However, FVIII inhibitor reappeared 7 months later, and disappeared spontaneously 4 months ago. Long-term and close follow-up is needed to observe the long-term prognosis in this child.

  19. Uniparental Isodisomy of Chromosome 1 Unmasking an Autosomal Recessive 3-Beta Hydroxysteroid Dehydrogenase Type II-Related Congenital Adrenal Hyperplasia

    PubMed Central

    Panzer, Karin; Ekhaguere, Osayame A.; Darbro, Benjamin; Cook, Jennifer; Shchelochkov, Oleg A.

    2017-01-01

    Steroid 3-beta hydroxysteroid dehydrogenase type II (3β-HSD2) deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia (CAH). We report the genetic basis of 3β-HSD2 deficiency arising from uniparental isodisomy (UPD) of chromosome 1. We describe a term undervirilized male whose newborn screen indicated borderline CAH. The patient presented on the 7th day of life in salt-wasting adrenal crisis. Steroid hormone testing revealed a complex pattern suggestive of 3β-HSD deficiency. Chromosomal microarray and single nucleotide polymorphism analysis revealed complete UPD of chromosome 1. Sanger sequencing of HSD3B2 revealed a previously described missense mutation, c.424G>A (p.E142K) in homozygous state, thus confirming the diagnosis of 3β-HSD2 deficiency. We provide evidence of the existence of an uncommon mechanism for HSD3B2 gene-related CAH arising from UPD of chromosome 1. PMID:27796263

  20. Disruption of the Basal Body Protein POC1B Results in Autosomal-Recessive Cone-Rod Dystrophy

    PubMed Central

    Roosing, Susanne; Lamers, Ideke J.C.; de Vrieze, Erik; van den Born, L. Ingeborgh; Lambertus, Stanley; Arts, Heleen H.; Boldt, Karsten; de Baere, Elfride; Klaver, Caroline C.W.; Coppieters, Frauke; Koolen, David A.; Lugtenberg, Dorien; Neveling, Kornelia; van Reeuwijk, Jeroen; Ueffing, Marius; van Beersum, Sylvia E.C.; Zonneveld-Vrieling, Marijke N.; Peters, Theo A.; Hoyng, Carel B.; Kremer, Hannie; Hetterschijt, Lisette; Letteboer, Stef J.F.; van Wijk, Erwin; Roepman, Ronald; den Hollander, Anneke I.; Cremers, Frans P.M.

    2014-01-01

    Exome sequencing revealed a homozygous missense mutation (c.317C>G [p.Arg106Pro]) in POC1B, encoding POC1 centriolar protein B, in three siblings with autosomal-recessive cone dystrophy or cone-rod dystrophy and compound-heterozygous POC1B mutations (c.199_201del [p.Gln67del] and c.810+1G>T) in an unrelated person with cone-rod dystrophy. Upon overexpression of POC1B in human TERT-immortalized retinal pigment epithelium 1 cells, the encoded wild-type protein localized to the basal body of the primary cilium, whereas this localization was lost for p.Arg106Pro and p.Gln67del variant forms of POC1B. Morpholino-oligonucleotide-induced knockdown of poc1b translation in zebrafish resulted in a dose-dependent small-eye phenotype, impaired optokinetic responses, and decreased length of photoreceptor outer segments. These ocular phenotypes could partially be rescued by wild-type human POC1B mRNA, but not by c.199_201del and c.317C>G mutant human POC1B mRNAs. Yeast two-hybrid screening of a human retinal cDNA library revealed FAM161A as a binary interaction partner of POC1B. This was confirmed in coimmunoprecipitation and colocalization assays, which both showed loss of FAM161A interaction with p.Arg106Pro and p.Gln67del variant forms of POC1B. FAM161A was previously implicated in autosomal-recessive retinitis pigmentosa and shown to be located at the base of the photoreceptor connecting cilium, where it interacts with several other ciliopathy-associated proteins. Altogether, this study demonstrates that POC1B mutations result in a defect of the photoreceptor sensory cilium and thus affect cone and rod photoreceptors. PMID:25018096

  1. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis.

    PubMed

    Attali, Ruben; Warwar, Nasim; Israel, Ariel; Gurt, Irina; McNally, Elizabeth; Puckelwartz, Megan; Glick, Benjamin; Nevo, Yoram; Ben-Neriah, Ziva; Melki, Judith

    2009-09-15

    Arthrogryposis multiplex congenita (AMC) is a group of disorders characterized by congenital joint contractures caused by reduced fetal movements. AMC has an incidence of 1 in 3000 newborns and is genetically heterogeneous. We describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterized by bilateral clubfoot, decreased fetal movements, delay in motor milestones, then progressive motor decline after the first decade. Genome-wide linkage analysis revealed a single locus on chromosome 6q25 with Z(max) = 3.55 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Homozygous A to G nucleotide substitution of the conserved AG splice acceptor site at the junction of intron 136 and exon 137 of the SYNE-1 gene was found in patients. This mutation results in an aberrant retention of intron 136 of SYNE-1 RNA leading to premature stop codons and the lack of the C-terminal transmembrane domain KASH of nesprin-1, the SYNE-1 gene product. Mice lacking the KASH domain of nesprin-1 display a myopathic phenotype similar to that observed in patients. Altogether, these data strongly suggest that the splice site mutation of SYNE-1 gene found in the family is responsible for AMC. Recent reports have shown that mutations of the SYNE-1 gene might be responsible for autosomal recessive adult onset cerebellar ataxia. These data indicate that mutations of nesprin-1 which interacts with lamin A/C may lead to at least two distinct human disease phenotypes, myopathic or neurological, a feature similar to that found in laminopathies.

  2. Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation

    PubMed Central

    Tuntivanich, Nalinee; Pittler, Steven J.; Fischer, Andy J.; Omar, Ghezal; Kiupel, Matti; Weber, Arthur; Yao, Suxia; Steibel, Juan Pedro; Khan, Naheed Wali; Petersen-Jones, Simon M.

    2013-01-01

    Purpose To characterize a canine model of autosomal recessive RP due to a PDE6A gene mutation. Methods Affected and breed- and age-matched control puppies were studied by electroretinography (ERG), light and electron microscopy, immunohistochemistry and by assay for retinal PDE6 levels and enzymatic activity. Results The mutant puppies failed to develop normal rod-mediated ERG responses and had reduced light-adapted a-wave amplitudes from an early age. The residual ERG waveforms originated primarily from cone-driven responses. Development of photoreceptor outer segments was halted and rod cells were lost by apoptosis. Immunohistochemistry demonstrated a marked reduction in rod-opsin immunostaining outer segments and relative preservation of cones early in the disease process. With exception of rod bipolar cells that appeared to be reduced in number relatively early in the disease process other inner retinal cells were preserved in the early stages of the disease although there was marked and early activation of Müller glia. Western blotting showed that the PDE6A mutation not only resulted in a lack of PDE6A protein but the affected retinas also lacked the other PDE6 subunits, suggesting expression of PDE6A is required for normal expression of PDE6B and PDE6G. Affected retinas lacked PDE6 enzymatic activity. Conclusions This represents the first characterization of a PDE6A model of autosomal recessive retinitis pigmentosa and the PDE6A mutant dog shows promise as a large animal model for investigation of therapies to rescue mutant rod photoreceptors and to preserve cone photoreceptors in the face a rapid loss of rod cells. PMID:18775863

  3. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

    PubMed

    Harripaul, R; Vasli, N; Mikhailov, A; Rafiq, M A; Mittal, K; Windpassinger, C; Sheikh, T I; Noor, A; Mahmood, H; Downey, S; Johnson, M; Vleuten, K; Bell, L; Ilyas, M; Khan, F S; Khan, V; Moradi, M; Ayaz, M; Naeem, F; Heidari, A; Ahmed, I; Ghadami, S; Agha, Z; Zeinali, S; Qamar, R; Mozhdehipanah, H; John, P; Mir, A; Ansar, M; French, L; Ayub, M; Vincent, J B

    2017-04-11

    Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.Molecular Psychiatry advance online publication, 11 April 2017; doi:10.1038/mp.2017.60.

  4. Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.

    PubMed

    Eden, Emily R; Patel, Dilipkumar D; Sun, Xi-Ming; Burden, Jemima J; Themis, Michael; Edwards, Matthew; Lee, Philip; Neuwirth, Clare; Naoumova, Rossitza P; Soutar, Anne K

    2002-12-01

    Familial hypercholesterolemia is an autosomal dominant disorder with a gene-dosage effect that is usually caused by mutations in the LDL receptor gene that disrupt normal clearance of LDL. In the homozygous form, it results in a distinctive clinical phenotype, characterized by inherited hypercholesterolemia, cholesterol deposition in tendons, and severe premature coronary disease. We described previously two families with autosomal recessive hypercholesterolemia that is not due to mutations in the LDL receptor gene but is characterized by defective LDL receptor-dependent internalization and degradation of LDL by transformed lymphocytes from the patients. We mapped the defective gene to chromosome 1p36 and now show that the disorder in these and a third English family is due to novel mutations in ARH1, a newly identified gene encoding an adaptor-like protein. Cultured skin fibroblasts from affected individuals exhibit normal LDL receptor activity, but their monocyte-derived macrophages are similar to transformed lymphocytes, being unable to internalize and degrade LDL. Retroviral expression of normal human ARH1 restores LDL receptor internalization in transformed lymphocytes from an affected individual, as demonstrated by uptake and degradation of (125)I-labeled LDL and confocal microscopy of cells labeled with anti-LDL-receptor Ab.

  5. Autosomal recessive hypercholesterolemia: a mild phenotype of familial hypercholesterolemia: insight from the kinetic study using stable isotope and animal studies.

    PubMed

    Tada, Hayato; Kawashiri, Masa-Aki; Nohara, Atsushi; Inazu, Akihiro; Kobayashi, Junji; Mabuchi, Hiroshi; Yamagishi, Masakazu

    2015-01-01

    Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited disorder, the cause of which is mutations in the low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Only 36 families with 14 different mutations have been reported in the literature to date. The clinical phenotype of ARH is milder than that of homozygous familial hypercholesterolemia (FH) caused by LDL receptor gene mutations. Recently, the lipoprotein metabolism of ARH was investigated in both humans and mice by several investigators, including ourselves. Based on these findings the preserved clearance of LDL receptor-dependent very-LDL (VLDL) may be a possible mechanism underlying the responsiveness to statins and the milder phenotype of ARH. Although ARH has been described as being "recessive," several studies, including ours, have indicated that a heterozygous carrier status of the LDLRAP1 gene is associated with mild hypercholesterolemia and exacerbates the phenotype of FH resulting from LDL receptor gene mutations. This review summarizes current understanding regarding ARH and its causative gene, LDLRAP1, and attempts to provide new insight into novel pharmacological targets for treating dyslipidemic patients.

  6. Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia

    PubMed Central

    Lukacs, Viktor; Mathur, Jayanti; Mao, Rong; Bayrak-Toydemir, Pinar; Procter, Melinda; Cahalan, Stuart M.; Kim, Helen J.; Bandell, Michael; Longo, Nicola; Day, Ronald W.; Stevenson, David A.; Patapoutian, Ardem; Krock, Bryan L.

    2015-01-01

    Piezo1 ion channels are mediators of mechanotransduction in several cell types including the vascular endothelium, renal tubular cells and erythrocytes. Gain-of-function mutations in PIEZO1 cause an autosomal dominant haemolytic anaemia in humans called dehydrated hereditary stomatocytosis. However, the phenotypic consequence of PIEZO1 loss of function in humans has not previously been documented. Here we discover a novel role of this channel in the lymphatic system. Through whole-exome sequencing, we identify biallelic mutations in PIEZO1 (a splicing variant leading to early truncation and a non-synonymous missense variant) in a pair of siblings affected with persistent lymphoedema caused by congenital lymphatic dysplasia. Analysis of patients' erythrocytes as well as studies in a heterologous system reveal greatly attenuated PIEZO1 function in affected alleles. Our results delineate a novel clinical category of PIEZO1-associated hereditary lymphoedema. PMID:26387913

  7. Evidence of genetic heterogeneity in the autosomal recessive adult forms of limb-girdle muscular dystrophy following linkage analysis with 15q probes in Brazilian families.

    PubMed Central

    Passos-Bueno, M R; Richard, I; Vainzof, M; Fougerousse, F; Weissenbach, J; Broux, O; Cohen, D; Akiyama, J; Marie, S K; Carvalho, A A

    1993-01-01

    The autosomal recessive limb-girdle muscular dystrophies (LGMD) represent a heterogeneous group of diseases which may be characterised by one or more autosomal loci. A gene at 15q has recently been found to be responsible for a mild form of LGMD in a group of families from the isolated island of Réunion, now classified as LGMD2. Based on results of eight out of 11 large Brazilian LGMD families of different racial background (which were informative for the closest available probe to the LGMD2 gene), we confirmed linkage to the LGMD2 gene at 15q in two of these families and exclusion in six others. These data provide the first evidence of genetic heterogeneity for the autosomal recessive limb-girdle muscular dystrophies. PMID:8320700

  8. Polysyndactyly, complex heart malformations cardiopathy, and hepatic ductal plate anomalies: an autosomal recessive syndrome diagnosed antenatally.

    PubMed

    Stoll, Claude; Gasser, B

    2003-06-01

    A distinct syndrome was ascertained in a 3-year-old girl and her brother. The proband was the first child of first cousin parents. She was born after an uneventful pregnancy. At birth, multiple congenital anomalies were noted: ptosis of the left eyelid, hypertelorism, anteverted nares, large fontanel, long philtrum, ungueal hypoplasia, polysyndactyly, single transverse crease, complex cardiopathy, and hepatic cysts. During another pregnancy of the mother, fetal ultrasonographic examination showed an hypertrophy of the right ventricle and atria, a dextroposition of the aorta, a bilateral renal pelvis dilatation, and a club foot. After termination of the pregnancy, necropsy showed facial anomalies, a small penis, a polysyndactyly, a ventricular septum defect, and a malformation of the ductal plate. Bonneau et al. [1983: J Genet Hum 2:93-105] described a family in which three sibs had a complex cardiac malformation, hexadactyly of the first toe, and syndactyly of the third and fourth fingers. Rajab [1997: Clin Dysmorphol 6:85-88] described two sibs with similar features in an Omani family. The sibs described in this report had anomalies of the ductal plate which were not reported in the two other families. These new findings are in favor of autosomal inheritance of this condition which is amenable to antenatal diagnosis.

  9. Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.

    PubMed

    Thomas, Anna C; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O'Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J; Pai, Yun Jin; Saraiva, Jorge M; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E; Sousa, Sérgio B; Stanier, Philip

    2014-11-06

    Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.

  10. Two sisters with clinical diagnosis of Wiskott-Aldrich Syndrome: Is the condition in the family autosomal recessive?

    SciTech Connect

    Kondoh, T.; Hayashi, K.; Matsumoto, T.

    1995-10-09

    We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister`s for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS. 17 refs., 6 figs., 1 tab.

  11. Adaptor protein disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia.

    PubMed

    Eden, Emily R; Sun, Xi-Ming; Patel, Dilipkumar D; Soutar, Anne K

    2007-11-15

    Autosomal recessive hypercholesterolaemia (ARH), characterized clinically by severe inherited hypercholesterolaemia, is caused by recessive null mutations in LDLRAP1 (formerly ARH). Immortalized lymphocytes and monocyte-macrophages, and presumably hepatocytes, from ARH patients fail to take up and degrade plasma low density lipoproteins (LDL) because they lack LDLRAP1, a cargo-specific adaptor required for clathrin-mediated endocytosis of the LDL receptor. Surprisingly, LDL-receptor function is normal in ARH patients' skin fibroblasts in culture. Disabled-2 (Dab2) has been implicated previously in clathrin-mediated internalization of LDL-receptor family members, and we show here that Dab2 is highly expressed in skin fibroblasts, but not in lymphocytes. SiRNA-depletion of Dab2 profoundly reduced LDL-receptor activity in ARH fibroblasts as a result of profound reduction in LDL-receptor protein, but not mRNA; heterologous expression of murine Dab2 reversed this effect. In contrast, LDL-receptor protein content was unchanged in Dab-2-depleted control cells. Incorporation of 35S-labelled amino acids into LDL receptor protein revealed a corresponding apparent reduction in accumulation of newly synthesized LDL-receptor protein on depletion of Dab2 in ARH, but not in control, cells. This reduction in LDL-receptor protein in Dab2-depleted ARH cells could not be reversed by treatment of the cells with proteasomal or lysosomal inhibitors. Thus, we propose a novel role for Dab2 in ARH fibroblasts, where it is apparently required to allow normal translation of LDL receptor mRNA.

  12. Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment.

    PubMed

    Schraders, Margit; Ruiz-Palmero, Laura; Kalay, Ersan; Oostrik, Jaap; del Castillo, Francisco J; Sezgin, Orhan; Beynon, Andy J; Strom, Tim M; Pennings, Ronald J E; Zazo Seco, Celia; Oonk, Anne M M; Kunst, Henricus P M; Domínguez-Ruiz, María; García-Arumi, Ana M; del Campo, Miguel; Villamar, Manuela; Hoefsloot, Lies H; Moreno, Felipe; Admiraal, Ronald J C; del Castillo, Ignacio; Kremer, Hannie

    2012-11-02

    Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.

  13. Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis.

    PubMed

    Sugiura, Kazumitsu; Akiyama, Masashi

    2015-07-01

    Research on the molecular genetics and pathomechanisms of autosomal recessive congenital ichthyosis (ARCI) has advanced considerably and several causative genes and molecules underlying the disease have been identified. Three major ARCI phenotypes are harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE). Skin barrier defects are involved in the pathogenesis of ARCI. In this review, the causative genes of ARCI and its phenotypes as well as recent advances in the field are summarized. The known causative molecules underlying ARCI include ABCA12, TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, PNPLA1, CERS3, and LIPN. It is important to examine genetic associations and to elucidate the pathomechanisms of ARCI to establish effective therapies and beneficial genetic counseling. Next-generation sequencing is a promising method that enables the detection of causative disease mutations, even in cases of unexpected concomitant genetic diseases. For genetic diagnosis, obtaining mRNA from hair follicle epithelial cells, which are analogous to keratinocytes in the interfollicular epidermis, is convenient and minimally invasive in patients with ARCI. We confirmed that our mRNA analysis method using hair follicle samples can be applied not only to keratinization disorders, but also to other genetic diseases in the dermatology field. Studies that suggest potential next-generation therapies using ARCI model mice are also reviewed.

  14. Comprehensive Analysis via Exome Sequencing Uncovers Genetic Etiology in Autosomal Recessive Non-Syndromic Deafness in a Large Multiethnic Cohort

    PubMed Central

    Bademci, Guney; Foster, Joseph; Mahdieh, Nejat; Bonyadi, Mortaza; Duman, Duygu; Cengiz, F.Basak; Menendez, Ibis; Horta, Oscar Diaz; Shirkavand, Atefeh; Zeinali, Sirous; Subasioglu, Asli; Tokgoz-Yilmaz, Suna; Hernandez, Fabiola Huesca; de la Luz Arenas Sordo, Maria; Dominguez-Aburto, Juan; Hernandez-Zamora, Edgar; Montenegro, Paola; Paredes, Rosario; Moreta, Germania; Vinueza, Rodrigo; Villegas, Franklin; Mendoza Benitez, Santiago; Guo, Shengru; Bozan, Nazim; Tos, Tulay; Incesulu, Armagan; Sennaroglu, Gonca; Blanton, Susan H.; Ozturkmen Akay, Hatice; Yildirim-Baylan, Muzeyyen; Tekin, Mustafa

    2015-01-01

    Purpose Autosomal recessive non-syndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity with reported mutations in 58 different genes. This study was designed to detect deafness causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES). Methods After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador and Puerto Rico to screen for mutations in all known ARNSD genes. Results We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%) and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes suggesting founder effects. Conclusion We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families. PMID:26226137

  15. Examining non-syndromic autosomal recessive intellectual disability (NS-ARID) genes for an enriched association with intelligence differences☆

    PubMed Central

    Hill, W.D.; Davies, G.; Liewald, D.C.; Payton, A.; McNeil, C.J.; Whalley, L.J.; Horan, M.; Ollier, W.; Starr, J.M.; Pendleton, N.; Hansel, N.K.; Montgomery, G.W.; Medland, S.E.; Martin, N.G.; Wright, M.J.; Bates, T.C.; Deary, I.J.

    2016-01-01

    Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences. PMID:26912939

  16. Identification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family

    PubMed Central

    Siemiatkowska, Anna M.; Astuti, Galuh D.N.; Arimadyo, Kentar; den Hollander, Anneke I.; Faradz, Sultana M.H.; Cremers, Frans P.M.

    2012-01-01

    Purpose The purpose of this study was to identify the underlying molecular genetic defect in an Indonesian family with three affected individuals who had received a diagnosis of retinitis pigmentosa (RP). Methods Clinical evaluation of the family members included measuring visual acuity and fundoscopy, and assessing visual field and color vision. Genomic DNA of the three affected individuals was analyzed with Illumina 700k single nucleotide polymorphism (SNP) arrays, and homozygous regions were identified using PLINK software. Mutation analysis was performed with sequence analysis of the retinitis pigmentosa 1 (RP1) gene that resided in one of the homozygous regions. The frequency of the identified mutation in the Indonesian population was determined with TaqI restriction fragment length polymorphism analysis. Results A novel homozygous nonsense mutation in exon 4 of the RP1 gene, c.1012C>T (p.R338*), was identified in the proband and her two affected sisters. Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation. The mutation was not present in 184 Indonesian control samples. Conclusions Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4. Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP. PMID:23077400

  17. Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability.

    PubMed

    Heidari, Abolfazl; Tongsook, Chanakan; Najafipour, Reza; Musante, Luciana; Vasli, Nasim; Garshasbi, Masoud; Hu, Hao; Mittal, Kirti; McNaughton, Amy J M; Sritharan, Kumudesh; Hudson, Melissa; Stehr, Henning; Talebi, Saeid; Moradi, Mohammad; Darvish, Hossein; Arshad Rafiq, Muhammad; Mozhdehipanah, Hossein; Rashidinejad, Ali; Samiei, Shahram; Ghadami, Mohsen; Windpassinger, Christian; Gillessen-Kaesbach, Gabriele; Tzschach, Andreas; Ahmed, Iltaf; Mikhailov, Anna; Stavropoulos, D James; Carter, Melissa T; Keshavarz, Soraya; Ayub, Muhammad; Najmabadi, Hossein; Liu, Xudong; Ropers, Hans Hilger; Macheroux, Peter; Vincent, John B

    2015-10-15

    Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine N-methyltransferase (HNMT) inactivates HA by transferring a methyl group from S-adenosyl-l-methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous HNMT alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using in vitro toxicology assay. Using mutant and wild-type DNA constructs as well as in silico protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of HNMT for genetic testing of individuals presenting with intellectual disability.

  18. Identification of a Mutation Causing Deficient BMP1/mTLD Proteolytic Activity in Autosomal Recessive Osteogenesis Imperfecta

    PubMed Central

    Martínez-Glez, Víctor; Valencia, Maria; Caparrós-Martín, José A.; Aglan, Mona; Temtamy, Samia; Tenorio, Jair; Pulido, Veronica; Lindert, Uschi; Rohrbach, Marianne; Eyre, David; Giunta, Cecilia; Lapunzina, Pablo; Ruiz-Perez, Victor L.

    2013-01-01

    Herein, we have studied a consanguineous Egyptian family with two children diagnosed with severe autosomal recessive osteogenesis imperfecta (AR-OI) and a large umbilical hernia. Homozygosity mapping in this family showed lack of linkage to any of the previously known AR-OI genes, but revealed a 10.27 MB homozygous region on chromosome 8p in the two affected sibs, which comprised the procollagen I C-terminal propeptide (PICP) endopeptidase gene BMP1. Mutation analysis identified both patients with a Phe249Leu homozygous missense change within the BMP1 protease domain involving a residue, which is conserved in all members of the astacin group of metalloproteases. Type I procollagen analysis in supernatants from cultured fibroblasts demonstrated abnormal PICP processing in patient-derived cells consistent with the mutation causing decreased BMP1 function. This was further confirmed by overexpressing wild type and mutant BMP1 longer isoform (mammalian Tolloid protein [mTLD]) in NIH3T3 fibroblasts and human primary fibroblasts. While overproduction of normal mTLD resulted in a large proportion of proα1(I) in the culture media being C-terminally processed, proα1(I) cleavage was not enhanced by an excess of the mutant protein, proving that the Phe249Leu mutation leads to a BMP1/mTLD protein with deficient PICP proteolytic activity. We conclude that BMP1 is an additional gene mutated in AR-OI. PMID:22052668

  19. Whole exome sequencing identified novel CRB1 mutations in Chinese and Indian populations with autosomal recessive retinitis pigmentosa

    PubMed Central

    Yang, Yin; Yang, Yeming; Huang, Lulin; Zhai, Yaru; Li, Jie; Jiang, Zhilin; Gong, Bo; Fang, Hao; Kim, Ramasamy; Yang, Zhenglin; Sundaresan, Periasamy; Zhu, Xianjun; Zhou, Yu

    2016-01-01

    Retinitis pigmentosa (RP) is a leading cause of inherited blindness characterized by progressive degeneration of the retinal photoreceptor cells. This study aims to identify genetic mutations in a Chinese family RP-2236, an Indian family RP-IC-90 and 100 sporadic Indian individuals with autosomal recessive RP (arRP). Whole exome sequencing was performed on the index patients of RP-2236, RP-IC-90 and all of the 100 sporadic Indian patients. Direct Sanger sequencing was used to validate the mutations identified. Four novel mutations and one reported mutation in the crumbs homolog 1 (CRB1) gene, which has been known to cause severe retinal dystrophies, were identified. A novel homozygous splicing mutation c.2129-1G>C was found in the three patients In family RP-2236. A homozygous point mutation p.R664C was found in RP-IC-90. A novel homozygous mutation p.G1310C was identified in patient I-44, while novel compound heterozygous mutations p.N629D and p.A593T were found in patient I-7. All mutations described above were not present in the 1000 normal controls. In conclusion, we identified four novel mutations in CRB1 in a cohort of RP patients from the Chinese and Indian populations. Our data enlarges the CRB1 mutation spectrums and may provide new target loci for RP diagnose and treatment. PMID:27670293

  20. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

    PubMed Central

    Bultmann-Mellin, Insa; Conradi, Anne; Maul, Alexandra C.; Dinger, Katharina; Wempe, Frank; Wohl, Alexander P.; Imhof, Thomas; Wunderlich, F. Thomas; Bunck, Alexander C.; Nakamura, Tomoyuki; Koli, Katri; Bloch, Wilhelm; Ghanem, Alexander; Heinz, Andrea; von Melchner, Harald; Sengle, Gerhard; Sterner-Kock, Anja

    2015-01-01

    Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S−/−), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S−/− and Ltbp4-null (Ltbp4−/−) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C. PMID:25713297

  1. PKHD1 Sequence Variations in 78 Children and Adults with Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis

    PubMed Central

    Gunay-Aygun, Meral; Tuchman, Maya; Font-Montgomery, Esperanza; Lukose, Linda; Edwards, Hailey; Garcia, Angelica; Ausavarat, Surasawadee; Ziegler, Shira G.; Piwnica-Worms, Katie; Bryant, Joy; Bernardini, Isa; Fischer, Roxanne; Huizing, Marjan; Guay-Woodford, Lisa; Gahl, William A.

    2009-01-01

    PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/Congenital hepatic fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified. PMID:19914852

  2. COL9A2 and COL9A3 mutations in canine autosomal recessive Oculo-skeletal Dysplasia

    PubMed Central

    Goldstein, Orly; Guyon, Richard; Kukekova, Anna; Pearce-Kelling, Sue; Johnson, Jennifer; Aguirre, Gustavo D.; Acland, Gregory M.

    2010-01-01

    Oculo-skeletal dysplasia segregates in two canine breeds, the Labrador retriever and samoyed, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism together with severe ocular defects, and this phenotype is inherited as an autosomal recessive trait in both breeds. The clinical and pathological appearance resembles human hereditary arthro-ophthalmopathies such as Stickler syndrome, or Marshall Syndrome, although these human disorders are usually dominant. Linkage studies in drd1-informative pedigrees mapped the locus to canine chromosome 24, and led to the identification of an insertional mutation in exon 1 of the gene COL9A3 that cosegregates with the disease. The drd2 locus was similarly mapped to canine chromosome 15 and shown to cosegregate with a 1,267 bp deletion mutation in the 5′ end of COL9A2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed reduced RNA expression in affected retina compared to normal. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family; regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy. PMID:20686772

  3. The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits.

    PubMed

    Garuti, Rita; Jones, Christopher; Li, Wei-Ping; Michaely, Peter; Herz, Joachim; Gerard, Robert D; Cohen, Jonathan C; Hobbs, Helen H

    2005-12-09

    Autosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in low density lipoprotein receptor (LDLR) endocytosis. LDLR-mediated uptake of LDL is impaired in the liver, but not in fibroblasts of subjects with this disorder. The disease is caused by mutations in ARH, which encodes a putative adaptor protein that interacts with the cytoplasmic tail of the LDLR, phospholipids, and two components of the clathrin endocytic machinery, clathrin and adaptor protein-2 (AP-2) in vitro. To determine the physiological relevance of these interactions, we examined the effect of mutations in the ARH on LDLR location and function in polarized hepatocytes (WIF-B). The integrity of the FDNPVY sequence in the LDLR cytoplasmic tail was required for ARH-associated LDLR clustering into clathrin-coated pits. The phosphotyrosine binding domain of ARH plus either the clathrin box or the AP-2 binding region were required for both clustering and internalization of the LDLR. Parallel studies performed in vivo with the same recombinant forms of ARH in livers of Arh(-/-) mice confirmed the relevance of the cell culture findings. These results demonstrate that ARH must bind the LDLR tail and either clathrin or AP-2 to promote receptor clustering and internalization of LDL.

  4. Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia.

    PubMed

    Jones, Christopher; Hammer, Robert E; Li, Wei-Ping; Cohen, Jonathan C; Hobbs, Helen H; Herz, Joachim

    2003-08-01

    Autosomal recessive hypercholesterolemia (ARH) is a genetic form of hypercholesterolemia that clinically resembles familial hypercholesterolemia (FH). As in FH, the rate of clearance of circulating low density lipoprotein (LDL) by the LDL receptor (LDLR) in the liver is markedly reduced in ARH. Unlike FH, LDL uptake in cultured fibroblasts from ARH patients is normal or only slightly impaired. The gene defective in ARH encodes a putative adaptor protein that has been implicated in linking the LDLR to the endocytic machinery. To determine the role of ARH in the liver, ARH-deficient mice were developed. Plasma levels of LDL-cholesterol were elevated in the chow-fed Arh-/- mice (83 +/- 8 mg/dl versus 68 +/- 8 mg/dl) but were lower than those of mice expressing no LDLR (Ldlr-/-) (197 +/- 8 mg/dl). Cholesterol feeding elevated plasma cholesterol levels in both strains. The fractional clearance rate of radiolabeled LDL was reduced to similar levels in the Arh-/- and Ldlr-/- mice, whereas the rate of removal of alpha2-macroglobulin by the LDLR-related protein, which also interacts with ARH, was unchanged. Immunolocalization studies revealed that a much greater proportion of immunodetectable LDLR, but not LDLR-related protein, was present on the sinusoidal surface of hepatocytes in the Arh-/- mice. Taken together, these results are consistent with ARH playing a critical and specific role in LDLR endocytosis in the liver.

  5. Novel Mutations and Mutation Combinations of TMPRSS3 Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment

    PubMed Central

    Wang, Guo-Jian; Xu, Jin-Cao; Su, Yu

    2017-01-01

    Autosomal recessive hearing impairment with postlingual onset is rare. Exceptions are caused by mutations in the TMPRSS3 gene, which can lead to prelingual (DFNB10) as well as postlingual deafness (DFNB8). TMPRSS3 mutations can be classified as mild or severe, and the phenotype is dependent on the combination of TMPRSS3 mutations. The combination of two severe mutations leads to profound hearing impairment with a prelingual onset, whereas severe mutations in combination with milder TMPRSS3 mutations lead to a milder phenotype with postlingual onset. We characterized a Chinese family (number FH1523) with not only prelingual but also postlingual hearing impairment. Three mutations in TMPRSS3, one novel mutation c.36delC [p.(Phe13Serfs⁎12)], and two previously reported pathogenic mutations, c.916G>A (p.Ala306Thr) and c.316C>T (p.Arg106Cys), were identified. Compound heterozygous mutations of p.(Phe13Serfs⁎12) and p.Ala306Thr manifest as prelingual, profound hearing impairment in the patient (IV: 1), whereas the combination of p.Arg106Cys and p.Ala306Thr manifests as postlingual, milder hearing impairment in the patient (II: 2, II: 3, II: 5), suggesting that p.Arg106Cys mutation has a milder effect than p.(Phe13Serfs⁎12). We concluded that different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in this family. PMID:28246597

  6. Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

    PubMed

    Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

    2015-01-01

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

  7. Evidence for a “Pathogenic Triumvirate” in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease

    PubMed Central

    Fang, Pingping; Weemhoff, James L.; Apte, Udayan

    2016-01-01

    Autosomal recessive polycystic kidney disease (ARPKD) is a severe monogenic disorder that occurs due to mutations in the PKHD1 gene. Congenital hepatic fibrosis (CHF) associated with ARPKD is characterized by the presence of hepatic cysts derived from dilated bile ducts and a robust, pericystic fibrosis. Cyst growth, due to cyst wall epithelial cell hyperproliferation and fluid secretion, is thought to be the driving force behind disease progression. Liver fibrosis is a wound healing response in which collagen accumulates in the liver due to an imbalance between extracellular matrix synthesis and degradation. Whereas both hyperproliferation and pericystic fibrosis are hallmarks of CHF/ARPKD, whether or not these two processes influence one another remains unclear. Additionally, recent studies demonstrate that inflammation is a common feature of CHF/ARPKD. Therefore, we propose a “pathogenic triumvirate” consisting of hyperproliferation of cyst wall growth, pericystic fibrosis, and inflammation which drives CHF/ARPKD progression. This review will summarize what is known regarding the mechanisms of cyst growth, fibrosis, and inflammation in CHF/ARPKD. Further, we will discuss the potential advantage of identifying a core pathogenic feature in CHF/ARPKD to aid in the development of novel therapeutic approaches. If a core pathogenic feature does not exist, then developing multimodality therapeutic approaches to target each member of the “pathogenic triumvirate” individually may be a better strategy to manage this debilitating disease. PMID:27891514

  8. Mild osteopetrosis in the microphthalmia-oak ridge mouse. A model for intermediate autosomal recessive osteopetrosis in humans.

    PubMed

    Nii, A; Steingrímsson, E; Copeland, N G; Jenkins, N A; Ward, J M

    1995-12-01

    Mutations at the mouse microphthalmia (mi) locus affect coat color, eye development, and mast cells. The original allele, mi, also shows severe osteopetrosis. Mice homozygous for the microphthalmia-Oak Ridge (Mior) mutation are white, microphthalmic animals with retarded incisor development. To investigate whether this mutation causes osteopetrosis, we examined skeletal tissues of the Mior mouse. A typical osteopetrotic lesion, accumulation of unresorbed primary spongiosa, was found at the metaphyses of long bones and at the costochondral junctions in Mior/Mior mice from 10 days to 37 days of age, whereas no accumulation was seen at the mid-diaphyses in these bones. The osteopetrotic conditions of Mior/Mior mice increased progressively during the first 5 weeks after birth. However, adult Mior/Mior mice 3 months or older showed improvement of the osteopetrotic condition, although the disease was not completely resolved. Ultrastructurally, osteoclasts of Mior/Mior mice had well developed ruffled borders. These results show that the Mior mutation has milder osteopetrotic changes than the original mi mutation, a surprising observation given that both mutations affect the same functional domain of the mi protein, a basic-Helix-Loop-Helix-Zipper transcription factor. The Mior phenotype resembles the intermediate autosomal recessive osteopetrosis in humans.

  9. Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.

    PubMed

    Kalay, Ersan; Li, Yun; Uzumcu, Abdullah; Uyguner, Oya; Collin, Rob W; Caylan, Refik; Ulubil-Emiroglu, Melike; Kersten, Ferry F J; Hafiz, Gunter; van Wijk, Erwin; Kayserili, Hulya; Rohmann, Edyta; Wagenstaller, Janine; Hoefsloot, Lies H; Strom, Tim M; Nürnberg, Gudrun; Baserer, Nermin; den Hollander, Anneke I; Cremers, Frans P M; Cremers, Cor W R J; Becker, Christian; Brunner, Han G; Nürnberg, Peter; Karaguzel, Ahmet; Basaran, Seher; Kubisch, Christian; Kremer, Hannie; Wollnik, Bernd

    2006-07-01

    In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.

  10. Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27

    SciTech Connect

    Matsumine, Hiroto; Shimoda-Matsubayashi, Satoe; Nakagawa-Hattori, Yuko

    1997-03-01

    An autosomal recessive form of juvenile Parkinsonism (AR-JP) (MIM 600116) is a levodopa-responsive Parkinsonism whose pathological finding is a highly selective degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. By linkage analysis of diallelic polymorphism of the Mn-superoxide dismutase gene (SOD2), we found a family with AR-JP showing perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with AR-JP, we discovered strong evidence for the localization of the AR-JP gene at chromosome 6q25.2-27, including the SOD2 locus, with the maximal cumulative pairwise LOD scores of 7.26 and 7.71 at D6S305 ({theta} = .03) and D6S253 ({theta} = .02), respectively. Observation of obligate recombination events, as well as multipoint linkage analysis, placed the AR-JP gene in a 17-cM interval between D6S437 and D6S264. Delineation of the AR-JP gene will be an important step toward our understanding of the molecular mechanism underlying selective degeneration of the nigral neurons. 38 refs., 4 figs., 1 tab.

  11. Examining non-syndromic autosomal recessive intellectual disability (NS-ARID) genes for an enriched association with intelligence differences.

    PubMed

    Hill, W D; Davies, G; Liewald, D C; Payton, A; McNeil, C J; Whalley, L J; Horan, M; Ollier, W; Starr, J M; Pendleton, N; Hansel, N K; Montgomery, G W; Medland, S E; Martin, N G; Wright, M J; Bates, T C; Deary, I J

    2016-01-01

    Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.

  12. ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts.

    PubMed

    Akiyama, Masashi

    2010-10-01

    Mutations in ABCA12 have been described in autosomal recessive congenital ichthyoses (ARCI) including harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). HI shows the most severe phenotype. CIE and LI are clinically characterized by fine, whitish scales on a background of erythematous skin, and large, thick, dark scales over the entire body without serious background erythroderma, respectively. To date, a total of 56 ABCA12 mutations have been reported in 66 ARCI families including 48 HI, 10 LI, and 8 CIE families of African, European, Pakistani/Indian, and Japanese origin (online database: http://www.derm-hokudai.jp/ABCA12/). A total of 62.5% of reported ABCA12 mutations are expected to lead to truncated proteins. Most mutations in HI are truncation mutations and homozygous or compound heterozygous truncation mutations always results in HI phenotype. In CIE families, at least one mutation on each allele is typically a missense mutation. Combinations of missense mutations in the first ATP-binding cassette of ABCA12 underlie the LI phenotype. ABCA12 is a keratinocyte lipid transporter associated with lipid transport in lamellar granules, and loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in an ichthyotic phenotype. Recent work using mouse models confirmed ABCA12 roles in skin barrier formation.

  13. In Silico Analysis of SNPs in PARK2 and PINK1 Genes That Potentially Cause Autosomal Recessive Parkinson Disease

    PubMed Central

    Ibrahim, Mohamed Osama Mirghani; Mirghani, Yousra Abdelazim; Hassan, Mohamed Ahmed Salih

    2016-01-01

    Introduction. Parkinson's disease (PD) is a common neurodegenerative disorder. Mutations in PINK1 are the second most common agents causing autosomal recessive, early onset PD. We aimed to identify the pathogenic SNPs in PARK2 and PINK1 using in silico prediction software and their effect on the structure, function, and regulation of the proteins. Materials and Methods. We carried out in silico prediction of structural effect of each SNP using different bioinformatics tools to predict substitution influence on protein structure and function. Result. Twenty-one SNPs in PARK2 gene were found to affect transcription factor binding activity. 185 SNPs were found to affect splicing. Ten SNPs were found to affect the miRNA binding site. Two SNPs rs55961220 and rs56092260 affected the structure, function, and stability of Parkin protein. In PINK1 gene only one SNP (rs7349186) was found to affect the structure, function, and stability of the PINK1 protein. Ten SNPs were found to affect the microRNA binding site. Conclusion. Better understanding of Parkinson's disease caused by mutations in PARK2 and PINK1 genes was achieved using in silico prediction. Further studies should be conducted with a special consideration of the ethnic diversity of the different populations. PMID:28127307

  14. Identification of an autosomal recessive mode of inheritance in paediatric Behçet's families by segregation analysis.

    PubMed

    Molinari, N; Koné Paut, I; Manna, R; Demaille, J; Daures, J P; Touitou, I

    2003-10-01

    We have conducted a segregation analysis in order to characterise the transmission of Behçet Disease (BD), a multifactorial condition with a strong genetic component. Complete information about BD status and pedigree was obtained on 104 probands from our database. We used the criteria of the International Study Group for BD (ISBD) to delineate the clinical status of the sibs: possible BD (patients meeting two criteria), or ascertained BD (patients meeting at least three criteria). A proband was defined as "paediatric" when he/she completed ISBD criteria before/by the age of 16 years. Families were distinguished as paediatric (n = 67) (ascertained through a paediatric proband), and non-paediatric (n = 37) ones. An Expectation Maximization (EM) algorithm was used to estimate the Mendelian segregation ratio P in nuclear families (two parents and their offspring). The maximum likelihood estimate: Pcirc; = 0.248, calculated in the paediatric data set, was consistent with the theoretical value of P = (1/4) for autosomal recessive inheritance, whereas the Pcirc; value was 0.08 when using the non-paediatric data set. Our work provides the first evidence of genetic heterogeneity in BD, and of the existence of a Mendelian entity in the paediatric BD subgroup. Previous studies failed to show any simple mode of inheritance in BD, probably because they were performed on the whole BD population.

  15. Identification of a Novel MYO15A Mutation in a Chinese Family with Autosomal Recessive Nonsyndromic Hearing Loss

    PubMed Central

    Xia, Hong; Huang, Xiangjun; Guo, Yi; Hu, Pengzhi; He, Guangxiang; Deng, Xiong; Xu, Hongbo; Yang, Zhijian; Deng, Hao

    2015-01-01

    Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous sensorineural disorder, generally manifested with prelingual hearing loss and absence of other clinical manifestations. The aim of this study is to identify the pathogenic gene in a four-generation consanguineous Chinese family with ARNSHL. A novel homozygous variant, c.9316dupC (p.H3106Pfs*2), in the myoxin XVa gene (MYO15A) was identified by exome sequencing and Sanger sequencing. The homozygous MYO15A c.9316dupC variant co-segregated with the phenotypes in the ARNSHL family and was absent in two hundred normal controls. The variant was predicted to interfere with the formation of the Myosin XVa-whirlin-Eps8 complex at the tip of stereocilia, which is indispensable for stereocilia elongation. Our data suggest that the homozygous MYO15A c.9316dupC variant might be the pathogenic mutation, and exome sequencing is a powerful molecular diagnostic strategy for ARNSHL, an extremely heterogeneous disorder. Our findings extend the mutation spectrum of the MYO15A gene and have important implications for genetic counseling for the family. PMID:26308726

  16. Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and ldis1 mice

    PubMed Central

    Talamas, Elijah; Jackson, Lavinia; Koeberl, Matthew; Jackson, Todd; McElwee, John L.; Hawes, Norman L.; Chang, Bo; Jablonski, Monica M.; Sidjanin, D.J.

    2006-01-01

    Lens opacity 11 (lop11) is an autosomal recessive mouse cataract mutation that arose spontaneously in the RIIIS/J strain. At 3 weeks of age mice exhibit total cataracts with vacuoles. The lop11 locus was mapped to mouse chromosome 8. Analysis of the mouse genome for the lop11 critical region identified Hsf4 as a candidate gene. Molecular evaluation of Hsf4 revealed an early transposable element (ETn) in intron 9 inserted 61 bp upstream of the intron/exon junction. The same mutation was also identified in a previously mapped cataract mutant, ldis1. The ETn insertion altered splicing and expression of the Hsf4 gene, resulting in the truncated Hsf4 protein. In humans, mutations in HSF4 have been associated with both autosomal dominant and recessive cataracts. The lop11 mouse is an excellent resource for evaluating the role of Hsf4 in transparency of the lens. PMID:16595169

  17. Early transposable element insertion in intron 9 of the Hsf4 gene results in autosomal recessive cataracts in lop11 and ldis1 mice.

    PubMed

    Talamas, Elijah; Jackson, Lavinia; Koeberl, Matthew; Jackson, Todd; McElwee, John L; Hawes, Norman L; Chang, Bo; Jablonski, Monica M; Sidjanin, D J

    2006-07-01

    Lens opacity 11 (lop11) is an autosomal recessive mouse cataract mutation that arose spontaneously in the RIIIS/J strain. At 3 weeks of age mice exhibit total cataracts with vacuoles. The lop11 locus was mapped to mouse chromosome 8. Analysis of the mouse genome for the lop11 critical region identified Hsf4 as a candidate gene. Molecular evaluation of Hsf4 revealed an early transposable element (ETn) in intron 9 inserted 61 bp upstream of the intron/exon junction. The same mutation was also identified in a previously mapped cataract mutant, ldis1. The ETn insertion altered splicing and expression of the Hsf4 gene, resulting in the truncated Hsf4 protein. In humans, mutations in HSF4 have been associated with both autosomal dominant and recessive cataracts. The lop11 mouse is an excellent resource for evaluating the role of Hsf4 in transparency of the lens.

  18. Abnormal expression of laminin suggests disturbance of sarcolemma-extracellular matrix interaction in Japanese patients with autosomal recessive muscular dystrophy deficient in adhalin.

    PubMed Central

    Higuchi, I; Yamada, H; Fukunaga, H; Iwaki, H; Okubo, R; Nakagawa, M; Osame, M; Roberds, S L; Shimizu, T; Campbell, K P

    1994-01-01

    Dystrophin is associated with several novel sarcolemmal proteins, including a laminin-binding extracellular glycoprotein of 156 kD (alpha-dystroglycan) and a transmembrane glycoprotein of 50 kD (adhalin). Deficiency of adhalin characterizes a severe autosomal recessive muscular dystrophy prevalent in Arabs. Here we report for the first time two mongoloid (Japanese) patients with autosomal recessive muscular dystrophy deficient in adhalin. Interestingly, adhalin was not completely absent and was faintly detectable in a patchy distribution along the sarcolemma in our patients. Although the M and B2 subunits of laminin were preserved, the B1 subunit was greatly reduced in the basal lamina surrounding muscle fibers. Our results raise a possibility that the deficiency of adhalin may be associated with the disturbance of sarcolemma-extracellular matrix interaction leading to sarcolemmal instability. Images PMID:8040315

  19. Clinical and molecular characterization of seven Egyptian families with autosomal recessive robinow syndrome: Identification of four novel ROR2 gene mutations.

    PubMed

    Aglan, Mona; Amr, Khalda; Ismail, Samira; Ashour, Adel; Otaify, Ghada A; Mehrez, Mennat Allah I; Aboul-Ezz, Eman H A; El-Ruby, Mona; Mazen, Inas; Abdel-Hamid, Mohamed S; Temtamy, Samia A

    2015-12-01

    Robinow syndrome (RS) is a rare genetic disorder characterized by limb shortening, genital hypoplasia, and craniofacial/orodental abnormalities. The syndrome follows both autosomal dominant and recessive patterns of inheritance with similar phenotypic presentation and overlapping features. Autosomal recessive Robinow syndrome (ARRS) is caused by mutations in the ROR2 gene. Here, we present the clinical, radiological and molecular findings of 11 Egyptian patients from 7 unrelated consanguineous families with clinical features of ARRS. Mutation analyses of ROR2 gene identified five pathogenic mutations distributed all over the gene. The identified mutations included four novel (G326A, D166H, S677F, and R528Q) and one previously reported (Y192D). Our results extend the number of ROR2 mutations identified so far, suggest a founder effect in the Egyptian population, and emphasize the important role of genetic testing in proper counseling and patients' management.

  20. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy

    PubMed Central

    Lesage, Suzanne; Drouet, Valérie; Majounie, Elisa; Deramecourt, Vincent; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Maurage, Claude-Alain; Sahbatou, Mourad; Liebau, Stefan; Ding, Jinhui; Bilgic, Basar; Emre, Murat; Erginel-Unaltuna, Nihan; Guven, Gamze; Tison, François; Tranchant, Christine; Vidailhet, Marie; Corvol, Jean-Christophe; Krack, Paul; Leutenegger, Anne-Louise; Nalls, Michael A.; Hernandez, Dena G.; Heutink, Peter; Gibbs, J. Raphael; Hardy, John; Wood, Nicholas W.; Gasser, Thomas; Durr, Alexandra; Deleuze, Jean-François; Tazir, Meriem; Destée, Alain; Lohmann, Ebba; Kabashi, Edor; Singleton, Andrew; Corti, Olga; Brice, Alexis; Lesage, Suzanne; Tison, François; Vidailhet, Marie; Corvol, Jean-Christophe; Agid, Yves; Anheim, Mathieu; Bonnet, Anne-Marie; Borg, Michel; Broussolle, Emmanuel; Damier, Philippe; Destée, Alain; Dürr, Alexandra; Durif, Franck; Krack, Paul; Klebe, Stephan; Lohmann, Ebba; Martinez, Maria; Pollak, Pierre; Rascol, Olivier; Tranchant, Christine; Vérin, Marc; Viallet, François; Brice, Alexis; Lesage, Suzanne; Majounie, Elisa; Tison, François; Vidailhet, Marie; Corvol, Jean Christophe; Nalls, Michael A.; Hernandez, Dena G.; Gibbs, J. Raphael; Dürr, Alexandra; Arepalli, Sampath; Barker, Roger A.; Ben-Shlomo, Yoav; Berg, Daniela; Bettella, Francesco; Bhatia, Kailash; de Bie, Rob M.A.; Biffi, Alessandro; Bloem, Bastiaan R.; Bochdanovits, Zoltan; Bonin, Michael; Lesage, Suzanne; Tison, François; Vidailhet, Marie; Corvol, Jean-Christophe; Agid, Yves; Anheim, Mathieu; Bonnet, Anne-Marie; Borg, Michel; Broussolle, Emmanuel; Damier, Philippe; Destée, Alain; Dürr, Alexandra; Durif, Franck; Krack, Paul; Klebe, Stephan; Lohmann, Ebba; Martinez, Maria; Pollak, Pierre; Rascol, Olivier; Tranchant, Christine; Vérin, Marc; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Counsell, Carl; Damier, Philippe; Dartigues, Jean-François; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Dong, Jing; Durif, Frank; Edkins, Sarah; Escott-Price, Valentina; Evans, Jonathan R.; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Goate, Alison; Gray, Emma; Guerreiro, Rita; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holmans, Peter; Holton, Janice; Hu, Michèle; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Kilarski, Laura L.; Jansen, Iris E.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; Lubbe, Steven; Lungu, Codrin; Martinez, María; Mätzler, Walter; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morrison, Karen E.; Mudanohwo, Ese; O’Sullivan, Sean S.; Owen, Michael J.; Pearson, Justin; Perlmutter, Joel S.; Pétursson, Hjörvar; Plagnol, Vincent; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Saad, Mohamad; Simón-Sánchez, Javier; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Schulte, Claudia; Sharma, Manu; Shaw, Karen; Sheerin, Una-Marie; Shoulson, Ira; Shulman, Joshua; Sidransky, Ellen; Spencer, Chris C.A.; Stefánsson, Hreinn; Stefánsson, Kári; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Wurster, Isabel; Williams, Nigel; Morris, Huw R.; Heutink, Peter; Hardy, John; Wood, Nicholas W.; Gasser, Thomas; Singleton, Andrew B.; Brice, Alexis

    2016-01-01

    Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression. PMID:26942284

  1. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

    PubMed

    Lesage, Suzanne; Drouet, Valérie; Majounie, Elisa; Deramecourt, Vincent; Jacoupy, Maxime; Nicolas, Aude; Cormier-Dequaire, Florence; Hassoun, Sidi Mohamed; Pujol, Claire; Ciura, Sorana; Erpapazoglou, Zoi; Usenko, Tatiana; Maurage, Claude-Alain; Sahbatou, Mourad; Liebau, Stefan; Ding, Jinhui; Bilgic, Basar; Emre, Murat; Erginel-Unaltuna, Nihan; Guven, Gamze; Tison, François; Tranchant, Christine; Vidailhet, Marie; Corvol, Jean-Christophe; Krack, Paul; Leutenegger, Anne-Louise; Nalls, Michael A; Hernandez, Dena G; Heutink, Peter; Gibbs, J Raphael; Hardy, John; Wood, Nicholas W; Gasser, Thomas; Durr, Alexandra; Deleuze, Jean-François; Tazir, Meriem; Destée, Alain; Lohmann, Ebba; Kabashi, Edor; Singleton, Andrew; Corti, Olga; Brice, Alexis

    2016-03-03

    Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

  2. Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

    SciTech Connect

    Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. ); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya )

    1992-01-15

    Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

  3. Whole-exome sequencing identifies LRIT3 mutations as a cause of autosomal-recessive complete congenital stationary night blindness.

    PubMed

    Zeitz, Christina; Jacobson, Samuel G; Hamel, Christian P; Bujakowska, Kinga; Neuillé, Marion; Orhan, Elise; Zanlonghi, Xavier; Lancelot, Marie-Elise; Michiels, Christelle; Schwartz, Sharon B; Bocquet, Béatrice; Antonio, Aline; Audier, Claire; Letexier, Mélanie; Saraiva, Jean-Paul; Luu, Tien D; Sennlaub, Florian; Nguyen, Hoan; Poch, Olivier; Dollfus, Hélène; Lecompte, Odile; Kohl, Susanne; Sahel, José-Alain; Bhattacharya, Shomi S; Audo, Isabelle

    2013-01-10

    Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder. Two forms can be distinguished clinically: complete CSNB (cCSNB) and incomplete CSNB. Individuals with cCSNB have visual impairment under low-light conditions and show a characteristic electroretinogram (ERG). The b-wave amplitude is severely reduced in the dark-adapted state of the ERG, representing abnormal function of ON bipolar cells. Furthermore, individuals with cCSNB can show other ocular features such as nystagmus, myopia, and strabismus and can have reduced visual acuity and abnormalities of the cone ERG waveform. The mode of inheritance of this form can be X-linked or autosomal recessive, and the dysfunction of four genes (NYX, GRM6, TRPM1, and GPR179) has been described so far. Whole-exome sequencing in one simplex cCSNB case lacking mutations in the known genes led to the identification of a missense mutation (c.983G>A [p.Cys328Tyr]) and a nonsense mutation (c.1318C>T [p.Arg440(∗)]) in LRIT3, encoding leucine-rich-repeat (LRR), immunoglobulin-like, and transmembrane-domain 3 (LRIT3). Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G [p.Ser384(∗)]) and a deletion predicted to lead to a premature stop codon (c.1538_1539del [p.Ser513Cysfs(∗)59]) in the same gene. Human LRIT3 antibody staining revealed in the outer plexiform layer of the human retina a punctate-labeling pattern resembling the dendritic tips of bipolar cells; similar patterns have been observed for other proteins implicated in cCSNB. The exact role of this LRR protein in cCSNB remains to be elucidated.

  4. The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12.

    PubMed Central

    Moreira, E S; Vainzof, M; Marie, S K; Sertié, A L; Zatz, M; Passos-Bueno, M R

    1997-01-01

    The group of autosomal recessive (AR) muscular dystrophies includes, among others, two main clinical entities, the limb-girdle muscular dystrophies (LGMDs) and the distal muscular dystrophies. The former are characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. This clinical heterogeneity has been demonstrated at the molecular level, since the genes for six AR forms have been cloned and/or have been mapped to 15q15.1 (LGMD2A), 2p12-16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D),4q12 (LGMD2E), and 5q33-34 (LGMD2F). The AR distal muscular dystrophies originally included two subgroups, Miyoshi myopathy, characterized mainly by extremely elevated serum creatine kinase (CK) activity and by a dystrophic muscle pattern, and Nonaka myopathy, which is distinct from the others because of the normal to slightly elevated serum CK levels and a myopathic muscle pattern with rimmed vacuoles. With regard to our unclassified AR LGMD families, analysis of the affected sibs from one of them (family LG61) revealed some clinical and laboratory findings (early involvement of the distal muscles, mildly elevated serum CK levels, and rimmed vacuoles in muscle biopsies) that usually are not observed in the analysis of patients with LGMD2A-LGMD2F. In the present investigation, through a genomewide search in family LG61, we demonstrated linkage of the allele causing this form of muscular dystrophy to a 3-cM region on 17q11-12. We suggest that this form, which, interestingly, clinically resembles AR Kugelberg-Welander disease, should be classified as LGMD2G. In addition, our results indicate the existence of still another locus causing severe LGMD. Images Figure 1 PMID:9245996

  5. An easy test but a hard decision: ethical issues concerning non-invasive prenatal testing for autosomal recessive disorders

    PubMed Central

    Skirton, Heather; Goldsmith, Lesley; Chitty, Lyn S

    2015-01-01

    Prenatal testing based on cell-free fetal DNA in maternal serum is now possible for specific monogenic conditions, and studies have shown that the use of non-invasive testing is supported by prospective parents and health professionals. However, some ethical issues have been raised concerning informed consent and paternal rights. The objective of this study was to explore ethical aspects of the use of non-invasive prenatal diagnostic testing for autosomal recessive disorders. We used a qualitative cross-sectional design, based on Thematic Analysis, and recruited 27 individuals of reproductive age who were carriers of one of four conditions: thalassaemia, sickle cell disease, cystic fibrosis or spinal muscular atrophy. Data were collected via focus groups or interviews. Participants were aware of the potential for such tests to be viewed as routine and suggested that obtaining written consent and allowing time for consideration is needed to facilitate autonomous choice and informed consent. All participants felt that mothers should be able to request such tests, but fathers who declined carrier testing should be made aware that fetal test results may reveal their status. We suggest that a written record of consent for non-invasive prenatal diagnosis should be used as a standard to help reinforce the serious nature of the test results. Where the father's carrier status could be revealed through fetal testing, he should be made aware of this before the results are available. Health professionals should discuss with the pregnant woman the best way to manage unsought information about the father's carrier status to minimise family disruption. PMID:25351779

  6. Long-Term Clinical Outcome and Carrier Phenotype in Autosomal Recessive Hypophosphatemia Caused by a Novel DMP1 Mutation

    PubMed Central

    Mäkitie, Outi; Pereira, Renata C; Kaitila, Ilkka; Turan, Serap; Bastepe, Murat; Laine, Tero; Kröger, Heikki; Cole, William G; Jüppner, Harald

    2010-01-01

    Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets. © 2010 American Society for Bone and Mineral Research. PMID:20499351

  7. Mutations in ARL2BP, Encoding ADP-Ribosylation-Factor-Like 2 Binding Protein, Cause Autosomal-Recessive Retinitis Pigmentosa

    PubMed Central

    Davidson, Alice E.; Schwarz, Nele; Zelinger, Lina; Stern-Schneider, Gabriele; Shoemark, Amelia; Spitzbarth, Benjamin; Gross, Menachem; Laxer, Uri; Sosna, Jacob; Sergouniotis, Panagiotis I.; Waseem, Naushin H.; Wilson, Robert; Kahn, Richard A.; Plagnol, Vincent; Wolfrum, Uwe; Banin, Eyal; Hardcastle, Alison J.; Cheetham, Michael E.; Sharon, Dror; Webster, Andrew R.

    2013-01-01

    Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101−1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function. PMID:23849777

  8. Functional dissection of an AP-2 beta2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein.

    PubMed

    Mishra, Sanjay K; Keyel, Peter A; Edeling, Melissa A; Dupin, Amie L; Owen, David J; Traub, Linton M

    2005-05-13

    The autosomal recessive hypercholesterolemia (ARH) protein plays a critical role in regulating plasma low density lipoprotein (LDL) levels. Inherited defects in ARH lead to a hypercholesterolemia that closely phenocopies that caused by a defective LDL receptor. The elevated serum LDL-cholesterol levels typical of ARH patients and the pronounced accumulation of the LDL receptor at the cell surface of hepatocytes in ARH-null mice argue that ARH operates by promoting the internalization of the LDL receptor within clathrin-coated vesicles. ARH contains an amino-terminal phosphotyrosine-binding domain that associates physically with the LDL receptor internalization sequence and with phosphoinositides. The carboxyl-terminal half of ARH contains a clathrin-binding sequence and a separate AP-2 adaptor binding region providing a plausible mechanism for how ARH can act as an endocytic adaptor or CLASP (clathrin-associated sorting protein) to couple LDL receptors with the clathrin machinery. Because the interaction with AP-2 is highly selective for the independently folded appendage domain of the beta2 subunit, we have characterized the ARH beta2 appendage-binding sequence in detail. Unlike the known alpha appendage-binding motifs, ARH requires an extensive sequence tract to bind the beta appendage with comparably high affinity. A minimal 16-residue sequence functions autonomously and depends upon ARH residues Asp253, Phe259, Leu262, and Arg266. We suggested that biased beta subunit engagement by ARH and the only other beta2 appendage selective adaptor, beta-arrestin, promotes efficient incorporation of this mechanistically distinct subset of CLASPs into clathrin-coated buds.

  9. Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail.

    PubMed

    Dvir, Hay; Shah, Mehul; Girardi, Enrico; Guo, Lixia; Farquhar, Marilyn G; Zajonc, Dirk M

    2012-05-01

    Hypercholesterolemia, high serum cholesterol in the form of LDL, is a major risk factor for atherosclerosis. LDL is mostly degraded in the liver after its cellular internalization with the LDL receptor (LDLR). This clathrin-mediated endocytosis depends on the protein autosomal recessive hypercholesterolemia (ARH), which binds the LDLR cytoplasmic tail. Mutations in either the LDLR tail or in ARH lead to hypercholesterolemia and premature atherosclerosis. Despite the significance of this interaction for cholesterol homeostasis, no structure of either ARH or the LDLR tail is available to determine its molecular basis. We report the crystal structure at 1.37-Å resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY(0) internalization signal. Surprisingly, ARH interacts with a longer portion of the tail than previously recognized, which extends to I(-7)xF(-5)xNPxY(0)QK(+2). The LDLR tail assumes a unique "Hook"-like structure with a double β-turn conformation, which is accommodated in distinctive ARH structural determinants (i.e., an extended backbone hydrogen-bonding platform, three hydrophobic helical grooves, and a hydrophobic pocket for Y(0)). This unique complementarity differs significantly in related PTB proteins and may account for the unique physiological role of these partners in the hepatic uptake of cholesterol LDL. Moreover, the unusual hydrophobic pocket for Y(0) explains the distinctive ability of ARH to internalize proteins containing either FxNPxY(0) or FxNPxF(0) sequences. Biophysical measurements reveal how mutations associated with hypercholesterolemia destabilize ARH and its complex with LDLR and illuminate LDL internalization defects seen in patients.

  10. Telmisartan Ameliorates Fibrocystic Liver Disease in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

    PubMed Central

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M.; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  11. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.

    PubMed

    Abou Jamra, Rami; Philippe, Orianne; Raas-Rothschild, Annick; Eck, Sebastian H; Graf, Elisabeth; Buchert, Rebecca; Borck, Guntram; Ekici, Arif; Brockschmidt, Felix F; Nöthen, Markus M; Munnich, Arnold; Strom, Tim M; Reis, Andre; Colleaux, Laurence

    2011-06-10

    Intellectual disability inherited in an autosomal-recessive fashion represents an important fraction of severe cognitive-dysfunction disorders. Yet, the extreme heterogeneity of these conditions markedly hampers gene identification. Here, we report on eight affected individuals who were from three consanguineous families and presented with severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. Using a combination of autozygosity mapping and either Sanger sequencing of candidate genes or next-generation exome sequencing, we identified one mutation in each of three genes encoding adaptor protein complex 4 (AP4) subunits: a nonsense mutation in AP4S1 (NM_007077.3: c.124C>T, p.Arg42(∗)), a frameshift mutation in AP4B1 (NM_006594.2: c.487_488insTAT, p.Glu163_Ser739delinsVal), and a splice mutation in AP4E1 (NM_007347.3: c.542+1_542+4delGTAA, r.421_542del, p.Glu181Glyfs(∗)20). Adaptor protein complexes (AP1-4) are ubiquitously expressed, evolutionarily conserved heterotetrameric complexes that mediate different types of vesicle formation and the selection of cargo molecules for inclusion into these vesicles. Interestingly, two mutations affecting AP4M1 and AP4E1 have recently been found to cause cerebral palsy associated with severe intellectual disability. Combined with previous observations, these results support the hypothesis that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning and demonstrate the existence of a clinically recognizable syndrome due to deficiency of the AP4 complex.

  12. Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease.

    PubMed

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  13. Hypomorphic Mutations in PGAP2, Encoding a GPI-Anchor-Remodeling Protein, Cause Autosomal-Recessive Intellectual Disability

    PubMed Central

    Hansen, Lars; Tawamie, Hasan; Murakami, Yoshiko; Mang, Yuan; ur Rehman, Shoaib; Buchert, Rebecca; Schaffer, Stefanie; Muhammad, Safia; Bak, Mads; Nöthen, Markus M.; Bennett, Eric P.; Maeda, Yusuke; Aigner, Michael; Reis, André; Kinoshita, Taroh; Tommerup, Niels; Baig, Shahid Mahmood; Abou Jamra, Rami

    2013-01-01

    PGAP2 encodes a protein involved in remodeling the glycosylphosphatidylinositol (GPI) anchor in the Golgi apparatus. After synthesis in the endoplasmic reticulum (ER), GPI anchors are transferred to the proteins and are remodeled while transported through the Golgi to the cell membrane. Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been reported, and all are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and elevated alkaline phosphatase (ALP). We performed autozygosity mapping and ultra-deep sequencing followed by stringent filtering and identified two homozygous PGAP2 alterations, p.Tyr99Cys and p.Arg177Pro, in seven offspring with nonspecific autosomal-recessive intellectual disability from two consanguineous families. Rescue experiments with the altered proteins in PGAP2-deficient Chinese hamster ovary cell lines showed less expression of cell-surface GPI-anchored proteins DAF and CD59 than of the wild-type protein, substantiating the pathogenicity of the identified alterations. Furthermore, we observed a full rescue when we used strong promoters before the mutant cDNAs, suggesting a hypomorphic effect of the mutations. We report on alterations in the Golgi-located part of the GPI-anchor-biosynthesis pathway and extend the phenotypic spectrum of the GPI-anchor deficiencies to isolated intellectual disability with elevated ALP. GPI-anchor deficiencies can be interpreted within the concept of a disease family, and we propose that the severity of the phenotype is dependent on the location of the altered protein in the biosynthesis chain. PMID:23561846

  14. Whole-Exome Sequencing Identifies LRIT3 Mutations as a Cause of Autosomal-Recessive Complete Congenital Stationary Night Blindness

    PubMed Central

    Zeitz, Christina; Jacobson, Samuel G.; Hamel, Christian P.; Bujakowska, Kinga; Neuillé, Marion; Orhan, Elise; Zanlonghi, Xavier; Lancelot, Marie-Elise; Michiels, Christelle; Schwartz, Sharon B.; Bocquet, Béatrice; Antonio, Aline; Audier, Claire; Letexier, Mélanie; Saraiva, Jean-Paul; Luu, Tien D.; Sennlaub, Florian; Nguyen, Hoan; Poch, Olivier; Dollfus, Hélène; Lecompte, Odile; Kohl, Susanne; Sahel, José-Alain; Bhattacharya, Shomi S.; Audo, Isabelle

    2013-01-01

    Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder. Two forms can be distinguished clinically: complete CSNB (cCSNB) and incomplete CSNB. Individuals with cCSNB have visual impairment under low-light conditions and show a characteristic electroretinogram (ERG). The b-wave amplitude is severely reduced in the dark-adapted state of the ERG, representing abnormal function of ON bipolar cells. Furthermore, individuals with cCSNB can show other ocular features such as nystagmus, myopia, and strabismus and can have reduced visual acuity and abnormalities of the cone ERG waveform. The mode of inheritance of this form can be X-linked or autosomal recessive, and the dysfunction of four genes (NYX, GRM6, TRPM1, and GPR179) has been described so far. Whole-exome sequencing in one simplex cCSNB case lacking mutations in the known genes led to the identification of a missense mutation (c.983G>A [p.Cys328Tyr]) and a nonsense mutation (c.1318C>T [p.Arg440∗]) in LRIT3, encoding leucine-rich-repeat (LRR), immunoglobulin-like, and transmembrane-domain 3 (LRIT3). Subsequent Sanger sequencing of 89 individuals with CSNB identified another cCSNB case harboring a nonsense mutation (c.1151C>G [p.Ser384∗]) and a deletion predicted to lead to a premature stop codon (c.1538_1539del [p.Ser513Cysfs∗59]) in the same gene. Human LRIT3 antibody staining revealed in the outer plexiform layer of the human retina a punctate-labeling pattern resembling the dendritic tips of bipolar cells; similar patterns have been observed for other proteins implicated in cCSNB. The exact role of this LRR protein in cCSNB remains to be elucidated. PMID:23246293

  15. Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis.

    PubMed

    Palagano, Eleonora; Blair, Harry C; Pangrazio, Alessandra; Tourkova, Irina; Strina, Dario; Angius, Andrea; Cuccuru, Gianmauro; Oppo, Manuela; Uva, Paolo; Van Hul, Wim; Boudin, Eveline; Superti-Furga, Andrea; Faletra, Flavio; Nocerino, Agostino; Ferrari, Matteo C; Grappiolo, Guido; Monari, Marta; Montanelli, Alessandro; Vezzoni, Paolo; Villa, Anna; Sobacchi, Cristina

    2015-10-01

    Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease with genotypic and phenotypic heterogeneity, sometimes translating into delayed diagnosis and treatment. In particular, cases of intermediate severity often constitute a diagnostic challenge and represent good candidates for exome sequencing. Here, we describe the tortuous path to identification of the molecular defect in two siblings, in which osteopetrosis diagnosed in early childhood followed a milder course, allowing them to reach the adult age in relatively good conditions with no specific therapy. No clearly pathogenic mutation was identified either with standard amplification and resequencing protocols or with exome sequencing analysis. While evaluating the possible impact of a 3'UTR variant on the TCIRG1 expression, we found a novel single nucleotide change buried in the middle of intron 15 of the TCIRG1 gene, about 150 nucleotides away from the closest canonical splice site. By sequencing a number of independent cDNA clones covering exons 14 to 17, we demonstrated that this mutation reduced splicing efficiency but did not completely abrogate the production of the normal transcript. Prompted by this finding, we sequenced the same genomic region in 33 patients from our unresolved ARO cohort and found three additional novel single nucleotide changes in a similar location and with a predicted disruptive effect on splicing, further confirmed in one of them at the transcript level. Overall, we identified an intronic region in TCIRG1 that seems to be particularly prone to splicing mutations, allowing the production of a small amount of protein sufficient to reduce the severity of the phenotype usually associated with TCIRG1 defects. On this basis, we would recommend including TCIRG1 not only in the molecular work-up of severe infantile osteopetrosis but also in intermediate cases and carefully evaluating the possible effects of intronic changes.

  16. Autosomal Recessive Inheritance

    MedlinePlus

    ... Courier services use: Rockville, MD 20852) 301-451-2020 Research at NEI Office of the Scientific Director ... Eye Disease Education Program Glaucoma Education Program Low Vision Education Program Hispanic/Latino Program Vision and Aging ...

  17. Syndrome of mental retardation, seizures, hypotonic cerebral palsy and megalocorneae, recessively inherited.

    PubMed

    Neuhäuser, G; Kaveggia, E G; France, T D; Opitz, J M

    1975-07-01

    A previously apparently undescribed "syndrome" is reported in which megalocornea and iris anomalies are accompanied by minor facial and skeletal anomalies, severe mental retardation, hypotonia, and seizures. The condition was found in 3 siblings of one family and in 4 sporadic cases; it is thought to be recessively inherited.

  18. Unmasking an autosomal recessive disorder by a deletion in the DiGeorge/Velo-cardio-facial chromosome region (DGCR) in 22q11.2

    SciTech Connect

    Budarf, M.L.; Michaud, D.; Emanuel, B.

    1994-09-01

    Unmasking an autosomal recessive disorder by constitutional hemizygosity is well documented for the embryonal tumors RB and WAGR, where the second hit is a somatic event. Few deletion-mediated recessive conditions have been reported in patients with germline mutations. The major platelet receptor for von Willebrand factor, Glycoprotein Ib (GpIb), is a complex of two plasma membrane glycoproteins, Ib{alpha} and Ib{beta}, covalently linked by disulfide bonds. Defects in this receptor have been associated with the rare congenital autosomal recessive bleeding disorder, Bernard-Soulier syndrome (BSS). BSS is characterized by prolonged bleeding times, thrombocytopenia and very large platelets. The GpIb{beta} gene has been cloned and we have mapped it within the DGCR. We have identified a patient with phenotypic features of both BSS and VCFS. The patient was referred for 22q11-deletion FISH studies because of a conventricular VSD and mild dysmorphia. FISH with the N25 DiGeorge cosmid demonstrated a deletion in 22q11.2. Western blot analysis of the patient`s platelet proteins demonstrates a complete absence of GpIb{beta}. We suggest that haploinsufficiency for the DGCR in this patient unmasks a mutation in the remaining GpIb{beta} allele, resulting in manifestations of BSS. This mechanism, haploinsufficiency coupled with a mutation of the {open_quotes}normal{close_quotes} chromosome, might explain some of the phenotypic variability seen amongst patients with 22q11.2 microdeletions. These results further suggest that patients with contiguous gene deletion syndromes are at increased risk for autosomal recessive disorders and that they provide the opportunity to {open_quotes}map{close_quotes}disease loci.

  19. Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets

    PubMed Central

    Wacker, Michael J.; Touchberry, Chad D.; Silswal, Neerupma; Brotto, Leticia; Elmore, Chris J.; Bonewald, Lynda F.; Andresen, Jon; Brotto, Marco

    2016-01-01

    Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well-characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL–slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2α or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary

  20. Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets.

    PubMed

    Wacker, Michael J; Touchberry, Chad D; Silswal, Neerupma; Brotto, Leticia; Elmore, Chris J; Bonewald, Lynda F; Andresen, Jon; Brotto, Marco

    2016-01-01

    Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well-characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL-slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2α or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary, these

  1. Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

    PubMed

    Vermeer, Sascha; Hoischen, Alexander; Meijer, Rowdy P P; Gilissen, Christian; Neveling, Kornelia; Wieskamp, Nienke; de Brouwer, Arjan; Koenig, Michel; Anheim, Mathieu; Assoum, Mirna; Drouot, Nathalie; Todorovic, Slobodanka; Milic-Rasic, Vedrana; Lochmüller, Hanns; Stevanin, Giovanni; Goizet, Cyril; David, Albert; Durr, Alexandra; Brice, Alexis; Kremer, Berry; van de Warrenburg, Bart P C; Schijvenaars, Mascha M V A P; Heister, Angelien; Kwint, Michael; Arts, Peer; van der Wijst, Jenny; Veltman, Joris; Kamsteeg, Erik-Jan; Scheffer, Hans; Knoers, Nine

    2010-12-10

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations provide incomplete coverage for genotyping of patients. By combining SNP array-based linkage analysis and targeted resequencing of relevant sequences in the linkage interval with the use of next-generation sequencing technology, we identified a mutation in a gene and have shown its association with autosomal-recessive cerebellar ataxia. In a Dutch consanguineous family with three affected siblings a homozygous 12.5 Mb region on chromosome 3 was targeted by array-based sequence capture. Prioritization of all detected sequence variants led to four candidate genes, one of which contained a variant with a high base pair conservation score (phyloP score: 5.26). This variant was a leucine-to-arginine substitution in the DUF 590 domain of a 16K transmembrane protein, a putative calcium-activated chloride channel encoded by anoctamin 10 (ANO10). The analysis of ANO10 by Sanger sequencing revealed three additional mutations: a homozygous mutation (c.1150_1151del [p.Leu384fs]) in a Serbian family and a compound-heterozygous splice-site mutation (c.1476+1G>T) and a frameshift mutation (c.1604del [p.Leu535X]) in a French family. This illustrates the power of using initial homozygosity mapping with next-generation sequencing technology to identify genes involved in autosomal-recessive diseases. Moreover, identifying a putative calcium-dependent chloride channel involved in cerebellar ataxia adds another pathway to the list of pathophysiological mechanisms that may cause cerebellar ataxia.

  2. Two siblings with early onset fetal akinesia deformation sequence and hydranencephaly: further evidence for autosomal recessive inheritance of hydranencephaly, fowler type.

    PubMed

    Witters, I; Moerman, Ph; Devriendt, K; Braet, P; Van Schoubroeck, D; Van Assche, F A; Fryns, J P

    2002-02-15

    We report a 13-week-old female fetus with early onset fetal akinesia deformation sequence (FADS) and hydranencephaly. In a previous pregnancy, the same ultrasonographic findings were noted at 13 weeks. Fetopathological examination of both female fetuses confirmed FADS with severe arthogryposis, multiple pterygia, and muscular hypoplasia. Neuropathological examination showed massive cystic dilatation of the cerebral ventricles (hydranencephaly) with calcification of the basal ganglion and brain stem and a proliferative vasculopathy throughout the central nervous system. The findings in the two female siblings document the earliest echographic diagnosis of hydranencephaly, Fowler type, and this observation further supports autosomal recessive inheritance of this distinct type of hydranencephaly.

  3. Autosomal recessive hyper IgM syndrome associated with activation-induced cytidine deaminase gene in three Turkish siblings presented with tuberculosis lymphadenitis - Case report.

    PubMed

    Patiroglu, Turkan; Akar, H Haluk; van der Burg, Mirjam; Unal, Ekrem

    2015-09-01

    The hyper-immunoglobulin M (HIGM) syndrome is a heterogeneous group of genetic disorders characterized by recurrent infections, decreased serum levels of immunoglobulin G (IgG) and IgA, and normal/increased serum levels of IgM. Herein, we describe three Turkish siblings with HIGM syndrome who had a homozygous missense mutation (c.70C>T, p.Arg24Trp) in the activation-induced cytidine deaminase gene which results in autosomal recessive HIGM syndrome. Two of the siblings, sibling 1 and sibling 3, presented with cervical deep abscess and cervical tuberculosis lymphadenitis, respectively.

  4. Refining the map and defining flanking markers of the gene for autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12

    SciTech Connect

    Muecher, G.; Wirth, B.; Zerres, K.

    1994-12-01

    Autosomal recessive polycystic kidney disease (ARPKD) is one of the most important hereditary nephropathies in childhood. The reported incidence is 1:6,000 - 1:40,000 live births. We recently mapped the gene for ARPKD to chromosome 6p21-cen by linkage analysis. In a more extensive study, we analyzed two additional microsatellite markers of the region 6p21 in 12 multiplex and 4 simplex ARPKD families, which have previously been published by Zerres et al. (1994). Because of additional typing, more families have become informative for single markers. 12 refs., 2 figs., 2 tabs.

  5. Usher Syndrome 1D and Nonsyndromic Autosomal Recessive Deafness DFNB12 Are Caused by Allelic Mutations of the Novel Cadherin-Like Gene CDH23

    PubMed Central

    Bork, Julie M.; Peters, Linda M.; Riazuddin, Saima; Bernstein, Steve L.; Ahmed, Zubair M.; Ness, Seth L.; Polomeno, Robert; Ramesh, Arabandi; Schloss, Melvin; Srisailpathy, C. R. Srikumari; Wayne, Sigrid; Bellman, Susan; Desmukh, Dilip; Ahmed, Zahoor; Khan, Shaheen N.; Kaloustian, Vazken M. Der; Li, X. Cindy; Lalwani, Anil; Riazuddin, Sheikh; Bitner-Glindzicz, Maria; Nance, Walter E.; Liu, Xue-Zhong; Wistow, Graeme; Smith, Richard J. H.; Griffith, Andrew J.; Wilcox, Edward R.; Friedman, Thomas B.; Morell, Robert J.

    2001-01-01

    Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, ∼0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA. PMID:11090341

  6. Magnetic resonance microscopy of renal and biliary abnormalities in excised tissues from a mouse model of autosomal recessive polycystic kidney disease.

    PubMed

    Lee, Choong H; O'Connor, Amber K; Yang, Chaozhe; Tate, Joshua M; Schoeb, Trenton R; Flint, Jeremy J; Blackband, Stephen J; Guay-Woodford, Lisa M

    2015-08-01

    Polycystic kidney disease (PKD) is transmitted as either an autosomal dominant or recessive trait and is a major cause of renal failure and liver fibrosis. The cpk mouse model of autosomal recessive PKD (ARPKD) has been extensively characterized using standard histopathological techniques after euthanasia. In the current study, we sought to validate magnetic resonance microscopy (MRM) as a robust tool for assessing the ARPKD phenotype. We used MRM to evaluate the liver and kidney of wild-type and cpk animals at resolutions <100 μm and generated three-dimensional (3D) renderings for pathological evaluation. Our study demonstrates that MRM is an excellent method for evaluating the complex, 3D structural defects in this ARPKD mouse model. We found that MRM was equivalent to water displacement in assessing kidney volume. Additionally, using MRM we demonstrated for the first time that the cpk liver exhibits less extensive ductal arborization, that it was reduced in volume, and that the ductal volume was disproportionately smaller. Histopathology indicates that this is a consequence of bile duct malformation. With its reduced processing time, volumetric information, and 3D capabilities, MRM will be a useful tool for future in vivo and longitudinal studies of disease progression in ARPKD. In addition, MRM will provide a unique tool to determine whether the human disease shares the newly appreciated features of the murine biliary phenotype.

  7. Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

    PubMed Central

    Thevenon, Julien; Milh, Mathieu; Feillet, François; St-Onge, Judith; Duffourd, Yannis; Jugé, Clara; Roubertie, Agathe; Héron, Delphine; Mignot, Cyril; Raffo, Emmanuel; Isidor, Bertrand; Wahlen, Sandra; Sanlaville, Damien; Villeneuve, Nathalie; Darmency-Stamboul, Véronique; Toutain, Annick; Lefebvre, Mathilde; Chouchane, Mondher; Huet, Frédéric; Lafon, Arnaud; de Saint Martin, Anne; Lesca, Gaetan; El Chehadeh, Salima; Thauvin-Robinet, Christel; Masurel-Paulet, Alice; Odent, Sylvie; Villard, Laurent; Philippe, Christophe; Faivre, Laurence; Rivière, Jean-Baptiste

    2014-01-01

    Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy. PMID:24995870

  8. Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life.

    PubMed

    Thevenon, Julien; Milh, Mathieu; Feillet, François; St-Onge, Judith; Duffourd, Yannis; Jugé, Clara; Roubertie, Agathe; Héron, Delphine; Mignot, Cyril; Raffo, Emmanuel; Isidor, Bertrand; Wahlen, Sandra; Sanlaville, Damien; Villeneuve, Nathalie; Darmency-Stamboul, Véronique; Toutain, Annick; Lefebvre, Mathilde; Chouchane, Mondher; Huet, Frédéric; Lafon, Arnaud; de Saint Martin, Anne; Lesca, Gaetan; El Chehadeh, Salima; Thauvin-Robinet, Christel; Masurel-Paulet, Alice; Odent, Sylvie; Villard, Laurent; Philippe, Christophe; Faivre, Laurence; Rivière, Jean-Baptiste

    2014-07-03

    Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.

  9. Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population.

    PubMed

    Zhou, Yu; Saikia, Bibhuti B; Jiang, Zhilin; Zhu, Xiong; Liu, Yuqing; Huang, Lulin; Kim, Ramasamy; Yang, Yin; Qu, Chao; Hao, Fang; Gong, Bo; Tai, Zhengfu; Niu, Lihong; Yang, Zhenglin; Sundaresan, Periasamy; Zhu, Xianjun

    2015-10-01

    Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 50 genes. To identify genetic mutations underlying autosomal recessive RP (arRP), we performed whole-exome sequencing study on two consanguineous marriage Indian families (RP-252 and RP-182) and 100 sporadic RP patients. Here we reported novel mutation in FAM161A in RP-252 and RP-182 with two patients affected with RP in each family. The FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. By whole-exome sequencing we identified several homozygous genomic regions, one of which included the recently identified FAM161A gene mutated in RP28-linked arRP. Sequencing analysis revealed the presence of a novel homozygous frameshift mutation p.R592FsX2 in both patients of family RP-252 and family RP-182. In 100 sporadic Indian RP patients, this novel homozygous frameshift mutation p.R592FsX2 was identified in one sporadic patient ARRP-S-I-46 by whole-exome sequencing and validated by Sanger sequencing. Meanwhile, this homozygous frameshift mutation was absent in 1000 ethnicity-matched control samples screened by direct Sanger sequencing. In conclusion, we identified a novel homozygous frameshift mutations of RP28-linked RP gene FAM161A in Indian population.

  10. Localization of a Gene for Autosomal Recessive Distal Renal Tubular Acidosis with Normal Hearing (rdRTA2) to 7q33-34

    PubMed Central

    Karet, Fiona E.; Finberg, Karin E.; Nayir, Ahmet; Bakkaloglu, Aysin; Ozen, Seza; Hulton, Sally A.; Sanjad, Sami A.; Al-Sabban, Essam A.; Medina, Juan F.; Lifton, Richard P.

    1999-01-01

    Summary Failure of distal nephrons to excrete excess acid results in the “distal renal tubular acidoses” (dRTA). Early childhood features of autosomal recessive dRTA include severe metabolic acidosis with inappropriately alkaline urine, poor growth, rickets, and renal calcification. Progressive bilateral sensorineural hearing loss (SNHL) is evident in approximately one-third of patients. We have recently identified mutations in ATP6B1, encoding the B-subunit of the collecting-duct apical proton pump, as a cause of recessive dRTA with SNHL. We now report the results of genetic analysis of 13 kindreds with recessive dRTA and normal hearing. Analysis of linkage and molecular examination of ATP6B1 indicated that mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a genomewide linkage search for loci underlying this trait. The results strongly supported linkage with locus heterogeneity to a segment of 7q33-34, yielding a maximum multipoint LOD score of 8.84 with 68% of kindreds linked. The LOD-3 support interval defines a 14-cM region flanked by D7S500 and D7S688. That 4 of these 13 kindreds do not support linkage to rdRTA2 and ATP6B1 implies the existence of at least one additional dRTA locus. These findings establish that genes causing recessive dRTA with normal and impaired hearing are different, and they identify, at 7q33-34, a new locus, rdRTA2, for recessive dRTA with normal hearing. PMID:10577919

  11. Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism.

    PubMed

    Bowl, Michael R; Mirczuk, Samantha M; Grigorieva, Irina V; Piret, Sian E; Cranston, Treena; Southam, Lorraine; Allgrove, Jeremy; Bahl, Shailini; Brain, Caroline; Loughlin, John; Mughal, Zulf; Ryan, Fiona; Shaw, Nick; Thakker, Yogini V; Tiosano, Dov; Nesbit, M Andrew; Thakker, Rajesh V

    2010-05-15

    GCMB is a member of the small transcription factor family GCM (glial cells missing), which are important regulators of development, present in vertebrates and some invertebrates. In man, GCMB encodes a 506 amino acid parathyroid gland-specific protein, mutations of which have been reported to cause both autosomal dominant and autosomal recessive hypoparathyroidism. We ascertained 18 affected individuals from 12 families with autosomal recessive hypoparathyroidism and have investigated them for GCMB abnormalities. Four different homozygous germline mutations were identified in eight families that originate from the Indian Subcontinent. These consisted of a novel nonsense mutation R39X; a missense mutation, R47L in two families; a novel missense mutation, R110W; and a novel frameshifting deletion, I298fsX307 in four families. Haplotype analysis, using polymorphic microsatellites from chromosome 6p23-24, revealed that R47L and I298fsX307 mutations arose either as ancient founders, or recurrent de novo mutations. Functional studies including: subcellular localization studies, EMSAs and luciferase-reporter assays, were undertaken and these demonstrated that: the R39X mutant failed to localize to the nucleus; the R47L and R110W mutants both lost DNA-binding ability; and the I298fsX307 mutant had reduced transactivational ability. In order to gain further insights, we undertook 3D-modeling of the GCMB DNA-binding domain, which revealed that the R110 residue is likely important for the structural integrity of helix 2, which forms part of the GCMB/DNA binding interface. Thus, our results, which expand the spectrum of hypoparathyroidism-associated GCMB mutations, help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor.

  12. Nonsyndromic autosomal recessive deafness is linked to the DFNB1 locus in a large inbred Bedouin family from Israel

    SciTech Connect

    Scott, D.A.; Sheffield, V.C.; Stone, E.M.

    1995-10-01

    Nonsyndromic deafness accounts for {approximately}70% of all genetically determined deafness. Several types of nonsyndromic deafness, with a variety of inheritance patterns, have been genetically linked, including dominant, recessive and X-linked forms. Two of these forms - DFNA3, a dominant form causing moderate to severe hearing loss, predominantly in the high frequencies, and DFNB1, a recessive form causing profound, prelingual, neurosensory deafness affecting all frequencies - have been linked to the same pericentromeric region of chromosome 13. This finding is equally compatible with (1) the existence two closely linked deafness genes, (2) different mutations within a single deafness gene, and (3) a single mutation in a single gene that behaves differently in different genetic backgrounds. 12 refs., 2 figs., 1 tab.

  13. Biallelic truncating mutations in FMN2, encoding the actin-regulatory protein Formin 2, cause nonsyndromic autosomal-recessive intellectual disability.

    PubMed

    Law, Rosalind; Dixon-Salazar, Tracy; Jerber, Julie; Cai, Na; Abbasi, Ansar A; Zaki, Maha S; Mittal, Kirti; Gabriel, Stacey B; Rafiq, Muhammad Arshad; Khan, Valeed; Nguyen, Maria; Ali, Ghazanfar; Copeland, Brett; Scott, Eric; Vasli, Nasim; Mikhailov, Anna; Khan, Muhammad Nasim; Andrade, Danielle M; Ayaz, Muhammad; Ansar, Muhammad; Ayub, Muhammad; Vincent, John B; Gleeson, Joseph G

    2014-12-04

    Dendritic spines represent the major site of neuronal activity in the brain; they serve as the receiving point for neurotransmitters and undergo rapid activity-dependent morphological changes that correlate with learning and memory. Using a combination of homozygosity mapping and next-generation sequencing in two consanguineous families affected by nonsyndromic autosomal-recessive intellectual disability, we identified truncating mutations in formin 2 (FMN2), encoding a protein that belongs to the formin family of actin cytoskeleton nucleation factors and is highly expressed in the maturing brain. We found that FMN2 localizes to punctae along dendrites and that germline inactivation of mouse Fmn2 resulted in animals with decreased spine density; such mice were previously demonstrated to have a conditioned fear-learning defect. Furthermore, patient neural cells derived from induced pluripotent stem cells showed correlated decreased synaptic density. Thus, FMN2 mutations link intellectual disability either directly or indirectly to the regulation of actin-mediated synaptic spine density.

  14. Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome.

    PubMed

    Aziz, Abdul; Raza, Syed I; Ali, Salman; Ahmad, Wasim

    2016-01-01

    Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome.

  15. The search for mutations in the gene for the beta subunit of the cGMP phosphodiesterase (PDEB) in patients with autosomal recessive retinitis pigmentosa

    SciTech Connect

    Riess, O.; Weber, B.; Hayden, M.R. ); Noerremoelle, A. ); Musarella, M.A. )

    1992-10-01

    The finding of a mutation in the beta subunit of the cyclic GMP (cGMP) phosphodiesterase gene causing retinal degeneration in mice (the Pdeb gene) prompted a search for disease-causing mutations in the human phosphodiesterase gene (PDEB gene) in patients with retinitis pigmentosa. All 22 exons including 196 bp of the 5[prime] region of the PDEB gene have been assessed for mutations by using single-strand conformational polymorphism analysis in 14 patients from 13 unrelated families with autosomal recessive retinitis pigmentosa (ARRP). No disease-causing mutations were found in this group of affected individuals of seven different ancestries. However, a frequent intronic and two exonic polymorphisms (Leu[sup 489][yields]Gln and Gly[sup 842][yields]Gly) were identified. Segregation analysis using these polymorphic sites excludes linkage of ARRP to the PDEB gene in a family with two affected children. 43 refs., 3 figs., 2 tabs.

  16. Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features.

    PubMed

    Tüysüz, Beyhan; Bilguvar, Kaya; Koçer, Naci; Yalçınkaya, Cengiz; Çağlayan, Okay; Gül, Ece; Sahin, Sezgin; Çomu, Sinan; Günel, Murat

    2014-07-01

    Adaptor protein complex-4 (AP4) is a component of intracellular transportation of proteins, which is thought to have a unique role in neurons. Recently, mutations affecting all four subunits of AP4 (AP4M1, AP4E1, AP4S1, and AP4B1) have been found to cause similar autosomal recessive phenotype consisting of tetraplegic cerebral palsy and intellectual disability. The aim of this study was analyzing AP4 genes in three new families with this phenotype, and discussing their clinical findings with an emphasis on neuroimaging and facial features. Using homozygosity mapping followed by whole-exome sequencing, we identified two novel homozygous mutations in AP4M1 and a homozygous deletion in AP4B1 in three pairs of siblings. Spastic tetraplegia, microcephaly, severe intellectual disability, limited speech, and stereotypic laughter were common findings in our patients. All patients also had similar facial features consisting of coarse and hypotonic face, bitemporal narrowing, bulbous nose with broad nasal ridge, and short philtrum which were not described in patients with AP4M1 and AP4B1 mutations previously. The patients presented here and previously with AP4M1, AP4B1, and AP4E1 mutations shared brain abnormalities including asymmetrical ventriculomegaly, thin splenium of the corpus callosum, and reduced white matter volume. The patients also had hippocampal globoid formation and thin hippocampus. In conclusion, disorders due to mutations in AP4 complex have similar neurological, facial, and cranial imaging findings. Thus, these four genes encoding AP4 subunits should be screened in patients with autosomal recessive spastic tetraplegic cerebral palsy, severe intellectual disability, and stereotypic laughter, especially with the described facial and cranial MRI features.

  17. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.

    PubMed

    Sly, W S; Whyte, M P; Sundaram, V; Tashian, R E; Hewett-Emmett, D; Guibaud, P; Vainsel, M; Baluarte, H J; Gruskin, A; Al-Mosawi, M

    1985-07-18

    Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. In 1983, we reported a deficiency of carbonic anhydrase II, one of the isozymes of carbonic anhydrase, in three sisters with this disorder. We now describe our study of 18 similarly affected patients with this syndrome in 11 unrelated families of different geographic and ethnic origins. Virtual absence of the carbonic anhydrase II peak on high-performance liquid chromatography, of the esterase and carbon dioxide hydratase activities of carbonic anhydrase II, and of immunoprecipitable isozyme II was demonstrated on extracts of erythrocyte hemolysates from all patients studied. Reduced levels of isozyme II were found in obligate heterozygotes. These observations demonstrate the generality of the findings that we reported earlier in one family and provide further evidence that a deficiency of carbonic anhydrase II is the enzymatic basis for the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. We also summarize the clinical findings in these families, propose mechanisms by which a deficiency of carbonic anhydrase II could produce this metabolic disorder of bone, kidney, and brain, and discuss the clinical evidence for genetic heterogeneity in patients from different kindreds with this inborn error of metabolism.

  18. Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta

    PubMed Central

    Parry, David A.; Mighell, Alan J.; El-Sayed, Walid; Shore, Roger C.; Jalili, Ismail K.; Dollfus, Hélène; Bloch-Zupan, Agnes; Carlos, Roman; Carr, Ian M.; Downey, Louise M.; Blain, Katharine M.; Mansfield, David C.; Shahrabi, Mehdi; Heidari, Mansour; Aref, Parissa; Abbasi, Mohsen; Michaelides, Michel; Moore, Anthony T.; Kirkham, Jennifer; Inglehearn, Chris F.

    2009-01-01

    The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a positional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal transport in visual function and biomineralization. PMID:19200525

  19. Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly.

    PubMed

    Breuss, Martin W; Sultan, Tipu; James, Kiely N; Rosti, Rasim O; Scott, Eric; Musaev, Damir; Furia, Bansri; Reis, André; Sticht, Heinrich; Al-Owain, Mohammed; Alkuraya, Fowzan S; Reuter, Miriam S; Abou Jamra, Rami; Trotta, Christopher R; Gleeson, Joseph G

    2016-07-07

    The tRNA splicing endonuclease is a highly evolutionarily conserved protein complex, involved in the cleavage of intron-containing tRNAs. In human it consists of the catalytic subunits TSEN2 and TSEN34, as well as the non-catalytic TSEN54 and TSEN15. Recessive mutations in the corresponding genes of the first three are known to cause pontocerebellar hypoplasia (PCH) types 2A-C, 4, and 5. Here, we report three homozygous TSEN15 variants that cause a milder version of PCH2. The affected individuals showed progressive microcephaly, delayed developmental milestones, intellectual disability, and, in two out of four cases, epilepsy. None, however, displayed the central visual failure seen in PCH case subjects where other subunits of the TSEN are mutated, and only one was affected by the extensive motor defects that are typical in other forms of PCH2. The three amino acid substitutions impacted the protein level of TSEN15 and the stoichiometry of the interacting subunits in different ways, but all resulted in an almost complete loss of in vitro tRNA cleavage activity. Taken together, our results demonstrate that mutations in any known subunit of the TSEN complex can cause PCH and progressive microcephaly, emphasizing the importance of its function during brain development.

  20. SLC3A1 and SLC7A9 Mutations in Autosomal Recessive or Dominant Canine Cystinuria: A New Classification System

    PubMed Central

    Brons, A.-K.; Henthorn, P. S.; Raj, K.; Fitzgerald, C. A.; Liu, J.; Sewell, A. C.; Giger, U.

    2013-01-01

    Background Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. Hypothesis/Objectives To determine urinary cystine concentrations, inheritance and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Animals Mixed and purebred Labrador Retrievers (n=6), Australian Cattle Dogs (6), Miniature Pinschers (4) and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Methods Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. Results In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed specific DNA tests were developed, but the prevalence of each mutation remains unknown. Conclusions and clinical importance These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds. PMID:24001348

  1. Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome.

    PubMed

    Cabral, Rita M; Kurban, Mazen; Wajid, Muhammad; Shimomura, Yutaka; Petukhova, Lynn; Christiano, Angela M

    2012-04-01

    Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis. Using whole-genome homozygozity mapping and whole-exome sequencing, we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A. CHST8 encodes a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1), which we show by immunofluorescence staining to be expressed throughout normal epidermis. A colorimetric assay for total sulfated glycosaminoglycan (GAG) quantification, comparing human keratinocytes (CCD1106 KERTr) expressing wild type and mutant recombinant GalNAc4-ST1, revealed decreased levels of total sulfated GAGs in cells expressing mutant GalNAc4-ST1, suggesting loss of function. Western blotting revealed lower expression levels of mutant recombinant GalNAc4-ST1 compared to wild type, suggesting that accelerated degradation may result in loss of function, leading to PSS type A. This is the first report describing a mutation as the cause of PSS type A.

  2. The mapping of DFNB62, a new locus for autosomal recessive non-syndromic hearing impairment, to chromosome 12p13.2-p11.23.

    PubMed

    Ali, G; Santos, R L P; John, P; Wambangco, M A L; Lee, K; Ahmad, W; Leal, Sm

    2006-05-01

    Autosomal recessive non-syndromic hearing impairment (ARNSHI) is the most common form of prelingual inherited hearing impairment (HI). Here is described the mapping of a novel ARNSHI locus in a consanguineous Pakistani family with profound congenital HI. Two-point and multipoint linkage analyses were performed for the genome scan and fine mapping markers. Haplotypes were constructed to determine the region of homozygosity. At theta = 0, the maximum two-point LOD score of 4.0 was obtained at marker AAC040. A maximum multipoint LOD score of 5.3 was derived at marker D12S320, with the three-unit support interval demarcated by D12S89 and D12S1042. The region of homozygosity is flanked by markers D12S358 and D12S1042, which corresponds to 22.4 cM according to the Rutgers combined linkage-physical map of the human genome and spans 15.0 Mb on the sequence-based physical map. A novel ARNSHI locus DFNB62 was mapped to chromosome 12p13.2-p11.23. DFNB62 represents the second ARNSHI locus to map to chromosome 12.

  3. Genetic Linkage Analysis of DFNB3, DFNB9 and DFNB21 Loci in GJB2 Negative Families with Autosomal Recessive Non-syndromic Hearing Loss

    PubMed Central

    MASOUDI, Marjan; AHANGARI, Najmeh; POURSADEGH ZONOUZI, Ali Akbar; POURSADEGH ZONOUZI, Ahmad; NEJATIZADEH, Azim

    2016-01-01

    Background: Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common hereditary form of deafness, and exhibits a great deal of genetic heterogeneity. So far, more than seventy various DFNB loci have been mapped for ARNSHL by linkage analysis. The contribution of three common DFNB loci including DFNB3, DFNB9, DFNB21 and gap junction beta-2 (GJB2) gene mutations in ARNSHL was investigated in south of Iran for the first time. Methods: In this descriptive study, we investigated sixteen large families with at least two affected individuals. After DNA extraction, GJB2 gene mutations were analyzed using direct sequencing method. Negative samples for GJB2 gene mutations were analyzed for the linkage to DFNB3, DFNB9 and DFNB21 loci by genotyping the corresponding short tandem repeat (STR) markers using polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE) methods. Results: GJB2 mutations (283G>A and 29delT) were causes of hearing loss in 12.5% of families with ARNSHL and no evidence of linkage were found for any of DFNB3, DFNB9 and DFNB21 loci. Conclusion: GJB2 mutations are associated with ARNSHL. We failed to find linkage of the DFNB3, DFNB9 and DFNB21 loci among GJB2 negative families. Therefore, further studies on large-scale population and other loci will be needed to find conclusively linkage of DFNB loci and ARNSHL in the future. PMID:27398341

  4. Main clinical features of the three mapped autosomal recessive limb-girdle muscular dystrophies and estimated proportion of each form in 13 Brazilian families.

    PubMed Central

    Passos-Bueno, M R; Moreira, E S; Marie, S K; Bashir, R; Vasquez, L; Love, D R; Vainzof, M; Iughetti, P; Oliveira, J R; Bakker, E; Strachan, T; Bushby, K; Zatz, M

    1996-01-01

    Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a group of muscle diseases with a wide spectrum of clinical signs, varying from very severe to mild. Four different loci that when mutated cause the AR LGMD phenotype have been mapped or cloned or both: in two of them the linked families seem to have a relatively mild phenotype (LGMD2a and LGMD2b), in the third one the reported linked families show a more severe clinical course (LGMD2c), while mutations in the fourth locus may cause severe or mild phenotypes (LGMD2d). The relative proportion of each of these genetic forms among the LGMD families and whether there are other genes that when mutated cause this phenotype is unknown. The closest available informative markers for each of the mapped AR LGMD genes have been tested in 13 Brazilian families with at least three affected patients. The findings from the present report confirm non-allelic heterogeneity for LGMD and suggest that in our population about 33% of the LGMD families are caused by mutations in the 15q gene, 33% in the 2p gene, 17% by mutations in the adhalin gene, and less than 10% may be by mutations at the 13q locus. They also suggest that there is at least one other gene responsible for this phenotype. In addition, the main clinical features of the different forms are discussed. PMID:8929943

  5. Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8

    PubMed Central

    Boycott, Kym M.; Beaulieu, Chandree L.; Kernohan, Kristin D.; Gebril, Ola H.; Mhanni, Aziz; Chudley, Albert E.; Redl, David; Qin, Wen; Hampson, Sarah; Küry, Sébastien; Tetreault, Martine; Puffenberger, Erik G.; Scott, James N.; Bezieau, Stéphane; Reis, André; Uebe, Steffen; Schumacher, Johannes; Hegele, Robert A.; McLeod, D. Ross; Gálvez-Peralta, Marina; Majewski, Jacek; Ramaekers, Vincent T.; Nebert, Daniel W.; Innes, A. Micheil; Parboosingh, Jillian S.; Abou Jamra, Rami

    2015-01-01

    Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development. PMID:26637978

  6. Animals deficient in C2Orf71, an autosomal recessive retinitis pigmentosa-associated locus, develop severe early-onset retinal degeneration.

    PubMed

    Kevany, Brian M; Zhang, Ning; Jastrzebska, Beata; Palczewski, Krzysztof

    2015-05-01

    Genetic mapping was recently used to identify the underlying cause for a previously uncharacterized cohort of autosomal recessive retinitis pigmentosa cases. Genetic mapping of affected individuals resulted in the identification of an uncharacterized gene, C2Orf71, as the causative locus. However, initial homology searches failed to reveal similarities to any previously characterized protein or domain. To address this issue, we characterized the mouse homolog, BC027072. Immunohistochemistry with a custom polyclonal antibody showed staining localized to the inner segments (IS) of photoreceptor cells, as well as the outer segments (OS) of cone cells. A knockout mouse line (BC(-/-)) was generated and demonstrated that loss of this gene results in a severe, early-onset retinal degeneration. Histology and electron microscopy (EM) revealed disorganized OS as early as 3 weeks with complete loss by 24 weeks of age. EM micrographs displayed packets of cellular material containing OS discs or IS organelles in the OS region and abnormal retinal pigmented epithelium cells. Analyses of retinoids and rhodopsin levels showed <20% in BC(-/-) versus wild-type mice early in development. Electroretinograms demonstrated that affected mice were virtually non-responsive to light by 8 weeks of age. Lastly, RNAseq analysis of ocular gene expression in BC(-/-) mice revealed clues to the causes of the progressive retinal degenerations. Although its function remains unknown, this protein appears essential for normal OS development/maintenance and vision in humans and mice. RNAseq data are available in the GEO database under accession: GSE63810.

  7. Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12.

    PubMed

    Muhammad, Emad; Leventhal, Neta; Parvari, Galit; Hanukoglu, Aaron; Hanukoglu, Israel; Chalifa-Caspi, Vered; Feinstein, Yael; Weinbrand, Jenny; Jacoby, Harel; Manor, Esther; Nagar, Tal; Beck, John C; Sheffield, Val C; Hershkovitz, Eli; Parvari, Ruti

    2011-04-01

    Genetic disorders of excessive salt loss from sweat glands have been observed in pseudohypoaldosteronism type I (PHA) and cystic fibrosis that result from mutations in genes encoding epithelial Na+ channel (ENaC) subunits and the transmembrane conductance regulator (CFTR), respectively. We identified a novel autosomal recessive form of isolated salt wasting in sweat, which leads to severe infantile hyponatremic dehydration. Three affected individuals from a small Bedouin clan presented with failure to thrive, hyponatremic dehydration and hyperkalemia with isolated sweat salt wasting. Using positional cloning, we identified the association of a Glu143Lys mutation in carbonic anhydrase 12 (CA12) with the disease. Carbonic anhydrase is a zinc metalloenzyme that catalyzes the reversible hydration of carbon dioxide to form a bicarbonate anion and a proton. Glu143 in CA12 is essential for zinc coordination in this metalloenzyme and lowering of the protein-metal affinity reduces its catalytic activity. This is the first presentation of an isolated loss of salt from sweat gland mimicking PHA, associated with a mutation in the CA12 gene not previously implicated in human disorders. Our data demonstrate the importance of bicarbonate anion and proton production on salt concentration in sweat and its significance for sodium homeostasis.

  8. Mutations in TUBGCP4 Alter Microtubule Organization via the γ-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy

    PubMed Central

    Scheidecker, Sophie; Etard, Christelle; Haren, Laurence; Stoetzel, Corinne; Hull, Sarah; Arno, Gavin; Plagnol, Vincent; Drunat, Séverine; Passemard, Sandrine; Toutain, Annick; Obringer, Cathy; Koob, Mériam; Geoffroy, Véronique; Marion, Vincent; Strähle, Uwe; Ostergaard, Pia; Verloes, Alain; Merdes, Andreas; Moore, Anthony T.; Dollfus, Hélène

    2015-01-01

    We have identified TUBGCP4 variants in individuals with autosomal-recessive microcephaly and chorioretinopathy. Whole-exome sequencing performed on one family with two affected siblings and independently on another family with one affected child revealed compound-heterozygous mutations in TUBGCP4. Subsequent Sanger sequencing was performed on a panel of individuals from 12 French families affected by microcephaly and ophthalmic manifestations, and one other individual was identified with compound-heterozygous mutations in TUBGCP4. One synonymous variant was common to all three families and was shown to induce exon skipping; the other mutations were frameshift mutations and a deletion. TUBGCP4 encodes γ-tubulin complex protein 4, a component belonging to the γ-tubulin ring complex (γ-TuRC) and known to regulate the nucleation and organization of microtubules. Functional analysis of individual fibroblasts disclosed reduced levels of the γ-TuRC, altered nucleation and organization of microtubules, abnormal nuclear shape, and aneuploidy. Moreover, zebrafish treated with morpholinos against tubgcp4 were found to have reduced head volume and eye developmental anomalies with chorioretinal dysplasia. In summary, the identification of TUBGCP4 mutations in individuals with microcephaly and a spectrum of anomalies in eye development, particularly photoreceptor anomalies, provides evidence of an important role for the γ-TuRC in brain and eye development. PMID:25817018

  9. High prevalence of the W24X mutation in the gene encoding connexin-26 (GJB2) in Spanish Romani (gypsies) with autosomal recessive non-syndromic hearing loss.

    PubMed

    Alvarez, Araceli; del Castillo, Ignacio; Villamar, Manuela; Aguirre, Luis A; González-Neira, Anna; López-Nevot, Alicia; Moreno-Pelayo, Miguel A; Moreno, Felipe

    2005-09-01

    Molecular testing for mutations in the gene encoding connexin-26 (GJB2) at the DFNB1 locus has become the standard of care for genetic diagnosis and counseling of autosomal recessive non-syndromic hearing impairment (ARNSHI). The spectrum of mutations in GJB2 varies considerably among the populations, different alleles predominating in different ethnic groups. A cohort of 34 families of Spanish Romani (gypsies) with ARNSHI was screened for mutations in GJB2. We found that DFNB1 deafness accounts for 50% of all ARNSHI in Spanish gypsies. The predominating allele is W24X (79% of the DFNB1 alleles), and 35delG is the second most common allele (17%). An allele-specific PCR test was developed for the detection of the W24X mutation. By using this test, carrier frequencies were determined in two sample groups of gypsies from different Spanish regions (Andalusia and Catalonia), being 4% and 0%, respectively. Haplotype analysis for microsatellite markers closely flanking the GJB2 gene revealed five different haplotypes associated with the W24X mutation, all sharing the same allele from marker D13S141, suggesting that a founder effect for this mutation is responsible for its high prevalence among Spanish gypsies.

  10. A novel class of antihyperlipidemic agents with low density lipoprotein receptor up-regulation via the adaptor protein autosomal recessive hypercholesterolemia.

    PubMed

    Asano, Shigehiro; Ban, Hitoshi; Tsuboya, Norie; Uno, Shinsaku; Kino, Kouichi; Ioriya, Katsuhisa; Kitano, Masafumi; Ueno, Yoshihide

    2010-04-22

    We have previously reported compound 2 as a inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) and up-regulator of the low density lipoprotein receptor (LDL-R) expression. In this study we focused on compound 2, a unique LDL-R up-regulator, and describe the discovery of a novel class of up-regulators of LDL-R. Replacement the methylene urea linker in compound 2 with an acylsulfonamide linker kept a potent LDL-R up-regulatory activity, and subsequent optimization work gave compound 39 as a highly potent LDL-R up-regulator (39; EC(25) = 0.047 microM). Compound 39 showed no ACAT inhibitory activity even at 1 microM. The sodium salts of compound 39 reduced plasma total and LDL cholesterol levels in a dose-dependent manner in an experimental animal model of hyperlipidemia. Moreover, we revealed in this study using RNA interference that autosomal recessive hypercholesterolemia (ARH), an adaptor protein of LDL-R, is essential for compound 39 up-regulation of LDL-R expression.

  11. Autosomal recessive pure hair and nail ectodermal dysplasia linked to chromosome 12p11.1-q14.3 without KRTHB5 gene mutation.

    PubMed

    Rasool, Mahmood; Nawaz, Sadia; Azhar, Aysha; Wajid, Muhammad; Westermark, Per; Baig, Shahid M; Klar, Joakim; Dahl, Niklas

    2010-01-01

    Hair-nail ectodermal dysplasia (HNED; OMIM 602032) constitutes a rare subgroup of ectodermal dysplasias characterised by onychodystrophy, hypotrichosis and brittle hair. We identified a large consanguineous Pakistani family with four siblings affected by a congenital autosomal recessive form of the disease. Based on previous genetic findings in HNED we performed linkage analysis in the family using chromosome 12 markers. A genetic linkage analysis revealed a lod score of 2.92 ( = 0.0) at locus D12S368, indicating the disease gene to be located on chromosome 12. Candidate genes on chromosome 12, including the KRTHB5 gene and four additional keratin II genes, were sequenced in affected family members. Sequence analysis of the coding regions of keratin KRTHB5 gene, previously associated with a distinct clinical form of hair-nail dysplasia, revealed normal coding regions. Our study confirms linkage of a variant clinical form of hair-nail ectodermal dysplasia to chromosome 12 without any mutation in the coding sequences of the KRTHB5 gene. The results suggest this family to have either a non-coding mutation in the KRTHB5 gene, or a mutation in a yet unknown gene within the linked region on chromosome 12.

  12. Mutations in CDC14A, Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness.

    PubMed

    Delmaghani, Sedigheh; Aghaie, Asadollah; Bouyacoub, Yosra; El Hachmi, Hala; Bonnet, Crystel; Riahi, Zied; Chardenoux, Sebastien; Perfettini, Isabelle; Hardelin, Jean-Pierre; Houmeida, Ahmed; Herbomel, Philippe; Petit, Christine

    2016-06-02

    By genetic linkage analysis in a large consanguineous Iranian family with eleven individuals affected by severe to profound congenital deafness, we were able to define a 2.8 Mb critical interval (at chromosome 1p21.2-1p21.1) for an autosomal-recessive nonsyndromic deafness locus (DFNB). Whole-exome sequencing allowed us to identify a CDC14A biallelic nonsense mutation, c.1126C>T (p.Arg376(∗)), which was present in the eight clinically affected individuals still alive. Subsequent screening of 115 unrelated individuals affected by severe or profound congenital deafness of unknown genetic cause led us to identify another CDC14A biallelic nonsense mutation, c.1015C>T (p.Arg339(∗)), in an individual originating from Mauritania. CDC14A encodes a protein tyrosine phosphatase. Immunofluorescence analysis of the protein distribution in the mouse inner ear showed a strong labeling of the hair cells' kinocilia. By using a morpholino strategy to knockdown cdc14a in zebrafish larvae, we found that the length of the kinocilia was reduced in inner-ear hair cells. Therefore, deafness caused by loss-of-function mutations in CDC14A probably arises from a morphogenetic defect of the auditory sensory cells' hair bundles, whose differentiation critically depends on the proper growth of their kinocilium.

  13. A VARIANT OF NESPRIN1 GIANT DEVOID OF KASH DOMAIN UNDERLIES THE MOLECULAR ETIOLOGY OF AUTOSOMAL RECESSIVE CEREBELLAR ATAXIA TYPE I

    PubMed Central

    Razafsky, David; Hodzic, Didier

    2015-01-01

    Nonsense mutations across the whole coding sequence of Syne1/ Nesprin1 have been linked to Autosomal Recessive Cerebellar Ataxia Type I (ARCA1). However, nothing is known about the molecular etiology of this late-onset debilitating pathology. In this work, we report that Nesprin1 giant is specifically expressed in CNS tissues. We also identified a CNS-specific splicing event that leads to the abundant expression of a KASH-LESS variant of Nesprin1giant (KLNes1g) in the cerebellum. KLNes1g displayed a noncanonical localization at glomeruli of cerebellar mossy fibers whereas Nesprin2 exclusively decorated the nuclear envelope of all cerebellar neurons. In immunogold electron microscopy, KLNes1g colocalized both with synaptic vesicles within mossy fibers and with dendritic membranes of cerebellar granule neurons. We further identified vesicle- and membrane-associated proteins in KLNes1g immunoprecipitates. Together, our results suggest that the loss of function of KLNes1g resulting from Nesprin1 nonsense mutations underlie the molecular etiology of ARCA1. PMID:25843669

  14. Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families.

    PubMed

    Aziz, Abdul; Irfanullah; Khan, Saadullah; Zimri, Faridullah Khan; Muhammad, Noor; Rashid, Sajid; Ahmad, Wasim

    2014-01-25

    Split-hand/split-foot malformation (SHFM), representing variable degree of median clefts of hands and feet, is a genetically heterogeneous group of limb malformations with seven loci mapped on different human chromosomes. However, only 3 genes (TP63, WNT10B, DLX5) for the seven loci have been identified. The study, presented here, described three consanguineous Pakistani families segregating SHFM in autosomal recessive manner. Linkage in the families was searched by genotyping microsatellite markers and mutation screening of candidate gene was performed by Sanger DNA sequencing. Clinical features of affected members of these families exhibited SHFM phenotype with involvement of hands and feet. Genotyping using microsatellite markers mapped the families to WNT10B gene at SHFM6 on chromosome 12q13.11-q13. Subsequently, sequence analysis of WNT10B gene revealed a novel 4-bp deletion mutation (c.1165_1168delAAGT) in one family and 7-bp duplication (c.300_306dupAGGGCGG) in two other families. Structure-based analysis showed a significant conformational shift in the active binding site of mutated WNT10B (p.Lys388Glufs*36), influencing binding with Fzd8. The mutations identified in the WNT10B gene extend the body of evidence implicating it in the pathogenesis of SHFM.

  15. Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.

    PubMed

    Boycott, Kym M; Beaulieu, Chandree L; Kernohan, Kristin D; Gebril, Ola H; Mhanni, Aziz; Chudley, Albert E; Redl, David; Qin, Wen; Hampson, Sarah; Küry, Sébastien; Tetreault, Martine; Puffenberger, Erik G; Scott, James N; Bezieau, Stéphane; Reis, André; Uebe, Steffen; Schumacher, Johannes; Hegele, Robert A; McLeod, D Ross; Gálvez-Peralta, Marina; Majewski, Jacek; Ramaekers, Vincent T; Nebert, Daniel W; Innes, A Micheil; Parboosingh, Jillian S; Abou Jamra, Rami

    2015-12-03

    Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.

  16. Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31-q32.1 in an inbred and genetically heterogeneous disease population

    SciTech Connect

    Van Soest, S.; Ingeborgh Van Den Born, L.; Bergen, A.A.B.

    1994-08-01

    Linkage analysis was carried out in a large family segregating for autosomal recessive retinitis pigmentosa (arRP), originating from a genetically isolated population in The Netherlands. Within the family, clinical heterogeneity was observed, with a major section of the family segregating arRP with characteristic para-arteriolar preservation of the retinal pigment epithelium (PPRPE). In the remainder of the arRP patients no PPRPE was found. Initially, all branches of the family were analyzed jointly, and linkage was found between the marker F13B, located at 1q31-q32.1, and RP12 ({Zeta}{sub max} = 4.99 at 8% recombination). Analysis of linkage heterogeneity between five branches of the family yielded significant evidence for nonallelic genetic heterogeneity within this family, coinciding with the observed clinical differences. Multipoint analysis, carried out in the branches that showed linkage, favored the locus order 1cen-D1S158-(F13B, RP12)-D1S53-1qter ({Zeta}{sub max} = 9.17). The finding of a single founder allele associated with the disease phenotype supports this localization. This study reveals that even in a large family, apparently segregating for a single disease entity, genetic heterogeneity can be detected and resolved successfully. 35 refs., 5 figs.

  17. Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development

    SciTech Connect

    Tan, J.; Schachter, H.; Dunn, J.

    1996-10-01

    Carbohydrate-deficient glycoprotein syndrome (CDGS) type II is a multisystemic congenital disease with severe involvement of the nervous system. Two unrelated CDGS type II patients are shown to have point mutations (one patient having Ser{r_arrow}Phe and the other having His{r_arrow}Arg) in the catalytic domain of the gene MGAT2, encoding UDP-GlcNAc:{alpha}-6-D-mannoside {Beta}-1,2-N-ace-tylglucosaminyltransferase II (GnT II), an enzyme essential for biosynthesis of complex Asn-linked glycans. Both mutations caused both decreased expression of enzyme protein in a baculovirus/insect cell system and inactivation of enzyme activity. Restriction-endonuclease analysis of DNA from 23 blood relatives of one of these patients showed that 13 donors were heterozygotes; the other relatives and 21 unrelated donors were normal homozygotes. All heterozygotes showed a significant reduction (33%-68%) in mononuclear-cell GnT II activity. The data indicate that CDGS type II is an autosomal recessive disease and that complex Asn-linked glycans are essential for normal neurological development. 38 refs., 4 figs., 1 tab.

  18. The Study of SLC26A4 Gene Causing Autosomal Recessive Hearing Loss by Linkage Analysis in a Cohort of Iranian Populations

    PubMed Central

    Reiisi, Somayeh; Sanati, Mohammad Hosein; Tabatabaiefar, Mohammad Amin; Ahmadian, Shahla; Reiisi, Salimeh; Parchami, Shahrbanoo; Porjafari, Hamid; Shahi, Heshmat; Shavarzi, Afsaneh; Hashemzade Chaleshtori, Morteza

    2014-01-01

    Sensorineural non-syndromic hearing loss is the most common disorder which affects 1 in 500 newborns. Hearing loss is an extremely heterogeneous defect with more than 100 loci identified to date. According to the studies, mutations in GJB2 are estimated to be involved in 50- 80% of autosomal recessive non-syndromic hearing loss cases, but contribution of other loci in this disorder is yet ambiguous. With regard to studies, DFNB4 locus (SLC26A4) can be classified as the second cause of hearing loss. So, this study aimed to determine the contribution of this locus in hearing loss as well as the frequency of SLC26A4 gene mutations in a population in the west of Iran. In this descriptive laboratory study, we included 30 families from the west of Iran with no mutation in GJB2 gene. Linkage analysis was performed by DFNB4 (SLC26A4) molecular markers (STR). The families with hearing loss linked to this locus were further analyzed for mutation detection. SLC26A4 gene exons were amplified and analyzed using direct DNA sequencing. In studied families, 2 families displayed linkage to DFNB4 locus. Identified mutations include mutation in exon 5 (c.416 G>T) and in splicing site of exon 7 (IVS-2 A>G or c.919-2 A>G). PMID:25317404

  19. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.

    PubMed

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher's exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10-41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure

  20. X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

    PubMed Central

    Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

    2016-01-01

    Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10−41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal

  1. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

    PubMed

    Stover, E H; Borthwick, K J; Bavalia, C; Eady, N; Fritz, D M; Rungroj, N; Giersch, A B S; Morton, C C; Axon, P R; Akil, I; Al-Sabban, E A; Baguley, D M; Bianca, S; Bakkaloglu, A; Bircan, Z; Chauveau, D; Clermont, M-J; Guala, A; Hulton, S A; Kroes, H; Li Volti, G; Mir, S; Mocan, H; Nayir, A; Ozen, S; Rodriguez Soriano, J; Sanjad, S A; Tasic, V; Taylor, C M; Topaloglu, R; Smith, A N; Karet, F E

    2002-11-01

    Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

  2. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss

    PubMed Central

    Stover, E; Borthwick, K; Bavalia, C; Eady, N; Fritz, D; Rungroj, N; Giersch, A; Morton, C; Axon, P; Akil, I; Al-Sabban, E; Baguley, D; Bianca, S; Bakkaloglu, A; Bircan, Z; Chauveau, D; Clermont, M; Guala, A; Hulton, S; Kroes, H; Li, V; Mir, S; Mocan, H; Nayir, A; Ozen, S; Rodriguez, S; Sanjad, S; Tasic, V; Taylor, C; Topaloglu, R; Smith, A; Karet, F

    2002-01-01

    Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal α-intercalated cell's apical H+-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time. PMID:12414817

  3. Mutations in the delta-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2).

    PubMed

    Duggan, D J; Manchester, D; Stears, K P; Mathews, D J; Hart, C; Hoffman, E P

    1997-05-01

    The dystrophin-based membrane cytoskeleton of muscle fibers has emerged as a critical multi-protein complex which seems to impart structural integrity on the muscle fiber plasma membrane. Deficiency of dystrophin causes the most common types of muscular dystrophy, Duchenne and Becker muscular dystrophies. Muscular dystrophy patients showing normal dystrophin protein and gene analysis are generally isolated cases with a presumed autosomal recessive inheritance pattern (limb-girdle muscular dystrophy). Recently, linkage and candidate gene analyses have shown that some cases of limb-girdle muscular dystrophy can be caused by deficiency of other components of the dystrophin membrane cytoskeleton. The most recently identified component, delta-sarcoglycan, has been found to show mutations in a series of Brazilian muscular dystrophy patients. All patients were homozygous for a protein-truncating carboxy-terminal mutation, and showed a deficiency of the four sarcoglycan proteins. To determine if delta-sarcoglycan deficiency occurred in other world populations, to identify the range of mutations and clinical phenotypes, and to test for the biochemical consequences of delta-sarcoglycan gene mutations, we studied Duchenne-like and limb-girdle muscular dystrophy patients who we had previously shown not to exhibit gene mutations of dystrophin, alpha-, beta-, or gamma-sarcoglycan for delta-sarcoglycan mutations (n = 54). We identified two American patients with novel nonsense mutations of delta-sarcoglycan (W30X, R165X). One was apparently homozygous, and we show likely consanguinity through homozygosity for 13 microsatellite loci covering a 38 cM region of chromosome 5. The second was heterozygous. Both were girls who showed clinical symptoms consistent with Duchenne muscular dystrophy in males. Our data shows that delta-sarcoglycan deficiency occurs in other world populations, and that most or all patients show a deficiency of the entire sarcoglycan complex, adding support to

  4. Clinical and molecular diagnosis of a Costa Rican family with autosomal recessive myotonia congenita (Becker disease) carrying a new mutation in the CLCN1 gene.

    PubMed

    Morales, Fernando; Cuenca, Patricia; del Valle, Gerardo; Vásquez, Melissa; Brian, Roberto; Sittenfeld, Mauricio; Johnson, Keith; Lin, Xi; Ashizawa, Tetsuo

    2008-03-01

    Myotonia congenita is a muscular disease characterized by myotonia, hypertrophy, and stiffness. It is inherited as either autosomal dominant or recessive known as Thomsen and Becker diseases, respectively. Here we confirm the clinical diagnosis of a family diagnosed with a myotonic condition many years ago and report a new mutation in the CLCN1 gene. The clinical diagnosis was established using ocular, cardiac, neurological and electrophysiological tests and the molecular diagnosis was done by PCR, SSCP and sequencing of the CLCN1 gene. The proband and the other affected individuals exhibited proximal and distal muscle weakness but no hypertrophy or muscular pain was found. The myotatic reflexes were lessened and sensibility was normal. Electrical and clinical myotonia was found only in the sufferers. Slit lamp and electrocardiogram tests were normal. Two affected probands presented diminution of the sensitive conduction velocities and prolonged sensory distal latencies. The clinical spectrum for this family is in agreement with a clinical diagnosis of Becker myotonia. This was confirmed by molecular diagnosis where a new disease-causing mutation (Q412P) was found in the family and absent in 200 unaffected chromosomes. No latent myotonia was found in this family; therefore the ability to cause this subclinical sign might be intrinsic to each mutation. Implications of the structure-function-genotype relationship for this and other mutations are discussed. Adequate clinical diagnosis of a neuromuscular disorder would allow focusing the molecular studies toward the confirmation of the initial diagnosis, leading to a proper clinical management, genetic counseling and improving in the quality of life of the patients and relatives.

  5. Confirmation of a third locus, at 2p, for autosomal recessive limb-girdle muscular dystrophy indicates that at least 4 genes are responsible for this condition

    SciTech Connect

    Passos-Bueno, M.R.; Moreira, E.S.; Vasques, L.R.

    1994-09-01

    Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a heterogeneous group of diseases with a wide spectrum of clinical signs, varying from very severe to mild ones. One gene for a mild form was mapped at 15q while another gene for a severe form was mapped at 13p. In both cases, evidence of genetic heterogeneity were demonstrated following analysis of Brazilian families. More recently, a third gene was identified at 2p based on linkage analysis in 2 LGMD families with the markers D2S166, D2S136 and D2S134. The relative proportion of each genetic form among affected families is unknown. Therefore, the closest available markers for each of the LGMD genes have been tested in 12 Brazilian families with at least 3 affected patients. The following results have been observed: 3 were 15q-linked families, 1 was 13p-linked, at least 2 were linked to 2p and 2 were excluded for any of these 3 loci. In relation to the 2p locus, we have tested a total of 12 markers in the 2 linked Brazilian families. The maximum lod score for the marker which was informative for the two families (D2S291) was 8.35 at {theta}=0.01. Therefore, these results suggest the existence of at least 4 different genes causing the LGMD phenotype and confirm linkage to the 2p locus. In addition, our data refine the localization of the third locus since the marker D2S291 is at least 9 cM closer to this gene (FAPESP, CNPq, MDA, PADCT).

  6. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease.

    PubMed

    Yoshihara, Daisuke; Kurahashi, Hiroki; Morita, Miwa; Kugita, Masanori; Hiki, Yoshiyuki; Aukema, Harold M; Yamaguchi, Tamio; Calvet, James P; Wallace, Darren P; Nagao, Shizuko

    2011-02-01

    In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. In the current study, we determined that pioglitazone (PIO), a PPAR-γ agonist, decreases polycystic kidney and liver disease progression in the polycystic kidney rat, an orthologous model of human ARPKD. Daily treatment with 10 mg/kg PIO for 16 wk decreased kidney weight (% of body weight), renal cystic area, serum urea nitrogen, and the number of Ki67-, pERK1/2-, and pS6-positive cells in the kidney. There was also a decrease in liver weight (% of body weight), liver cystic area, fibrotic index, and the number of Ki67-, pERK1/2-, pERK5-, and TGF-β-positive cells in the liver. Taken together, these data suggest that PIO inhibits the progression of polycystic kidney and liver disease in a model of human ARPKD by inhibiting cell proliferation and fibrosis. These findings suggest that PPAR-γ agonists may have therapeutic value in the treatment of the renal and hepatic manifestations of ARPKD.

  7. The effect of two endogenous retinoids on the mRNA expression profile in human primary keratinocytes, focusing on genes causing autosomal recessive congenital ichthyosis.

    PubMed

    Törmä, H; Bergström, A; Ghiasifarahani, G; Berne, B

    2014-10-01

    Retinoids (natural forms and synthetic derivatives of vitamin A) are used as therapeutic agents for numerous skin diseases such as keratinization disorders (e.g. ichthyoses) and psoriasis. Two endogenous ligands for retinoic acid receptors exist, retinoic acid (atRA) and 3,4-didehydroretinoic acid (ddRA). In primary human epidermal keratinocytes many transcriptional targets for atRA are known, whereas the targets for ddRA are unknown. In an attempt to determine the targets, we compared the effect of atRA and ddRA on transcriptional profiles in undifferentiated and differentiating human primary keratinocytes. First, as expected, many genes were induced or suppressed in response to keratinocyte differentiation. Furthermore, the two retinoids affected substantially more genes in differentiated keratinocytes (>350) than in proliferating keratinocytes (≈20). In differentiating keratinocytes markers of cornification were suppressed suggesting a de-differentiating effect by the two retinoids. When comparing the expression profile of atRA to that of ddRA, no differently regulated genes were found. The array analysis also found that a minor number of miRNAs and a large number of non-coding transcripts were changed during differentiation and in response to the two retinoids. Furthermore, the expression of all, except one, genes known to cause autosomal recessive congenital ichthyosis (ARCI) were found to be induced by differentiation. These results comprehensively document that atRA and ddRA exert similar transcriptional changes in keratinocytes and also add new insights into the molecular mechanism influenced by retinoids in the epidermis. Furthermore, it suggests which ARCI patients could benefit from therapy with retinoids.

  8. Initial evaluation of hepatic T1 relaxation time as an imaging marker of liver disease associated with autosomal recessive polycystic kidney disease (ARPKD).

    PubMed

    Gao, Ying; Erokwu, Bernadette O; DeSantis, David A; Croniger, Colleen M; Schur, Rebecca M; Lu, Lan; Mariappuram, Jose; Dell, Katherine M; Flask, Chris A

    2016-01-01

    Autosomal recessive polycystic kidney disease (ARPKD) is a potentially lethal multi-organ disease affecting both the kidneys and the liver. Unfortunately, there are currently no non-invasive methods to monitor liver disease progression in ARPKD patients, limiting the study of potential therapeutic interventions. Herein, we perform an initial investigation of T1 relaxation time as a potential imaging biomarker to quantitatively assess the two primary pathologic hallmarks of ARPKD liver disease: biliary dilatation and periportal fibrosis in the PCK rat model of ARPKD. T1 relaxation time results were obtained for five PCK rats at 3 months of age using a Look-Locker acquisition on a Bruker BioSpec 7.0 T MRI scanner. Six three-month-old Sprague-Dawley (SD) rats were also scanned as controls. All animals were euthanized after the three-month scans for histological and biochemical assessments of bile duct dilatation and hepatic fibrosis for comparison. PCK rats exhibited significantly increased liver T1 values (mean ± standard deviation = 935 ± 39 ms) compared with age-matched SD control rats (847 ± 26 ms, p = 0.01). One PCK rat exhibited severe cholangitis (mean T1  = 1413 ms), which occurs periodically in ARPKD patients. The observed increase in the in vivo liver T1 relaxation time correlated significantly with three histological and biochemical indicators of biliary dilatation and fibrosis: bile duct area percent (R = 0.85, p = 0.002), periportal fibrosis area percent (R = 0.82, p = 0.004), and hydroxyproline content (R = 0.76, p = 0.01). These results suggest that hepatic T1 relaxation time may provide a sensitive and non-invasive imaging biomarker to monitor ARPKD liver disease.

  9. Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation

    PubMed Central

    Liu, Yo-Tsen; Hersheson, Joshua; Plagnol, Vincent; Fawcett, Katherine; Duberley, Kate E C; Preza, Elisavet; Hargreaves, Iain P; Chalasani, Annapurna; Laurá, Matilde; Wood, Nick W; Reilly, Mary M; Houlden, Henry

    2014-01-01

    Background The autosomal-recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The large number of ARCA genes leads to delay and difficulties obtaining an exact diagnosis in many patients and families. Ubiquinone (CoQ10) deficiency is one of the potentially treatable causes of ARCAs as some patients respond to CoQ10 supplementation. The AarF domain containing kinase 3 gene (ADCK3) is one of several genes associated with CoQ10 deficiency. ADCK3 encodes a mitochondrial protein which functions as an electron-transfer membrane protein complex in the mitochondrial respiratory chain (MRC). Methods We report two siblings from a consanguineous Pakistani family who presented with cerebellar ataxia and severe myoclonus from adolescence. Whole exome sequencing and biochemical assessment of fibroblasts were performed in the index patient. Results A novel homozygous frameshift mutation in ADCK3 (p.Ser616Leufs*114), was identified in both siblings. This frameshift mutation results in the loss of the stop codon, extending the coding protein by 81 amino acids. Significant CoQ10 deficiency and reduced MRC enzyme activities in the index patient's fibroblasts suggested that the mutant protein may reduce the efficiency of mitochondrial electron transfer. CoQ10 supplementation was initiated following these genetic and biochemical analyses. She gained substantial improvement in myoclonic movements, ataxic gait and dysarthric speech after treatment. Conclusion This study highlights the importance of diagnosing ADCK3 mutations and the potential benefit of treatment for patients. The identification of this new mutation broadens the phenotypic spectrum associated with ADCK3 mutations and provides further understanding of their pathogenic mechanism. PMID:24218524

  10. Prevalence and range of GJB2 and SLC26A4 mutations in patients with autosomal recessive non‑syndromic hearing loss.

    PubMed

    Jiang, Hua; Chen, Jia; Shan, Xin-Ji; Li, Ying; He, Jian-Guo; Yang, Bei-Bei

    2014-07-01

    The frequency and distribution of genetic mutations that cause deafness differ significantly according to ethnic group and region. Zhejiang is a province in the southeast of China, with an exceptional racial composition of the population caused by mass migration in ancient China. The purpose of the present study was to investigate the prevalence and spectrum of gap junction‑β2 (GJB2), solute carrier family 26 (anion exchanger) member 4 (SLC26A4) and GJB3 mutations in patients with autosomal recessive non‑syndromic hearing loss (ARNHL) in this area. A total of 176 unrelated pediatric patients with ARNHL were enrolled in the study. A genomic DNA sample was extracted from the peripheral blood. Polymerase chain reaction was employed, and the products were sequenced to screen for mutations in GJB2. In addition, a SNaPshot sequencing method was utilized to detect four hotspot mutations in SLC26A4 (IVS7‑2A>G and c.2168A>G) and GJB3 (c.538C>T and c.547G>A). All patients were subjected to a temporal bone computed tomography scan to identify enlarged vestibular aqueducts (EVA). In total, 14 different mutations, including two new mutations (p.W44L and p.D66N) of GJB2, were detected. The most common pathogenic mutation of GJB2 was c.235delC (15.1%), followed by c.176_191del16 (1.7%), c.299_300delAT (1.7%), c.508_511dup (0.85%) and c.35delG (0.28%) of the total alleles. Mutation analysis of SLC26A4 demonstrated that 13.6% (24/176) of patients carried at least one mutant allele. The patients with EVA (84.2%) had SLC26A4 mutations, and 31% had homozygous mutations. Only one patient carried a heterozygous mutation of GJB3 (c.538C>T). Compared with the other regions of China, in the present population cohort, the prevalence and spectrum of mutations in GJB2 was unique, and in patients with EVA the frequency of a homozygous mutation in SLC26A4 was significantly lower. These findings may be of benefit in genetic counseling and risk assessment for families from this area of

  11. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: New insights into molecular mechanisms responsible for the disease

    SciTech Connect

    Hahnen, E.; Schoenling, J.; Zerres, K.

    1996-11-01

    Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5{prime} end of the SMN genes, suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-simulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the {alpha}-globin cluster, and the polymerase {alpha} arrest sites. This may explain why independent hybrid SMN genes show identical sequences. 35 refs., 4 figs., 1 tab.

  12. Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa

    PubMed Central

    Méndez-Vidal, Cristina; González-del Pozo, María; Vela-Boza, Alicia; Santoyo-López, Javier; López-Domingo, Francisco J.; Vázquez-Marouschek, Carmen; Dopazo, Joaquin; Borrego, Salud

    2013-01-01

    Purpose Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. Methods We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. Results Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. Conclusions Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with

  13. Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

    PubMed Central

    2010-01-01

    Background The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only. Methods/Design This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis. Discussion This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children

  14. Uniparental disomy of chromosome 8 leading to homozygosity of a CYP11B1 mutation in a patient with congenital adrenal hyperplasia: implication for a rare etiology of an autosomal recessive disorder.

    PubMed

    Matsubara, Keiko; Kataoka, Naoki; Ogita, Satoko; Sano, Shinichiro; Ogata, Tsutomu; Fukami, Maki; Katsumata, Noriyuki

    2014-01-01

    Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder that usually results from paternally and maternally transmitted mutations in genes for steroidogenic enzymes. Recent studies on steroid 21-hydroxylase deficiency, the most common form of CAH, have revealed that a small percentage of patients have a non-carrier parent; uniparental disomy (UPD) and de novo mutations were reported as disease-causing mechanisms in these patients. However, it remains unknown whether UPD and de novo mutations underlie other forms of CAH. Here, we report a male patient with steroid 11β-hydroxylase deficiency (11OHD) born to a non-carrier mother. The patient was identified by an elevated 17-hydroxyprogesterone level at a neonatal mass-screening test. His clinical features were comparable to those of previously reported patients with 11OHD. Direct sequencing of CYP11B1 identified a homozygous IVS7+1G>A mutation in the patient, which was not shared by his mother. Comparative genomic hybridization of the patient detected UPD of chromosome 8 [UPD(8)]. Microsatellite analysis indicated non-maternal origin of the UPD(8) and confirmed parentage of other chromosomes. This study shows for the first time that 11OHD can be caused by UPD in the presence of a non-carrier parent. Awareness of such rare cases should improve the accuracy of genetic counseling for families with CAH. Our data support the importance of UPD as an underlying mechanism of autosomal recessive disorders.

  15. Recession Depression: Mental Health Effects of the 2008 Stock Market Crash*

    PubMed Central

    McInerney, Melissa; Mellor, Jennifer M.; Nicholas, Lauren Hersch

    2013-01-01

    Do sudden, large wealth losses affect mental health? We use exogenous variation in the interview dates of the 2008 Health and Retirement Study to assess the impact of large wealth losses on mental health among older U.S. adults. We compare cross-wave changes in wealth and mental health for respondents interviewed before and after the October 2008 stock market crash. We find that the crash reduced wealth and increased feelings of depression and use of antidepressant drugs, and that these effects were largest among respondents with high levels of stock holdings prior to the crash. These results suggest that sudden wealth losses cause immediate declines in subjective measures of mental health. However, we find no evidence that wealth losses lead to increases in clinically-validated measures of depressive symptoms or indicators of depression. PMID:24113241

  16. Recession depression: mental health effects of the 2008 stock market crash.

    PubMed

    McInerney, Melissa; Mellor, Jennifer M; Nicholas, Lauren Hersch

    2013-12-01

    Do sudden, large wealth losses affect mental health? We use exogenous variation in the interview dates of the 2008 Health and Retirement Study to assess the impact of large wealth losses on mental health among older U.S. adults. We compare cross-wave changes in wealth and mental health for respondents interviewed before and after the October 2008 stock market crash. We find that the crash reduced wealth and increased feelings of depression and use of antidepressant drugs, and that these effects were largest among respondents with high levels of stock holdings prior to the crash. These results suggest that sudden wealth losses cause immediate declines in subjective measures of mental health. However, we find no evidence that wealth losses lead to increases in clinically-validated measures of depressive symptoms or indicators of depression.

  17. Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome

    PubMed Central

    Handley, Mark T; Mégarbané, André; Meynert, Alison M; Brown, Stephen; Freyer, Elisabeth; Taylor, Martin S; Jackson, Ian J; Aligianis, Irene A

    2014-01-01

    Autosomal recessive cutis laxa type 3A is caused by mutations in ALDH18A1, a gene encoding the mitochondrial enzyme Δ1-pyrroline-5-carboxylate synthase (P5CS). It is a rare disorder with only six pathogenic mutations and 10 affected individuals from five families previously described in the literature. Here we report the identification of novel compound heterozygous missense mutations in two affected siblings from a Lebanese family by whole-exome sequencing. The mutations alter a conserved C-terminal domain of the encoded protein and reduce protein stability as determined through Western blot analysis of patient fibroblasts. Patient fibroblasts exhibit a lipid droplet phenotype similar to that recently reported in Warburg Micro syndrome, a disorder with similar features but hitherto unrelated cellular etiology. PMID:25077174

  18. A neonate with Coombs-negative hemolytic jaundice with spherocytes but normal erythrocyte indices: a rare case of autosomal-recessive hereditary spherocytosis due to alpha-spectrin deficiency.

    PubMed

    Yaish, H M; Christensen, R D; Agarwal, A

    2013-05-01

    The diagnosis of hereditary spherocytosis (HS) in a newborn infant is generally made on the basis of a positive family history, spherocytes on blood film and Coombs-negative hemolytic jaundice of variable severity with an elevated mean corpuscular hemoglobin concentration (MCHC) and a low mean corpuscular volume (MCV). In general, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) quantification of erythrocyte membrane proteins is not needed to make the clinical diagnosis of HS. However, we observed that a neonate with no family history of HS, but with abundant spherocytosis on repeated blood films, Coombs-negative hemolytic jaundice and normal MCHC and MCV measurements, where SDS-PAGE revealed alpha-spectrin deficiency, a rare autosomal-recessive variety of HS that generally has a severe clinical phenotype.

  19. Confirmation of the 2p locus for the mild autosomal recessive lim-girdle muscular dystrophy gene (LGMD2B) in three families allows refinement of the candidate region

    SciTech Connect

    Bashir, R.; Iughetti, P.; Strachan, T.

    1995-05-01

    The mild autosomal recessive limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of muscle diseases. The first gene to be mapped and associated with this phenotype was a locus on 15q geographic isolate. These results have been confirmed in other populations, but it was shown that there is genetic heterogeneity for this form of LGMD. Recently, a second locus has been mapped to chromosome 2p. The confirmation of the mapping of this second locus in LGMD families from different populations is of utmost importance for the positional cloning of this gene (HGMW-approved symbol LGMD2B). In this publication, haplotypes generated from five chromosome 2 markers from all of the known large families linked to chromosome 2p are reported together with the recombinants that show the current most likely location of the LGMD 2B gene. 9 refs., 2 figs., 1 tab.

  20. A prescription for unemployment? Recessions and the demand for mental health drugs.

    PubMed

    Bradford, W David; Lastrapes, William D

    2014-11-01

    We estimate the relationship between mental health drug prescriptions and the level of labor market activity in the USA. Based on monthly data from the National Ambulatory Medical Care Survey of physicians and aggregated by US census regions, we find that the number of mental health drug prescriptions (those aimed at alleviating depression and anxiety) rises by about 10% when employment falls by 1% and when unemployment rises by 100 basis points, but only for patients in the Northeast region. This paper is one of the first to look at compensatory health behavior in response to the business cycle.

  1. Autosomal Recessive Nonsyndromic Neurosensory Deafness at DFNB1 Not Associated with the Compound-Heterozygous GJB2 (Connexin 26) Genotype M34T/167delT

    PubMed Central

    Griffith, Andrew J.; Chowdhry, Aqeel A.; Kurima, Kiyoto; Hood, Linda J.; Keats, Bronya; Berlin, Charles I.; Morell, Robert J.; Friedman, Thomas B.

    2000-01-01

    Previous studies of the gap-junction β-2 subunit gene GJB2 (connexin 26) have suggested that the 101T→C (M34T) nucleotide substitution may be a mutant allele responsible for recessive deafness DFNB1. This hypothesis was consistent with observations of negligible intercellular coupling and gap-junction assembly of the M34T allele product expressed in Xenopus oocytes and HeLa cells. The results of our current study of a family cosegregating the 167delT allele of GJB2 and severe DFNB1 deafness demonstrate that this phenotype did not cosegregate with the compound-heterozygous genotype M34T/167delT. Since 167delT is a null allele of GJB2, this result indicates that the in vivo activity of a single M34T allele is not sufficiently reduced to cause the typical deafness phenotype associated with DFNB1. This observation raises the possibility that other GJB2 missense substitutions may not be recessive mutations that cause severe deafness and emphasizes the importance of observing cosegregation with deafness in large families to confirm that these missense alleles are mutant DFNB1 alleles. PMID:10903123

  2. Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy

    PubMed Central

    Shamseldin, Hanan E.; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S.; Gleeson, Joseph G.; Alkuraya, Fowzan S.

    2016-01-01

    Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. PMID:26708753

  3. Is health care a right or a commodity? Implementing mental health reform in a recession.

    PubMed

    Aggarwal, Neil Krishan; Rowe, Michael; Sernyak, Michael A

    2010-11-01

    The Patient Protection and Affordable Care Act, signed into law by President Obama in March 2010, contains elements of two seemingly contradictory positions: health care as a commodity and as a right. The commodity argument posits that the marketplace should govern demand, supply, and costs of care. The law's establishment of state insurance exchanges reflects this position. The argument that health care is a right posits that it is a need, not a choice, and that government should regulate care standards that may be compromised as insurers attempt to minimize costs. The law's requirement for coverage of mental and substance use disorders reflects this position. This Open Forum examines these arguments in light of current state fiscal crises and impending reforms. Despite the federal government's interest in expanding prevention and treatment of mental illness, states may demonstrate varying levels of commitment, based in part on their perception of health care as a right or a commodity. The federal government should outline clear performance standards, with minimum services specified to maximize state commitments to services.

  4. Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene.

    PubMed

    Kernohan, Kristin D; Dyment, David A; Pupavac, Mihaela; Cramer, Zvi; McBride, Arran; Bernard, Genevieve; Straub, Isabella; Tetreault, Martine; Hartley, Taila; Huang, Lijia; Sell, Erick; Majewski, Jacek; Rosenblatt, David S; Shoubridge, Eric; Mhanni, Aziz; Myers, Tara; Proud, Virginia; Vergano, Samanta; Spangler, Brooke; Farrow, Emily; Kussman, Jennifer; Safina, Nicole; Saunders, Carol; Boycott, Kym M; Thiffault, Isabelle

    2017-02-10

    Deleterious variants in the same gene present in two or more families with overlapping clinical features provide convincing evidence of a disease-gene association; this can be a challenge in the study of ultrarare diseases. To facilitate the identification of additional families, several groups have created "matching" platforms. We describe four individuals from three unrelated families "matched" by GeneMatcher and MatchMakerExchange. Individuals had microcephaly, developmental delay, epilepsy, and recessive mutations in TRIT1. A single homozygous mutation in TRIT1 associated with similar features had previously been reported in one family. The identification of these individuals provides additional evidence to support TRIT1 as the disease-causing gene and interprets the variants as "pathogenic." TRIT1 functions to modify mitochondrial tRNAs and is necessary for protein translation. We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder.

  5. Exclusion of the GNAS locus in PHP-Ib patients with broad GNAS methylation changes: evidence for an autosomal recessive form of PHP-Ib?

    PubMed

    Fernández-Rebollo, Eduardo; Pérez de Nanclares, Guiomar; Lecumberri, Beatriz; Turan, Serap; Anda, Emma; Pérez-Nanclares, Gustavo; Feig, Denice; Nik-Zainal, Serena; Bastepe, Murat; Jüppner, Harald

    2011-08-01

    Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation.

  6. Exclusion of the GNAS Locus in PHP-Ib Patients With Broad GNAS Methylation Changes: Evidence for an Autosomal Recessive Form of PHP-Ib?

    PubMed Central

    Fernández-Rebollo, Eduardo; de Nanclares, Guiomar Pérez; Lecumberri, Beatriz; Turan, Serap; Anda, Emma; Pérez-Nanclares, Gustavo; Feig, Denice; Nik-Zainal, Serena; Bastepe, Murat; Jüppner, Harald

    2013-01-01

    Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. PMID:21523828

  7. Screening of DFNB3 in Iranian families with autosomal recessive non-syndromic hearing loss reveals a novel pathogenic mutation in the MyTh4 domain of the MYO15A gene in a linked family

    PubMed Central

    Reiisi, Somayeh; Tabatabaiefar, Mohammad Amin; Sanati, Mohammad Hosein; Chaleshtori, Morteza Hashemzadeh

    2016-01-01

    Objective(s): Non-syndromic sensorineural hearing loss (NSHL) is a common disorder affecting approximately 1 in 500 newborns. This type of hearing loss is extremely heterogeneous and includes over 100 loci. Mutations in the GJB2 gene have been implicated in about half of autosomal recessive non-syndromic hearing loss (ARNSHL) cases, making this the most common cause of ARNSHL. For the latter form of deafness, most frequent genes proposed include GJB2, SLC26A4, MYO15A, OTOF, and CDH23 worldwide. Materials and Methods: The aim of the present study was to define the role and frequency of MYO15A gene mutation in Iranian families. In this study 30 Iranian families were enrolled with over three deaf children and negative for GJB2. Then linkage analysis was performed by six DFNB3 short tandem repeat markers. Following that, mutation detection accomplished using DNA sequencing. Results: One family (3.33%) showed linkage to DFNB3 and a novel mutation was identified in the MYO15A gene (c.6442T>A): as the disease-causing mutation. Mutation co-segregated with hearing loss in the family but was not present in the 100 ethnicity-matched controls. Conclusion: Our results confirmed that the hearing loss of the linked Iranian family was caused by a novel missense mutation in the MYO15A gene. This mutation is the first to be reported in the world and affects the first MyTH4 domain of the protein. PMID:27635202

  8. Rescue of the temperature-sensitive, autosomal-recessive mutation R298S in the sodium-bicarbonate cotransporter NBCe1-A characterized by a weakened dimer and abnormal aggregation

    PubMed Central

    Gill, Harindarpal S.; Choi, Kun-Young; Kammili, Lakshmi; Popratiloff, Anastas

    2015-01-01

    Background Band keratopathy, an ocular disease that is characterized by hypercalcemia and opaque bands across the cornea, has been associated with kidney disease. Type-II renal tubular acidosis (RTA), a condition in which the kidneys fail to recover bicarbonate (HCO3−) in the proximal tubule of the nephron, results in HCO3− wastage in the urine and low blood pH. The development of these diseases is associated with autosomal-recessive mutations in the Na+-coupled HCO3− cotransporter NBCe1-A located at the basolateral membranes of either cell type. Methods We provide insight into the devastating R298S mutation found in type-II RTA-afflicted individuals using confocal-microscopy imaging of fluorescently-tagged NBCe1-A and NBCe1-A-R298S molecules expressed in human corneal endothelial and proximal tubule cells and from in-depth biophysical studies of their cytoplasmic N-terminal domains (Nt and Nt-R298S), including Nt crystal structure, melting-temperature, and homodimer dissociation constant (KD) analyses. Results We illuminate and rescue trafficking defects of the R298S mutation of NBCe1-A. The KD for Nt monomer-dimer equilibrium is established. The KD for Nt-R298S is significantly higher, but immeasurable due to environmental factors (pH, temperature, concentration) that result in dimer instability leading to precipitation. The crystal structure of Nt-dimer shows that R298 is part of a putative substrate conduit and resides near the dimer interface held together by hydrogen-bond networks. Conclusions The R298S is a temperature-sensitive mutation in Nt that results in instability of the colloidal system leading to abnormal aggregation. General significance Our findings provide new perspectives to the aberrant mechanism of certain ocular pathologies and type-II RTA associated with the R298S mutation. PMID:25743102

  9. Genetics Home Reference: autosomal recessive hypotrichosis

    MedlinePlus

    ... bumps called hyperkeratotic follicular papules that develop around hair follicles , which are specialized structures in the skin where ... division (proliferation) and maturation (differentiation) of cells within hair follicles . These cell processes are important for the normal ...

  10. [Autosomal recessive limb-girdle muscular dystrophy].

    PubMed

    Hernández-Caballero, Marta E; Miranda-Duarte, Antonio; Escobar-Cedillo, Rosa E; Villegas-Castrejon, Hilda

    2010-10-16

    Muscular dystrophies are a heterogeneous group of hereditary diseases characterized by loss of muscle and weakness of non neurogenic origin. They are caused by mutations in one or more genes involved in the formation of muscle cells. The discovery of several proteins in the muscle began with the discovery of dystrophin, 130 years after the clinical description of muscular dystrophy. Currently, due to a better understanding of the biology of normal and diseased muscle, has achieved a classification at the molecular level of different types of muscular dystrophies, according to the protein that is affected. This has been particularly important for limb girdle muscular dystrophies, which present clinical features that can lead to confusion with Duchenne muscular dystrophy. Moreover, in recent years has encouraged the development of therapies in the near future could provide a solution for restoring the function of the muscle fiber.

  11. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome.

    PubMed

    Budny, Bartlomiej; Chen, Wei; Omran, Heymut; Fliegauf, Manfred; Tzschach, Andreas; Wisniewska, Marzena; Jensen, Lars R; Raynaud, Martine; Shoichet, Sarah A; Badura, Magda; Lenzner, Steffen; Latos-Bielenska, Anna; Ropers, Hans-Hilger

    2006-09-01

    We report on a large family in which a novel X-linked recessive mental retardation (XLMR) syndrome comprising macrocephaly and ciliary dysfunction co-segregates with a frameshift mutation in the OFD1 gene. Mutations of OFD1 have been associated with oral-facial-digital type 1 syndrome (OFD1S) that is characterized by X-chromosomal dominant inheritance and lethality in males. In contrast, the carrier females of our family were clinically inconspicuous, and the affected males suffered from severe mental retardation, recurrent respiratory tract infections and macrocephaly. All but one of the affected males died from respiratory problems in infancy; and impaired ciliary motility was confirmed in the index patient by high-speed video microscopy examination of nasal epithelium. This family broadens the phenotypic spectrum of OFD1 mutations in an unexpected way and sheds light on the complexity of the underlying disease mechanisms.

  12. Cytochrome b[sub 558]-negative, autosomal recessive chronic granulomatous disease: Two new mutations in the cyctochrome b[sub 558] light chain of the NADPH oxidase (p22-phox)

    SciTech Connect

    Boer, M. de; Klein, A. de; Weening, R.S.; Roos, D. ); Hossle, J.P.; Seger, R.; Corbeel, L.

    1992-11-01

    Chronic granulomatous disease (CGD) is characterized by the failure of activated phagocytes to generate superoxide. Defects in at least four different genes lead to CGD. Patients with the X-linked form of CGD have mutations in the gene for the beta-subunit of cytochrome b[sub 558] (gp91-phox). Patients with a rare autosomal recessive form of CGD have mutations in the gene for the alpha-subunit of this cytochrome (p22-phox). Usually, this leads to the absence of cytochrome b[sub 558] in the phagocytes (A22[sup 0] CGD). The authors studied the molecular defect in five European patients from three unrelated families with this type of CGD. P22-phox mRNA was reverse-transcribed, and the coding region was amplified by PCR in one fragment and sequenced. Three patients from one family, with parents that were first cousins, were homozygous for a single base substitution (G-297[yields]A) resulting in a nonconservative amino acid change (Arg-90-Gln). This mutation was previously found in a compound heterozygote A22[sup 0] CGD patient. Another patient, also from first-cousin parents, was homozygous for an A-309[yields]G mutation in the open reading frame that predicts a nonconservative amino acid replacement (His-94[yields]Arg). The fifth patient was also born from a first-cousin marriage and was shown to be homozygous for the absence of exon 4 from the cDNA. In this patient, a G[yields]A substitution was found at position 1 one intron 4 in the genomic DNA. Therefore, the absence of exon 4 in the cDNA of this patient is due to a splicing error. Two additional polymorphisms were also identified - one silent mutation in the open reading frame (G-508[l arrow][r arrow]A) and one A-640[l arrow][r arrow]G mutation in the 3'untranslated region of the p22-phox mRNA. This last mutation destroys a DraIII recognition site and is therefore potentially useful for RFLP analysis of CGD families. 22 refs., 4 figs., 2 tabs.

  13. The impact of the great recession on community-based mental health organizations: an analysis of top managers' perceptions of the economic downturn's effects and adaptive strategies used to manage the consequences in Ohio.

    PubMed

    Sweeney, Helen Anne; Knudsen, Kraig

    2014-04-01

    The Great Recession of 2007-2009 adversely affected the financial stability of the community-based mental health infrastructure in Ohio. This paper presents survey results of the type of adaptive strategies used by Ohio community-based mental health organizations to manage the consequences of the economic downturn. Results were aggregated into geographical classifications of rural, mid-sized urban, and urban. Across all groups, respondents perceived, to varying degrees, that the Great Recession posed a threat to their organization's survival. Urban organizations were more likely to implement adaptive strategies to expand operations while rural and midsized urban organizations implemented strategies to enhance internal efficiencies.

  14. Recombination suppression in the vicinity of the breakpoints of a balanced 1:11 autosomal translocation associated with schizophrenia and other forms of major mental illness

    SciTech Connect

    He, L.; Blackwood, D.H.R.; Maclean, A.W.

    1994-09-01

    The frequency and extent of pairing failure around human translocations is unknown. We have examined the pattern of recombination around the breakpoints of a balanced autosomal translocation t(1:11)(q43:q21) associated with major mental illness. We have postulated that the association with mental illness in the family has not arisen by chance, but rather that functional disruption of a gene at or near a breakpoint site is responsible. Efforts to isolate the breakpoints for molecular analysis of the region are now at an advanced stage. On the other hand if pairing failure is occurring in the family in the region of the breakpoints, a susceptibility allele for mental illness, acting independently of the translocation, may be located some distance away. DNA was available from seventeen carriers and ten non-translocation carriers, giving a total of thirty-one informative meioses spanning 4 generations. The derivative one and eleven chromosomes were also isolated in somatic cell hybrids and were used to confirm allele phase. We genotyped the pedigree members using nine markers covering 30 cMs on either side of both the chromosome one and eleven breakpoints. No recombinants were found with markers within 3 cMs of either breakpoint. Four markers at an average of 7 cMs respectively on either side of the two breakpoints gave a total of three crossovers from thirty-one meioses versus an expected 9, demonstrating (p<0.05) significant recombination suppression. By contrast, examination of chromosome regions at greater distances from the breakpoints showed recombination rates similar to those expected from CEPH data with no evidence of suppression. We conclude that crossover suppression occurs in this family but is restricted to a region within 7 cMs of the breakpoints.

  15. Absence of PAX6 gene mutations in Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation)

    SciTech Connect

    Glaser, T.; Maas, R.L. ); Ton, C.C.T.; Housman, D.E. ); Mueller, R.; Oliver, C. ); Petzl-Erler, M.L. ); Nevin, N.C. )

    1994-01-01

    The PAX6 gene is expressed at high levels in the developing eye and cerebellum and is mutated in patients with autosomal dominant aniridia. The authors have tested the role of PAX6 mutations in three families with Gillespie syndrome, a rare autosomal recessive condition consisting of partial aniridia, cerebellar ataxia, and mental retardation. Single-strand conformational polymorphism analysis of affected individuals revealed no alteration of PAX6 sequences. In two families, the disease trait segregates independently from chromosome 11p markers flanking PAX6. The authors conclude that Gillespie syndrome is genetically distinct from autosomal dominant aniridia. 28 refs., 2 figs., 1 tab.

  16. Localization to Xq22 and clinical update of a family with X-linked recessive mental retardation with progression sensorineural deafness, progressive tapeto-retinal degeneration and dystonia

    SciTech Connect

    Tranebjaerg, L.; Schwartz, C.; Huggins, K.; Barker, D.; Stevenson, R.; Arena, J.F.; Gedde-Dahl, T.; Mikkelsen, M.; Mellgren, S.; Anderson, K. ||||

    1994-07-15

    In a reinvestigation of a six-generation Norwegian family, originally reported with non-syndromic X-linked recessive deafness by Mohr and Mageroy, we have demonstrated several syndromic manifestations. The 10 clinically characterized affected males range in age from 14-61 years, and show progressive mental deterioration and visual disability. Ophthalmological and electrophysiological studies showed myopia, decreased visual acuity, combined cone-rod dystrophy as well as central areolar dystrophy by means of ERG. Brain CT-scans showed cortical and central atrophy without predilection to specific areas. Linkage analysis, using X-chromosomal RFLPs and CA-repeats, yielded a maximum LOD score of 4.37 with linkage to DXS17. DXS17 is localized to Xq22. One recombinant with COL4A5 (deficient in Alport syndrome) was observed. Results from the studies of this family will be important in reclassification of non-syndromic X-linked deafness since the family now represents syndromic deafness and XLMR with a specific phenotype.

  17. TBC1D24 Mutation Causes Autosomal Dominant Non-Syndromic Hearing Loss

    PubMed Central

    Azaiez, Hela; Booth, Kevin T.; Bu, Fengxiao; Huygen, Patrick; Shibata, Seiji; Shearer, A. Eliot; Kolbe, Diana; Meyer, Nicole; Black-Ziegelbein, E. Ann; Smith, Richard J.H.

    2014-01-01

    Hereditary hearing loss (HHL) is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal dominant non-syndromic hearing loss (ADNSHL) we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole exome sequencing (WES) to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase-activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL (ARNSHL), syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation and seizures (DOORS syndrome), and a wide range of epileptic disorders. PMID:24729539

  18. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome.

    PubMed

    Krawitz, Peter M; Schweiger, Michal R; Rödelsperger, Christian; Marcelis, Carlo; Kölsch, Uwe; Meisel, Christian; Stephani, Friederike; Kinoshita, Taroh; Murakami, Yoshiko; Bauer, Sebastian; Isau, Melanie; Fischer, Axel; Dahl, Andreas; Kerick, Martin; Hecht, Jochen; Köhler, Sebastian; Jäger, Marten; Grünhagen, Johannes; de Condor, Birgit Jonske; Doelken, Sandra; Brunner, Han G; Meinecke, Peter; Passarge, Eberhard; Thompson, Miles D; Cole, David E; Horn, Denise; Roscioli, Tony; Mundlos, Stefan; Robinson, Peter N

    2010-10-01

    Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.

  19. Recession Rebound

    ERIC Educational Resources Information Center

    Weinstein, Margery

    2011-01-01

    A return to normal after a crisis is a good thing. Who doesn't want back what once seemed lost? The problem is it usually isn't a simple task figuring out how to patch together a scaled-back training program. When the recession hit in fall 2008, trainers were asked to scale down programming and make do with fewer resources. With a recovery in full…

  20. Gastrocnemius recession.

    PubMed

    Anderson, John G; Bohay, Donald R; Eller, Erik B; Witt, Bryan L

    2014-12-01

    The Grand Rapids Arch Collapse classifications create a novel system for categorizing and correlating numerous common foot and ankle conditions related to a falling arch. The algorithm for treating these conditions is exceptionally replicable and has excellent outcomes. Gastrocnemius equinus diagnosis plays a crucial role in the pathology of arch collapse. A contracture of the gastrocnemius muscle is increasingly recognized as the cause of several foot and ankle conditions. The authors have expanded their indications for gastrocnemius recession to include arch pain without radiographic abnormality, calcaneus apophysitis, plantar fasciitis/fibromas, Achilles tendonosis, early-onset diabetic Charcot arthropathy, and neuropathic forefoot ulcers.

  1. Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1.

    PubMed

    Haque, M Emdadul; Mount, Matthew P; Safarpour, Farzaneh; Abdel-Messih, Elizabeth; Callaghan, Steve; Mazerolle, Chantal; Kitada, Tohru; Slack, Ruth S; Wallace, Valerie; Shen, Jie; Anisman, Hymie; Park, David S

    2012-06-29

    Mutations in the mitochondrial PTEN-induced kinase 1 (Pink1) gene have been linked to Parkinson disease (PD). Recent reports including our own indicated that ectopic Pink1 expression is protective against toxic insult in vitro, suggesting a potential role for endogenous Pink1 in mediating survival. However, the role of endogenous Pink1 in survival, particularly in vivo, is unclear. To address this critical question, we examined whether down-regulation of Pink1 affects dopaminergic neuron loss following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the adult mouse. Two model systems were utilized: virally delivered shRNA-mediated knockdown of Pink1 and germ line-deficient mice. In both instances, loss of Pink1 generated significant sensitivity to damage induced by systemic MPTP treatment. This sensitivity was associated with greater loss of dopaminergic neurons in the Substantia Nigra pars compacta and terminal dopamine fiber density in the striatum region. Importantly, we also show that viral mediated expression of two other recessive PD-linked familial genes, DJ-1 and Parkin, can protect dopaminergic neurons even in the absence of Pink1. This evidence not only provides strong evidence for the role of endogenous Pink1 in neuronal survival, but also supports a role of DJ-1 and Parkin acting parallel or downstream of endogenous Pink1 to mediate survival in a mammalian in vivo context.

  2. A new locus (SPG47) maps to 1p13.2-1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum.

    PubMed

    Blumkin, Lubov; Lerman-Sagie, Tally; Lev, Dorit; Yosovich, Keren; Leshinsky-Silver, Esther

    2011-06-15

    The hereditary spastic paraplegias (HSP) are a heterogeneous group of genetic neurodegenerative disorders in which the main feature is progressive spasticity of the lower limbs due to pyramidal tract dysfunction. Clinically HSP are divided into two forms: a pure form that presents with progressive lower limb spasticity and weakness, sensory signs and bladder dysfunction, and a complicated form, associated with more extensive neurological and extra neurological signs as well as pathological findings on brain imaging. The clinical variability observed in HSP is supported by the large underlying genetic heterogeneity. Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterized by a slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the most frequent gene associated with HSP-TCC, encodes spatacsin, a protein of unknown function. We describe two siblings from an Arabic consanguineous family with slowly progressive spastic paraparesis, mental retardation, seizures, thin corpus callosum and periventricular white matter abnormalities. Homozygosity mapping identified a novel single candidate region of 7.3 Mb on chromosome 1p13.2-1p12. The finding of a new locus for AR-HSP-TCC further demonstrates the extensive genetic heterogeneity of this condition.

  3. Genetics Home Reference: autosomal recessive hyper-IgE syndrome

    MedlinePlus

    ... is a disorder of the immune system. A hallmark feature of the condition is recurrent infections that ... have a greater-than-average risk of developing cancer, particularly cancers of the blood or skin. Related ...

  4. Mutation of ATF6 causes autosomal recessive achromatopsia.

    PubMed

    Ansar, Muhammad; Santos-Cortez, Regie Lyn P; Saqib, Muhammad Arif Nadeem; Zulfiqar, Fareeha; Lee, Kwanghyuk; Ashraf, Naeem Mahmood; Ullah, Ehsan; Wang, Xin; Sajid, Sundus; Khan, Falak Sher; Amin-ud-Din, Muhammad; Smith, Joshua D; Shendure, Jay; Bamshad, Michael J; Nickerson, Deborah A; Hameed, Abdul; Riazuddin, Saima; Ahmed, Zubair M; Ahmad, Wasim; Leal, Suzanne M

    2015-09-01

    Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1-q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.

  5. Genetics Home Reference: autosomal recessive axonal neuropathy with neuromyotonia

    MedlinePlus

    ... with neuromyotonia is a rare form of inherited peripheral neuropathy. This group of conditions affects an estimated 1 ... Page National Institute of Neurological Disorders and Stroke: Peripheral Neuropathy Fact Sheet Educational Resources (2 links) Merck Manual ...

  6. Genetics Home Reference: autosomal recessive congenital stationary night blindness

    MedlinePlus

    ... PM, Lachapelle P, McCall MA, Koenekoop RK, Bergen AA, Kamermans M, Gregg RG. GPR179 is required for ... FM, McCall MA, Riemslag FC, Gregg RG, Bergen AA, Kamermans M. Mutations in TRPM1 are a common ...

  7. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    MedlinePlus

    ... Page Dupré N, Gros-Louis F, Chrestian N, Verreault S, Brunet D, de Verteuil D, Brais B, Bouchard ... F, Dupré N, Dion P, Fox MA, Laurent S, Verreault S, Sanes JR, Bouchard JP, Rouleau GA. Mutations in ...

  8. [Gingival recessions and orthodontics].

    PubMed

    Renkema, A M; Padmos, J A D; de Quincey, G de

    2015-11-01

    Gingival recessions represent the most visible periodontal disease. The prevalence of gingival recessions is high. The root surface is literally exposed to negative influences such as erosion, abrasion, discoloration and decay. Moreover, gingival recessions can affect the quality of life by increased thermal sensitivity and reduced dento-gingival aesthetics. The aetiology of gingival recessions is complex and considered to be multifactorial. In order to prevent the development of gingival recessions during and after orthodontic treatment, several factors should be taken into account, among which maintenance of optimal oral hygiene and respect for the 'biological envelope' are decisive. Once gingival recessions have developed, orthodontic therapy can play a positive role in their treatment.

  9. Array CGH characterization of an unbalanced X-autosome translocation associated with Xq27.2-qter deletion, 11q24.3-qter duplication and Xq22.3-q27.1 duplication in a girl with primary amenorrhea and mental retardation.

    PubMed

    Chen, Chih-Ping; Lin, Shuan-Pei; Chern, Schu-Rern; Kuo, Yu-Ling; Wu, Peih-Shan; Chen, Yu-Ting; Lee, Meng-Shan; Wang, Wayseen

    2014-02-01

    We present array comparative genomic hybridization (aCGH) characterization of an unbalanced X-autosome translocation with an Xq interstitial segmental duplication in a 16-year-old girl with primary ovarian failure, mental retardation, attention deficit disorder, learning difficulty and facial dysmorphism. aCGH analysis revealed an Xq27.2-q28 deletion, an 11q24.3-q25 duplication, and an inverted duplication of Xq22.3-q27.1. The karyotype was 46,X,der(X)t(X;11)(q27.2;q24.3) dup(X)(q27.1q22.3). We discuss the genotype-phenotype correlation in this case. Our case provides evidence for an association of primary amenorrhea and mental retardation with concomitant unbalanced X-autosome translocation and X chromosome rearrangement.

  10. HPGD mutations cause cranioosteoarthropathy but not autosomal dominant digital clubbing.

    PubMed

    Seifert, Wenke; Beninde, Julia; Hoffmann, Katrin; Lindner, Tom H; Bassir, Christian; Aksu, Fuat; Hübner, Christoph; Verbeek, Nienke E; Mundlos, Stefan; Horn, Denise

    2009-12-01

    Cranio-osteoarthropathy, clinically classified as a variant of primary hypertrophic osteoarthropathy, is a very rare autosomal-recessive condition characterized by delayed closure of the cranial sutures and fontanels, digital clubbing, arthropathy, and periostosis. Recently, mutations in the gene HPGD, which encodes the NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase, were reported in four families affected with primary hypertrophic osteoarthropathy and one family with autosomal-recessive isolated nail clubbing. We report the clinical and molecular findings in four patients from two families affected with cranio-osteoarthropathy and one family with isolated, autosomal dominant digital clubbing. Genome-wide homozygosity mapping identified a locus for cranio-osteoarthropathy harboring the HPGD gene in one affected family. We detected two novel homozygous mutations in HPGD in these families: a missense mutation affecting the NAD(+) binding motif and a frameshift mutation. The clinical presentation in our patients was variable. Digital clubbing and hyperhidrosis were present in all cases. Delayed closure of the cranial sutures and fontanels, periostosis, and arthropathy were not consistent clinical features. No HPGD mutation was detected in a familial case of autosomal dominant isolated digital clubbing. The failure to identify any mutation in a family with an autosomal dominant type of isolated digital clubbing suggests that HPGD is not the major gene for this condition.

  11. Towards a middle-range theory of mental health and well-being effects of employment transitions: Findings from a qualitative study on unemployment during the 2009-2010 economic recession.

    PubMed

    Giuntoli, Gianfranco; Hughes, Skye; Karban, Kate; South, Jane

    2015-07-01

    This article builds upon previous theoretical work on job loss as a status passage to help explain how people's experiences of involuntary unemployment affected their mental well-being during the 2009-2010 economic recession. It proposes a middle-range theory that interprets employment transitions as status passages and suggests that their health and well-being effects depend on the personal and social meanings that people give to them, which are called properties of the transitions. The analyses, which used a thematic approach, are based on the findings of a qualitative study undertaken in Bradford (North England) consisting of 73 people interviewed in 16 focus groups. The study found that the participants experienced their job losses as divestment passages characterised by three main properties: experiences of reduced agency, disruption of role-based identities, for example, personal identity crises, and experiences of 'spoiled identities', for example, experiences of stigma. The proposed middle-range theory allows us to federate these findings together in a coherent framework which makes a contribution to illuminating not just the intra-personal consequences of unemployment, that is, its impact on subjective well-being and common mental health problems, but also its inter-personal consequences, that is, the hidden and often overlooked social processes that affect unemployed people's social well-being. This article discusses how the study findings and the proposed middle-range theory can help to address the theoretical weaknesses and often contradictory empirical findings from studies that use alternative frameworks, for example, deprivation models and 'incentive theory' of unemployment.

  12. Recess Makes Kids Smarter

    ERIC Educational Resources Information Center

    Adams, Caralee

    2011-01-01

    Recess has been scaled back or cut altogether in a number of schools around the country. The trend can be traced back to the late eighties and was accelerated under No Child Left Behind. Districts under pressure to show academic progress began to squeeze as much instruction into the day as possible. Others eliminated recess because of concerns…

  13. Starving for Recess

    ERIC Educational Resources Information Center

    Patt, Mary Johnson

    2011-01-01

    Every weekday, millions of American schoolchildren throw away their half-eaten cafeteria lunches so that they can run outside to play. The traditional placement of lunch before recess, coupled with the recent decline in overall recess time to meet academic time constraints, forces children to choose between two essential needs: (1) food; and (2)…

  14. Recess--It's Indispensable!

    ERIC Educational Resources Information Center

    Jarrett, Olga; Waite-Stupiansky, Sandra

    2009-01-01

    The demise of recess in many elementary schools--and of outdoor play in general--is an issue of great concern to many members of the Play, Policy, and Practice Interest Forum. Most people remember recess as an important part of the school day. It was a time to be outdoors; to organize games; to play on the swings, slides, and other playground…

  15. More Recess Time, Please!

    ERIC Educational Resources Information Center

    Chang, Rong; Coward, Fanni Liu

    2015-01-01

    Students in Shanghai, China, get much more recess time than their U.S. counterparts throughout their education. As U.S. education reform efforts seek ways of raising achievement, they have begun replacing recess with academic time. The lesson from Shanghai is that this may not be the best strategy. But whether the Shanghai system of more and…

  16. Autosomal dominant vitreoretinochoroidopathy (ADVIRC).

    PubMed Central

    Blair, N P; Goldberg, M F; Fishman, G A; Salzano, T

    1984-01-01

    We report the second family recognised to have autosomal dominant vitreoretinochoroidopathy. The clinical features were (1) autosomal dominant inheritance; (2) peripheral, coarse pigmentary degeneration of the fundus for 360 degrees, with a relatively discrete posterior border in the equatorial region (this finding may be pathognomonic); (3) superficial punctate yellowish-white opacities in the retina; (4) various vascular abnormalities; (5) breakdown of the blood-retinal barrier; (6) retinal neovascularisation; (7) vitreous abnormalities; and (8) choroidal atrophy. Visual reduction was mainly due to macular oedema or vitreous haemorrhage. Images PMID:6689931

  17. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  18. Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia.

    PubMed

    Renaud, Mathilde; Guissart, Claire; Mallaret, Martial; Ferdinandusse, Sacha; Cheillan, David; Drouot, Nathalie; Muller, Jean; Claustres, Mireille; Tranchant, Christine; Anheim, Mathieu; Koenig, Michel

    2016-08-01

    Peroxisomal biogenesis disorders (PBDs) consist of a heterogeneous group of autosomal recessive diseases, in which peroxisome assembly and proliferation are impaired leading to severe multisystem disease and early death. PBDs include Zellweger spectrum disorders (ZSDs) with a relatively mild clinical phenotype caused by PEX1, (MIM# 602136), PEX2 (MIM# 170993), PEX6 (MIM# 601498), PEX10 (MIM# 602859), PEX12 (MIM# 601758), and PEX16 (MIM# 603360) mutations. Three adult patients are reported belonging to a non-consanguineous French family affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs. Mental retardation and diabetes mellitus were optional. The age at onset was in childhood or in adolescence (3-15 years). Brain MRI showed marked cerebellar atrophy. Biochemical blood analyses suggested a mild peroxisomal defect. With whole exome sequencing, two mutations in PEX10 were found in the three patients: c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the missense change p.Arg311Gln. The phenotypic spectrum related to PEX10 mutations includes slowly progressive, syndromic recessive ataxia.

  19. Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy

    SciTech Connect

    Rudnik-Schoeneborn, S.; Wirth, B.; Zerres, K. )

    1994-07-01

    Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explanation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (= .09[+-].06 for onset at 10-36 mo and .13[+-].07 for onset at >36 mo; and P = .09[+-]0.7 for SMA IIIa and .12[+-].07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given. 29 refs., 2 figs., 5 tabs.

  20. [Autosomal dominant polycystic kidney].

    PubMed

    Jorge Adad, S; Estevão Barbosa, M; Fácio Luíz, J M; Furlan Rodrigues, M C; Iwamoto, S

    1996-01-01

    A 48-year-old male had autosomic dominant polycystic kidneys with dimensions, to the best of our knowledge, never previously reported; the right kidney weighed 15,100 g and measured 53 x 33 x 9cm and the left one 10.200 g and 46 x 21 x 7cm, with cysts measuring up to 14cm in diameter. Nephrectomy was done to control persistent hematuria and to relief disconfort caused by the large kidneys. The renal function is stable four years after transplantation.

  1. A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis.

    PubMed

    Ugur Iseri, Sibel A; Durlu, Yusuf K; Tolun, Aslihan

    2010-10-01

    Cone-rod dystrophies are inherited retinal dystrophies that are characterized by progressive degeneration of cones and rods, causing an early decrease in central visual acuity and colour vision defects, followed by loss of peripheral vision in adolescence or early adult life. Both genetic and clinical heterogeneity are well known. In a family with autosomal recessive cone-rod dystrophy, genetic analyses comprising genome scan with microsatellite markers, fine mapping and candidate gene approach resulted in the identification of a homozygous missense GUCY2D mutation. This is the first GUCY2D mutation associated with autosomal recessive cone-rod dystrophy rather than Leber's congenital amaurosis (LCA), a severe disease leading to childhood blindness. This study hence establishes GUCY2D, which is a common cause for both recessive LCA and dominant cone-rod dystrophy, as a good candidate for autosomal recessive cone-rod dystrophy.

  2. The Recess Renaissance

    ERIC Educational Resources Information Center

    Keeler, Rusty

    2015-01-01

    The author tells of his work around the country and world on transforming how schools do recess, free play, and outside time by transforming their outdoor spaces to match. Instead of a playground of fixed structures like traditional school grounds, newer spaces are filled with loose materials that children can use to build forts, dens, and tree…

  3. The population genetics of X-autosome synthetic lethals and steriles.

    PubMed

    Lachance, Joseph; Johnson, Norman A; True, John R

    2011-11-01

    Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation-selection balance conditions for X-autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X-autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane's rule.

  4. What Is a Recessive Allele?

    ERIC Educational Resources Information Center

    American Biology Teacher, 1991

    1991-01-01

    Presents four misconceptions students have concerning the concepts of recessive and dominant alleles. Discusses the spectrum of dominant-recessive relationships, different levels of analysis between phenotype and genotype, possible causes of dominance, and an example involving wrinkled peas. (MDH)

  5. School Recess and Social Development.

    ERIC Educational Resources Information Center

    Jambor, Tom

    1994-01-01

    Discusses the role of school recess periods in children's social development and academic achievement. Also examines changing attitudes toward the use of recess periods in the United States and other nations, and presents strategies for classroom teachers to use in advocating school recess periods in their schools and communities. (MDM)

  6. Deep sequencing reveals 50 novel genes for recessive cognitive disorders.

    PubMed

    Najmabadi, Hossein; Hu, Hao; Garshasbi, Masoud; Zemojtel, Tomasz; Abedini, Seyedeh Sedigheh; Chen, Wei; Hosseini, Masoumeh; Behjati, Farkhondeh; Haas, Stefan; Jamali, Payman; Zecha, Agnes; Mohseni, Marzieh; Püttmann, Lucia; Vahid, Leyla Nouri; Jensen, Corinna; Moheb, Lia Abbasi; Bienek, Melanie; Larti, Farzaneh; Mueller, Ines; Weissmann, Robert; Darvish, Hossein; Wrogemann, Klaus; Hadavi, Valeh; Lipkowitz, Bettina; Esmaeeli-Nieh, Sahar; Wieczorek, Dagmar; Kariminejad, Roxana; Firouzabadi, Saghar Ghasemi; Cohen, Monika; Fattahi, Zohreh; Rost, Imma; Mojahedi, Faezeh; Hertzberg, Christoph; Dehghan, Atefeh; Rajab, Anna; Banavandi, Mohammad Javad Soltani; Hoffer, Julia; Falah, Masoumeh; Musante, Luciana; Kalscheuer, Vera; Ullmann, Reinhard; Kuss, Andreas Walter; Tzschach, Andreas; Kahrizi, Kimia; Ropers, H Hilger

    2011-09-21

    Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.

  7. A gene for autosomal dominant congenital nystagmus localizes to 6p12

    SciTech Connect

    Kerrison, J.B.; Arnould, V.J.; Koenekoop, R.K.

    1996-05-01

    Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at {theta} = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor mystagmus to an 18-cM region between D6S271 and D6S455. 16 refs., 1 fig., 1 tab.

  8. CT of the pericardial recesses

    SciTech Connect

    Levy-Ravetch, M.; Auh, Y.H.; Rubenstein, W.A.; Whalen, J.P.; Kazam, E.

    1985-04-01

    Within the pericardial cavity there are several recesses where fluid can collect in close contiguity to the major bronchi and lymph nodes. These include the transverse sinus, behind the ascending aorta and pulmonary trunk; the oblique sinus, behind the left atrium; and the left pulmonic recess, between the left pulmonary artery and the left superior pulmonary vein. There are also smaller pericardial recesses between the superior and inferior pulmonary veins, posterolateral to the superior vena cava, and between the inferior vena cava and coronary sinus. An understanding of sectional anatomy is valuable for differentiation of fluid within these recesses from mediastinal masses or enlarged lymph nodes on computed tomographic scans.

  9. Gingival overgrowth, congenital generalized hypertrichosis, mental retardation and epilepsy: case report and overview.

    PubMed

    Douzgou, Sofia; Mingarelli, Rita; Dallapiccola, Bruno

    2009-10-01

    We report on a patient with congenital generalized hypertrichosis, mental retardation, tonic-clonic seizures with onset during the first year of life and gingival overgrowth, unrelated to antiepileptic treatment. This phenotype represents a unique combination of features, bridging the variable association of gingival overgrowth, generalized hypertrichosis, mental retardation or epilepsy. This may occur in combination with nail and/or digital anomalies, as in Zimmermann-Laband syndrome, and the broader phenotypes of the Anavi, Göhlich-Ratmann and Ramon syndromes. On the basis of the clinical overlap between our patient and these disorders inherited either as autosomal dominant or recessive traits and unknown molecular defects, a recurrence risk of one in four was considered appropriate.

  10. Non-syndromic autosomal-dominant deafness.

    PubMed

    Petersen, M B

    2002-07-01

    Non-syndromic deafness is a paradigm of genetic heterogeneity. More than 70 loci have been mapped, and 25 of the nuclear genes responsible for non-syndromic deafness have been identified. Autosomal-dominant genes are responsible for about 20% of the cases of hereditary non-syndromic deafness, with 16 different genes identified to date. In the present article we review these 16 genes, their function and their contribution to deafness in different populations. The complexity is underlined by the fact that several of the genes are involved in both dominant and recessive non-syndromic deafness or in both non-syndromic and syndromic deafness. Mutations in eight of the genes have so far been detected in only single dominant deafness families, and their contribution to deafness on a population base might therefore be limited, or is currently unknown. Identification of all genes involved in hereditary hearing loss will help in the understanding of the basic mechanisms underlying normal hearing, will facilitate early diagnosis and intervention and might offer opportunities for rational therapy.

  11. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

    PubMed

    Akawi, Nadia; McRae, Jeremy; Ansari, Morad; Balasubramanian, Meena; Blyth, Moira; Brady, Angela F; Clayton, Stephen; Cole, Trevor; Deshpande, Charu; Fitzgerald, Tomas W; Foulds, Nicola; Francis, Richard; Gabriel, George; Gerety, Sebastian S; Goodship, Judith; Hobson, Emma; Jones, Wendy D; Joss, Shelagh; King, Daniel; Klena, Nikolai; Kumar, Ajith; Lees, Melissa; Lelliott, Chris; Lord, Jenny; McMullan, Dominic; O'Regan, Mary; Osio, Deborah; Piombo, Virginia; Prigmore, Elena; Rajan, Diana; Rosser, Elisabeth; Sifrim, Alejandro; Smith, Audrey; Swaminathan, Ganesh J; Turnpenny, Peter; Whitworth, James; Wright, Caroline F; Firth, Helen V; Barrett, Jeffrey C; Lo, Cecilia W; FitzPatrick, David R; Hurles, Matthew E

    2015-11-01

    Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

  12. Endoscopic Gastrocnemius Intramuscular Aponeurotic Recession

    PubMed Central

    Lui, Tun Hing

    2015-01-01

    Gastrocnemius aponeurotic recession is the surgical treatment for symptomatic gastrocnemius contracture. Endoscopic gastrocnemius recession procedures has been developed recently and reported to have fewer complications and better cosmetic outcomes. Classically, this is performed at the aponeurosis distal to the gastrocnemius muscle attachment. We describe an alternative endoscopic approach in which the intramuscular portion of the aponeurosis is released. PMID:26900563

  13. Fort Play Children Recreate Recess

    ERIC Educational Resources Information Center

    Powell, Mark

    2007-01-01

    Recess beckons well before it actually arrives. Its allure can be heard in children's lunchtime conversations as they discuss imaginary roles, plans, alliances and teams, with an obvious appetite for play and its unbounded possibility. For some children, recess provides the most important reasons to come to school. In team sports, games of chase…

  14. Endoscopic Gastrocnemius Intramuscular Aponeurotic Recession.

    PubMed

    Lui, Tun Hing

    2015-10-01

    Gastrocnemius aponeurotic recession is the surgical treatment for symptomatic gastrocnemius contracture. Endoscopic gastrocnemius recession procedures has been developed recently and reported to have fewer complications and better cosmetic outcomes. Classically, this is performed at the aponeurosis distal to the gastrocnemius muscle attachment. We describe an alternative endoscopic approach in which the intramuscular portion of the aponeurosis is released.

  15. LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.

    PubMed

    Kim, J W; Seymen, F; Lee, K E; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Shin, T J; Kyun, H K; Simmer, J P; Hu, J C-C

    2013-10-01

    Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.

  16. Recurrent Cholangitis in a Patient with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Caroli's Disease.

    PubMed

    Hasegawa, Eiko; Sawa, Naoki; Hoshino, Junichi; Suwabe, Tatsuya; Hayami, Noriko; Yamanouchi, Masayuki; Sekine, Akinari; Hiramatsu, Rikako; Imafuku, Aya; Kawada, Masahiro; Ubara, Yoshifumi; Imamura, Tsunao; Takaichi, Kenmei

    We herein present a rare case of an autosomal dominant polycystic kidney disease (ADPKD) patient with Caroli's disease, a congenital embryonic biliary tree ductal plate abnormality often associated with autosomal recessive polycystic kidney disease. A 76-year-old woman with ADPKD on hemodialysis was admitted to our hospital with recurrent cholangitis and hepatobiliary stones. Caroli's disease was diagnosed according to typical imaging findings of cystic intrahepatic bile duct dilatation and the central dot sign. Hepatobiliary system abnormalities such as Caroli's disease should be considered in febrile ADPKD patients, even in the absence of typical clinical signs or symptoms.

  17. Gingival Recession: Review and Strategies in Treatment of Recession

    PubMed Central

    Pradeep, Koppolu; Rajababu, Palaparthy; Satyanarayana, Durvasula; Sagar, Vidya

    2012-01-01

    One of the most common esthetic concerns associated with the periodontal tissues is gingival recession. Gingival recession is the exposure of root surfaces due to apical migration of the gingival tissue margins; gingival margin migrates apical to the cementoenamel junction. Although it rarely results in tooth loss, marginal tissue recession is associated with thermal and tactile sensitivity, esthetic complaints, and a tendency toward root caries. This paper reviews etiology, consequences, and the available surgical procedures for the coverage of exposed root surfaces, including three case reports. PMID:23082256

  18. Nonallelic heterogeneity in autosomal dominant retinitis pigmentosa with incomplete penetrance

    SciTech Connect

    Kim, S.K.; Berson, E.L.; Dryja, T.P.

    1994-08-01

    Retinitis pigmentosa is a group of retinal diseases in which photoreceptor cells throughout the retina degenerate. Although there is considerable genetic heterogeneity (autosomal dominant, autosomal recessive, and X-linked forms exist), there is a possibility that some clinically defined subtypes of the disease may be the result of mutations at the same locus. One possible clinically defined subtype is that of autosomal dominant retinitis pigmentosa (ADRP) with incomplete penetrance. Whereas in most families with ADRP, carriers can be clearly identified because of visual loss, ophthalmological findings, or abnormal electroretinograms (ERGs), in occasional families some obligate carriers are asymptomatic and have normal or nearly normal ERGs even late in life. A recent paper reported the mapping of the diseases locus in one pedigree (designated adRP7) with ADRP with incomplete penetrance to chromosome 7p. To test the idea that ADRP with incomplete penetrance may be genetically homogeneous, we have evaluated whether a different family with incomplete penetrance also has a disease gene linked to the same region. 4 refs., 1 fig., 1 tab.

  19. Hereditary sideroblastic anaemia in 4 siblings of a Libyan family--autosomal inheritance.

    PubMed

    Kasturi, J; Basha, H M; Smeda, S H; Swehli, M

    1982-01-01

    Most of the hereditary sideroblastic anaemias are inherited as x-linked recessive traits and are often pyridoxine responsive. The present paper describes the classical features of sideroblastic anaemia in 2 male and 2 female siblings of a Libyan family. All 4 children had severe anaemia and moderate hepato-splenomegaly. The equal severity of the disease in all 4 family members suggests autosomal inheritance.

  20. Neuroscience in recession?

    PubMed

    Amara, Susan G; Grillner, Sten; Insel, Tom; Nutt, David; Tsumoto, Tadaharu

    2011-05-01

    As the global financial downturn continues, its impact on neuroscientists - both on an individual level and at the level of their research institute - becomes increasingly apparent. How is the economic crisis affecting neuroscience funding, career prospects, international collaborations and scientists' morale in different parts of the world? Nature Reviews Neuroscience gauged the opinions of a number of leading neuroscientists: the President of the Society for Neuroscience, the President Elect of the British Neuroscience Association, the former President of the Japan Neuroscience Society, the President of the Federation of European Neuroscience Societies and the Director of the US National Institute of Mental Health. Their responses provide interesting and important insights into the regional impact of the global financial downturn, with some causes for optimism for the future of neuroscience research.

  1. Health Impacts of the Great Recession: A Critical Review

    PubMed Central

    Goldman-Mellor, Sidra; Falconi, April; Downing, Janelle

    2016-01-01

    The severity, sudden onset, and multipronged nature of the Great Recession (2007–2009) provided a unique opportunity to examine the health impacts of macroeconomic downturn. We comprehensively review empirical literature examining the relationship between the Recession and mental and physical health outcomes in developed nations. Overall, studies reported detrimental impacts of the Recession on health, particularly mental health. Macro- and individual-level employment- and housing-related sequelae of the Recession were associated with declining fertility and self-rated health, and increasing morbidity, psychological distress, and suicide, although traffic fatalities and population-level alcohol consumption declined. Health impacts were stronger among men and racial/ethnic minorities. Importantly, strong social safety nets in some European countries appear to have buffered those populations from negative health effects. This literature, however, still faces multiple methodological challenges, and more time may be needed to observe the Recession’s full health impact. We conclude with suggestions for future work in this field. PMID:27239427

  2. [Anesthesia for cesarean section in a patient with recessive dystrophic epidermolysis bullosa].

    PubMed

    García, I; Manrique, S; Muñoz, C; López-Gil, M V; Munar, F; Montferrer, N

    2009-11-01

    Recessive dystrophic epidermolysis bullosa is inherited as a rare autosomal disorder which causes blisters to form in the skin. We describe the treatment of a 39-year-old parturient with this condition. She was scheduled for elective cesarean section at 37 weeks' gestation. The patient had widespread skin lesions, had lost fingers, and had esophageal stenosis. The cesarean was performed under spinal anesthesia without complications. Recessive dystrophic epidermolysis bullosa requires adaptation of anesthetic technique that includes control over posture and careful handling of the skin. Material for attaching monitoring devices and inserting venous lines must be adapted to the particular deformities and skin lesions present.

  3. Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation.

    PubMed

    McDermott, David F; Gammon, Bryan; Snijders, Peter J; Mbata, Ihunanya; Phifer, Beth; Howland Hartley, A; Lee, Chyi-Chia Richard; Murphy, Philip M; Hwang, Sam T

    2009-01-01

    Epidermodysplasia verruciformis is a rare genodermatosis characterized by abnormal susceptibility to infection with specific human papillomavirus serotypes. Epidermodysplasia verruciformis is a genetically heterogeneous disease, and autosomal recessive and X-linked inheritance patterns have been reported. Nonsense mutations in the genes EVER1 and EVER2 have been identified in over 75% of cases. We present epidermodysplasia verruciformis in a father and a son with typical histologic and clinical findings that occur in the absence of mutations in EVER1 or EVER2. Epidermodysplasia verruciformis in this father/son pair in a nonconsanguinous pedigree is consistent with autosomal dominant inheritance. This is the first report of autosomal dominant transmission of epidermodysplasia verruciformis, providing further evidence of the genetic heterogeneity of epidermodysplasia verruciformis.

  4. Objective hydrograph baseflow recession analysis

    NASA Astrophysics Data System (ADS)

    Thomas, Brian F.; Vogel, Richard M.; Famiglietti, James S.

    2015-06-01

    A streamflow hydrograph recession curve expresses the theoretical relationship between aquifer structure and groundwater outflow to a stream channel. That theoretical relationship is often portrayed empirically using a recession plot defined as a plot of ln(-dQ/dt) versus ln(Q), where Q is streamflow discharge. Such hydrograph recession plots are commonly used to estimate recession parameters, aquifer properties and for evaluating alternative hydrologic hypotheses. We introduce a comprehensive and objective approach to analyze baseflow recessions with innovations including the use of quantile regression, efficient and objective numerical estimation of dQ/dt, inclusion of groundwater withdrawals, and incorporation of seasonal effects. We document that these innovations when all combined, lead to significant improvements, over previous studies, in our ability to discern the theoretical behavior of stream aquifer systems. A case study reveals that our methodology enables us to reject the simple linear reservoir hypothesis of stream aquifer interactions for watersheds in New Jersey and results in improved correlations between low flow statistics and aquifer properties for those same watersheds.

  5. Neonatal diabetes mellitus and cerebellar hypoplasia/agenesis: report of a new recessive syndrome

    PubMed Central

    Hoveyda, N.; Shield, J.; Garrett, C.; Chong, W; Beardsall, K.; Bentsi-Enchill, E.; Mallya, H.; Thompson, M.

    1999-01-01

    Classical neonatal diabetes mellitus is defined as hyperglycaemia occurring within the first six weeks of life in term infants. Cerebellar agenesis is rare. We report three cases of neonatal diabetes mellitus, cerebellar hypoplasia/agenesis, and dysmorphism occurring within a highly consanguineous family. This constellation of abnormalities has not previously been described. Two of these cases are sisters and the third case is a female first cousin. The pattern of inheritance suggests this is a previously undescribed autosomal recessive disorder. Prenatal diagnosis of the condition in this family was possible by demonstration of the absence of the cerebellum and severe IUGR.


Keywords: cerebellar agenesis/hypoplasia; neonatal diabetes mellitus; dysmorphic features; autosomal recessive PMID:10507728

  6. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia

    PubMed Central

    Coutelier, Marie; Goizet, Cyril; Durr, Alexandra; Habarou, Florence; Morais, Sara; Dionne-Laporte, Alexandre; Tao, Feifei; Konop, Juliette; Stoll, Marion; Charles, Perrine; Jacoupy, Maxime; Matusiak, Raphaël; Alonso, Isabel; Tallaksen, Chantal; Mairey, Mathilde; Kennerson, Marina; Gaussen, Marion; Schule, Rebecca; Janin, Maxime; Morice-Picard, Fanny; Durand, Christelle M.; Depienne, Christel; Calvas, Patrick; Coutinho, Paula; Saudubray, Jean-Marie; Rouleau, Guy; Brice, Alexis; Nicholson, Garth; Darios, Frédéric; Loureiro, José L.; Zuchner, Stephan; Ottolenghi, Chris; Mochel, Fanny

    2015-01-01

    Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes. PMID:26026163

  7. Algebra, Home Mortgages, and Recessions

    ERIC Educational Resources Information Center

    Mariner, Jean A. Miller; Miller, Richard A.

    2009-01-01

    The current financial crisis and recession in the United States present an opportunity to discuss relevant applications of some topics in typical first-and second-year algebra and precalculus courses. Real-world applications of percent change, exponential functions, and sums of finite geometric sequences can help students understand the problems…

  8. Firms Still Training Despite Recession

    ERIC Educational Resources Information Center

    Felstead, Alan; Green, Francis; Jewson, Nick

    2011-01-01

    It is commonly assumed that company training is one of the first casualties in times of recession. Falling recruitment, pressures to cut costs and a focus on short-term survival force businesses to put training on the backburner. Expecting the worst, the UK Commission for Employment and Skills (UKCES), the Confederation of British Industry (CBI)…

  9. Autosomal dominant epidermodysplasia verruciformis: a clinicotherapeutic experience in two cases.

    PubMed

    Vohra, Surbhi; Sharma, Nand Lal; Shanker, Vinay; Mahajan, Vikram K; Jindal, Nidhi

    2010-01-01

    Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by a unique susceptibility to cutaneous infection by a group of phylogenetically related human papilloma viruses (HPVs). These patients show a defect in cell-mediated immunity specific toward the causative HPVs that lead to lifelong disease. The defect is usually inherited as autosomal recessive trait and presents clinically with plane warts, pityriasis versicolor-like lesions and reddish verrucous plaques. Dysplastic and malignant changes in the form of actinic keratoses, Bowen's disease and squamous cell carcinoma (SCC) are common but metastasis occurs rarely. A totally effective treatment against EV is as yet highly desirable. Two siblings having autosomal dominant EV presented with multiple actinic keratoses in addition to classic lesions. One of them had also developed well-differentiated SCC over forehead with metastases to regional lymph nodes. They were treated with combination of excision of small malignant/premalignant lesions, topical 5-flurouracil and sun protection. Additionally, elective excision/grafting of large SCC was performed after chemotherapy/radiotherapy in patient with metastatic SCC. Oral acitretin (25 mg/day) was of benefit in the other patient. Overall clinicotherapeutic experience in both the patients is discussed here.

  10. An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13.

    PubMed

    Hatsell, S J; Stevens, H; Jackson, A P; Kelsell, D P; Zvulunov, A

    2003-07-01

    A new variant of congenital exfoliative ichthyosis in two related Bedouin families is reported. The ichthyosis appeared shortly after birth as a fine peeling of nonerythematous skin on the palms and soles. The prominent well-demarcated areas of denuded skin in moist and traumatized regions resembled the 'mauserung' phenomenon of ichthyosis bullosa of Siemens (IBS). Unlike in IBS, epidermolysis is absent on histological examination. Electron microscopy revealed a prominent intercellular oedema and numerous aggregates of keratin filaments in basal keratinocytes. Abnormal keratin (K) 1 expression was seen in the affected epidermis; however, all other keratins, including K2e, had a distribution comparable to that seen in normal controls. A maximum two-point LOD score of 2.53 and multipoint LOD score of 3.76 were obtained for marker D12S390, suggesting linkage to the type II keratin cluster on chromosome 12q13. Sequencing of both the K1 gene, the promotor and the 3' calcium regulatory region did not reveal a mutation. K2e and K5 genes, as well as the genes harboured within the minimal region, such as retinoic acid receptor gamma, sterol O-acyltransferase 2, integrin beta7 and insulin-like growth factor binding protein-6, were also excluded. This combination of clinical, histological, ultrastructural and genetic features has not been previously reported in other congenital exfoliative ichthyoses. We therefore suggest that it represents a new form of exfoliative ichthyosis.

  11. Characterization of six novel mutations in CYBA: the gene causing autosomal recessive chronic granulomatous disease.

    PubMed

    Teimourian, Shahram; Zomorodian, Elham; Badalzadeh, Mohsen; Pouya, Alireza; Kannengiesser, Caroline; Mansouri, Davood; Cheraghi, Taher; Parvaneh, Nima

    2008-06-01

    One of the rarest forms of chronic granulomatous disease (CGD) is caused by mutations in CYBA, which encodes the p22-phox subunit of the phagocyte NADPH oxidase, leading to defective intracellular killing. This study investigated eight patients (six males and two females) from seven consanguineous, unrelated families with clinical CGD, positive family history and p22-phox deficiency. Mutation analysis of CYBA showed six different novel mutations: deletion of exons 3, 4 and 5; a missense mutation in exon 6 (c.373G>A); a splice site mutation in intron 5 (c.369+1G>A); a frameshift in exon 6 (c.385delGAGC); a frameshift in exon 3 (c.174delG); and a frameshift in exon 4 (c.223delC).

  12. A new autosomal recessive congenital contractural syndrome in an Israeli Bedouin kindred.

    PubMed

    Landau, Daniella; Mishori-Dery, Anat; Hershkovitz, Reli; Narkis, Ginat; Elbedour, Khalil; Carmi, Rivka

    2003-02-15

    We describe 23 cases with a syndrome of congenital contractures belonging to a large, inbred Israeli-Bedouin kindred. The phenotype described is similar to the Finnish type lethal congenital contracture syndrome yet differs in the following ways: by some additional craniofacial/ocular findings, by the lack of hydrops, multiple pterygia, and fractures, and by the normal duration of pregnancy. The major unique and previously undescribed clinical feature in our patients is a markedly distended urinary bladder as well as other urinary abnormalities. The vast majority of the cases died shortly after birth. Sonographic prenatal diagnosis was possible as early as 15 weeks gestation by demonstrating fetal akinesia, limb contractures, hydramnios, and distended urinary bladder. Linkage to 5q and 9q34 loci has been excluded.

  13. [An autosomal recessive syndrome with myopathy and central and peripheral nervous system involvement (author's transl)].

    PubMed

    Warter, J M; Marescaux, C; Coquillat, G; Walter, P; Micheletti, G; Rohmer, F

    1981-01-01

    Three of 11 children, offspring of a consanguineous marriage, presented a progressive myopathy and seizures, associated with symptoms suggesting both central and peripheral nervous system involvement. The ultrastructural muscular lesions were not specific. The association of severe impairment of muscle tissue and of central nervous system is rare, being described in centronuclear myopathy, cerebromuscular dystrophy, Kearns-Sayre syndrome and in a few isolated cases. Clinically only these isolated observations and especially the Kearns-Sayre syndrome demonstrate analogies to our observations. These data lead us to the discussion of the specificity of ultrastructural lesions, especially mitochondrial abnormalities. Some authors consider these abnormalities to be the biochemical hallmark for ophthalmoplegia plus, whereas for others, especially Drachman, they are an inconstant and nonspecific finding, merely the consequence and not the cause of this disease. These observations argue for the relationship between muscular pathology and nervous system dysfunction.

  14. Aquaporin-2: new mutations responsible for autosomal-recessive nephrogenic diabetes insipidus—update and epidemiology

    PubMed Central

    El Tarazi, Abdulah; Matar, Jessica; Lussier, Yoann; Arthus, Marie-Françoise; Lonergan, Michèle; Bockenhauer, Detlef; Bissonnette, Pierre

    2012-01-01

    It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a ‘pure’ type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O. PMID:26069764

  15. SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome

    PubMed Central

    Horga, Alejandro; Tomaselli, Pedro J.; Gonzalez, Michael A.; Laurà, Matilde; Muntoni, Francesco; Manzur, Adnan Y.; Hanna, Michael G.; Blake, Julian C.; Houlden, Henry; Züchner, Stephan

    2016-01-01

    Objective: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor–1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene. Methods: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations. Results: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN. Conclusions: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies. PMID:27629094

  16. Genetics Home Reference: autosomal recessive spastic ataxia of Charlevoix-Saguenay

    MedlinePlus

    ... also been identified in Japan, Turkey, Tunisia, Spain, Italy, and Belgium. The signs and symptoms of ARSACS ... some genetic conditions more common in particular ethnic groups? Genetic Changes Mutations in the SACS gene cause ...

  17. [Autosomal recessive GTPCH 1 deficiency: the importance of the analysis of neurotransmitters in cerebrospinal fluid].

    PubMed

    Moreno-Medinilla, E E; Mora-Ramirez, M D; Calvo-Medina, R; Martinez-Anton, J

    2016-06-01

    Introduccion. El deficit de la enzima trifosfato de guanosina ciclohidrolasa 1 (GTPCH 1) origina una disminucion de la sintesis de la tetrahidrobiopterina (BH4), cofactor indispensable en la sintesis de la tirosina, la dopamina y la serotonina. Es una enfermedad poco frecuente que produce un retraso o regresion psicomotora y trastornos del movimiento, y en la que el tratamiento puede mejorar o incluso corregir la clinica. Caso clinico. Niña afecta de deficit de GTPCH con herencia autosomica recesiva, diagnosticada a los 14 meses con estudio del liquido cefalorraquideo con deficit de pterinas, HVA y 5-HIAA, test de sobrecarga de fenilalanina y estudio genetico positivos. La clinica comenzo a los 5 meses con temblor cefalico y de las extremidades superiores, en reposo e intencional, intermitente, que desaparecio en un mes. El desarrollo psicomotor era normal, destacaba una hipotonia axial leve en la exploracion y las pruebas complementarias realizadas fueron normales. Posteriormente presento regresion psicomotora con perdida del sosten cefalico, disminucion de los movimientos activos, dificultad para la manipulacion bimanual, hipomimia e hipotonia global grave, lo que motivo el estudio de una encefalopatia progresiva. Tras el diagnostico de deficit de GTPCH, inicio tratamiento sustitutivo con levodopa/carbidopa, OH triptofano y BH4, con muy buena evolucion tanto motora como cognitiva. Actualmente, la paciente tiene 5 años, presenta un desarrollo psicomotor adecuado a su edad, cursa tercer curso de educacion infantil y ha alcanzado el nivel de su clase. Conclusion. Hay que destacar en este caso la mejoria tan satisfactoria, tanto motora como cognitiva, tras iniciar el tratamiento sustitutivo, ya que el nivel cognitivo suele quedar afectado en muchos casos.

  18. Genetics Home Reference: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

    MedlinePlus

    ... Infarcts and Leukoencephalopathy MalaCards: carasil syndrome Merck Manual Consumer Version: Overview of Delirium and Dementia Merck Manual Consumer Version: Overview of Stroke Orphanet: CARASIL Patient Support ...

  19. Aquaporin-2: new mutations responsible for autosomal-recessive nephrogenic diabetes insipidus-update and epidemiology.

    PubMed

    Bichet, Daniel G; El Tarazi, Abdulah; Matar, Jessica; Lussier, Yoann; Arthus, Marie-Françoise; Lonergan, Michèle; Bockenhauer, Detlef; Bissonnette, Pierre

    2012-06-01

    It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a 'pure' type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a pure NDI phenotype with loss of water but normal conservation of sodium, potassium, chloride and calcium. Patients with hereditary hypokalemic salt-losing tubulopathies have a complex phenotype with loss of water and ions. They have polyhydramnios, hypercalciuria and hypo- or isosthenuria and were found to bear KCNJ1 (ROMK) and SLC12A1 (NKCC2) mutations. Patients with polyhydramnios, profound polyuria, hyponatremia, hypochloremia, metabolic alkalosis and sensorineural deafness were found to bear BSND mutations. These clinical phenotypes demonstrate the critical importance of the proteins ROMK, NKCC2 and Barttin to transfer NaCl in the medullary interstitium and thereby to generate, together with urea, a hypertonic milieu. This editorial describes two new developments: (i) the genomic information provided by the sequencing of the AQP2 gene is key to the routine care of these patients, and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families and (ii) the expression of AQP2 mutants in Xenopus oocytes and in polarized renal tubular cells recapitulates the clinical phenotypes and reveals a continuum from severe loss of function with urinary osmolalities <150 mOsm/kg H2O to milder defects with urine osmolalities >200 mOsm/kg H2O.

  20. A second family with autosomal recessive spondylometaphyseal dysplasia and early death.

    PubMed

    Mégarbané, André; Mehawej, Cybel; El Zahr, Amir; Haddad, Soha; Cormier-Daire, Valérie

    2014-04-01

    We report on a consanguineous Lebanese family in which two sibs had pre- and post-natal growth retardation, developmental delay, large anterior fontanel, prominent forehead, low-set ears, depressed nasal bridge, short nose, anteverted nares, increased nasal width, prominent abdomen, and short limbs. Radiographs disclosed the presence of wormian bones, platyspondyly, decreased interpedicular distance at the lumbar vertebrae, square iliac bones, horizontal acetabula, trident acetabula, hypoplastic ischia, partial agenesis of the sacrum, ribs with cupped ends, short long bones with abnormal modeling, slight widening of the distal femoral metaphyses, and delayed epiphyseal ossification. Both sibs had a severe cardiomegaly and died at around 24 months from a heart failure. Differential diagnosis suggests that this is a second family presenting a newly described early lethal chondrodysplasia first reported by [Mégarbané et al. (2008); Am J Med Genet Part A 146A:2916-2919].

  1. ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta

    PubMed Central

    Wang, Shih-Kai; Choi, Murim; Richardson, Amelia S.; Reid, Bryan M.; Lin, Brent P.; Wang, Susan J.; Kim, Jung-Wook; Simmer, James P.; Hu, Jan C.-C.

    2014-01-01

    Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell–ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three integrin beta 6 (ITGB6) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an ITGB6 transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an ITGB6 transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an ITGB6 transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of Nance–Horan Syndrome (NHS Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing ITGB6 mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell–matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects. PMID:24305999

  2. Mutations in the lipase-H gene causing autosomal recessive hypotrichosis and woolly hair.

    PubMed

    Mehmood, Sabba; Jan, Abid; Muhammad, Dost; Ahmad, Farooq; Mir, Hina; Younus, Muhammad; Ali, Ghazanfar; Ayub, Muhammad; Ansar, Muhammad; Ahmad, Wasim

    2015-08-01

    Hypotrichosis is characterised by sparse scalp hair, sparse to absent eyebrows and eyelashes, or absence of hair from other parts of the body. In few cases, the condition is associated with tightly curled woolly scalp hair. The present study searched for disease-causing sequence variants in the genes in four Pakistani lineal consanguineous families exhibiting features of hypotrichosis or woolly hair. A haplotype analysis established links in all four families to the LIPH gene located on chromosome 3q27.2. Subsequently, sequencing LIPH identified a novel non-sense mutation (c.328C>T; p.Arg110*) in one and a previously reported 2-bp deletion mutation (c.659_660delTA, p.Ile220ArgfsX29) in three other families.

  3. ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta.

    PubMed

    Wang, Shih-Kai; Choi, Murim; Richardson, Amelia S; Reid, Bryan M; Lin, Brent P; Wang, Susan J; Kim, Jung-Wook; Simmer, James P; Hu, Jan C-C

    2014-04-15

    Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell-ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three integrin beta 6 (ITGB6) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an ITGB6 transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an ITGB6 transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an ITGB6 transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of Nance-Horan Syndrome (NHS Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing ITGB6 mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell-matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects.

  4. Loss-of-Function Mutations of ILDR1 Cause Autosomal-Recessive Hearing Impairment DFNB42

    PubMed Central

    Borck, Guntram; Rehman, Atteeq Ur; Lee, Kwanghyuk; Pogoda, Hans-Martin; Kakar, Naseebullah; von Ameln, Simon; Grillet, Nicolas; Hildebrand, Michael S.; Ahmed, Zubair M.; Nürnberg, Gudrun; Ansar, Muhammad; Basit, Sulman; Javed, Qamar; Morell, Robert J.; Nasreen, Nabilah; Shearer, A. Eliot; Ahmad, Adeel; Kahrizi, Kimia; Shaikh, Rehan S.; Ali, Rana A.; Khan, Shaheen N.; Goebel, Ingrid; Meyer, Nicole C.; Kimberling, William J.; Webster, Jennifer A.; Stephan, Dietrich A.; Schiller, Martin R.; Bahlo, Melanie; Najmabadi, Hossein; Gillespie, Peter G.; Nürnberg, Peter; Wollnik, Bernd; Riazuddin, Saima; Smith, Richard J.H.; Ahmad, Wasim; Müller, Ulrich; Hammerschmidt, Matthias; Friedman, Thomas B.; Riazuddin, Sheikh; Leal, Suzanne M.; Ahmad, Jamil; Kubisch, Christian

    2011-01-01

    By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment. PMID:21255762

  5. Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa

    PubMed Central

    Bandah-Rozenfeld, Dikla; Collin, Rob W.J.; Banin, Eyal; Ingeborgh van den Born, L.; Coene, Karlien L.M.; Siemiatkowska, Anna M.; Zelinger, Lina; Khan, Muhammad I.; Lefeber, Dirk J.; Erdinest, Inbar; Testa, Francesco; Simonelli, Francesca; Voesenek, Krysta; Blokland, Ellen A.W.; Strom, Tim M.; Klaver, Caroline C.W.; Qamar, Raheel; Banfi, Sandro; Cremers, Frans P.M.; Sharon, Dror; den Hollander, Anneke I.

    2010-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases caused by progressive degeneration of the photoreceptor cells. Using autozygosity mapping, we identified two families, each with three affected siblings sharing large overlapping homozygous regions that harbored the IMPG2 gene on chromosome 3. Sequence analysis of IMPG2 in the two index cases revealed homozygous mutations cosegregating with the disease in the respective families: three affected siblings of Iraqi Jewish ancestry displayed a nonsense mutation, and a Dutch family displayed a 1.8 kb genomic deletion that removes exon 9 and results in the absence of seven amino acids in a conserved SEA domain of the IMPG2 protein. Transient transfection of COS-1 cells showed that a construct expressing the wild-type SEA domain is properly targeted to the plasma membrane, whereas the mutant lacking the seven amino acids appears to be retained in the endoplasmic reticulum. Mutation analysis in ten additional index cases that were of Dutch, Israeli, Italian, and Pakistani origin and had homozygous regions encompassing IMPG2 revealed five additional mutations; four nonsense mutations and one missense mutation affecting a highly conserved phenylalanine residue. Most patients with IMPG2 mutations showed an early-onset form of RP with progressive visual-field loss and deterioration of visual acuity. The patient with the missense mutation, however, was diagnosed with maculopathy. The IMPG2 gene encodes the interphotoreceptor matrix proteoglycan IMPG2, which is a constituent of the interphotoreceptor matrix. Our data therefore show that mutations in a structural component of the interphotoreceptor matrix can cause arRP. PMID:20673862

  6. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4.

    PubMed

    Bras, Jose; Alonso, Isabel; Barbot, Clara; Costa, Maria Manuela; Darwent, Lee; Orme, Tatiana; Sequeiros, Jorge; Hardy, John; Coutinho, Paula; Guerreiro, Rita

    2015-03-05

    Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.

  7. Recessive congenital myotonia resulting from maternal isodisomy of chromosome 7: a case report

    PubMed Central

    2009-01-01

    Autosomal dominant (Thomsen) and recessive (Becker) congenital myotonia are two different non dystrophic disorders, due to allelic mutations of the muscle chloride channel gene, located on chromosome 7q35. More than two thirds of the muscle chloride channel gene mutations occur independently in unique families and cause the recessive form of the disease. Becker disease is more common and severe than Thomsen disease. Here, we report on the clinical and molecular data of the first patient with maternal uniparental disomy for chromosome 7 and recessive congenital myotonia. The proband is a 15-year-old male, homozygous for a missense mutation within muscle chloride channel gene, showing few characteristic signs of the Silver Russell Syndrome. PMID:20181190

  8. School recess, social connectedness and health: a Canadian perspective.

    PubMed

    McNamara, Lauren; Colley, Paige; Franklin, Nicole

    2015-10-25

    Children need opportunities to establish positive social connections at school, yet many school playgrounds are challenged by social conflict that can undermine these connections. When children's social needs go unmet, the resultant feelings of loneliness, isolation and self-doubt can cumulatively lead to mental and physical illness. Because recess is typically the only time during the school day that children are free to socialize and play, we propose a more thoughtful way of thinking about it: from the lens of belongingness. Schools are, historically, designed for instruction. We argue, however, that we need to attend to children's social needs at school. We highlight current research from social neuroscience, belonging and social connectedness in order to delineate the pathways between daily school recess and developmental health trajectories. We then consolidate an array of research on play, social interaction and school change to suggest four areas that could benefit from consideration in research, practice and policy: (i) the culture of recess, (ii) the importance of healthy role models on the playground, (iii) the necessity of activities, options and variety during recess and (iv) the significance of space and spatial layout (indoor and outdoor). We bridge our discussion with the conception of health as described in the Ottawa Charter and emphasize the need to build alliances across sectors to assist schools in their efforts to support children's overall health needs.

  9. A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition.

    PubMed

    Xu, Guoqiang; Jiang, Xiaogang; Jaffrey, Samie R

    2013-10-11

    A nonsense mutation in cereblon (CRBN) causes autosomal recessive nonsyndromic mental retardation. Cereblon is a substrate receptor for the Cullin-RING E3 ligase complex and couples the ubiquitin ligase to specific ubiquitination targets. The CRBN nonsense mutation (R419X) results in a protein lacking 24 amino acids at its C terminus. Although this mutation has been linked to mild mental retardation, the mechanism by which the mutation affects CRBN function is unknown. Here, we used biochemical and mass spectrometric approaches to explore the function of this mutant. We show that the protein retains its ability to assemble into a Cullin-RING E3 ligase complex and catalyzes the ubiquitination of CRBN-target proteins. However, we find that this mutant exhibits markedly increased levels of autoubiquitination and is more readily degraded by the proteasome than the wild type protein. We also show that the level of the mutant protein can be restored by a treatment of cells with a clinically utilized proteasome inhibitor, suggesting that this agent may be useful for the treatment of mental retardation associated with the CRBN R419X mutation. These data demonstrate that enhanced autoubiquitination and degradation account for the defect in CRBN activity that leads to mental retardation.

  10. Differences in Physical Activity during School Recess

    ERIC Educational Resources Information Center

    Ridgers, Nicola D.; Saint-Maurice, Pedro F.; Welk, Gregory J.; Siahpush, Mohammad; Huberty, Jennifer

    2011-01-01

    Background: School recess provides a daily opportunity for physical activity engagement. The purpose of this study was to examine physical activity levels during recess by gender, ethnicity, and grade, and establish the contribution of recess to daily school physical activity levels. Methods: Two hundred and ten children (45% boys) from grades 3…

  11. A new locus for autosomal dominant stargardt-like disease maps to chromosome 4.

    PubMed Central

    Kniazeva, M; Chiang, M F; Morgan, B; Anduze, A L; Zack, D J; Han, M; Zhang, K

    1999-01-01

    Stargardt disease (STGD) is the most common hereditary macular dystrophy and is characterized by decreased central vision, atrophy of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD is most commonly inherited as an autosomal recessive trait, but many families have been described in which features of the disease are transmitted in an autosomal dominant manner. A recessive locus has been identified on chromosome 1p (STGD1), and dominant loci have been mapped to both chromosome 13q (STGD2) and chromosome 6q (STGD3). In this study, we describe a kindred with an autosomal dominant Stargardt-like phenotype. A genomewide search demonstrated linkage to a locus on chromosome 4p, with a maximum LOD score of 5.12 at a recombination fraction of.00, for marker D4S403. Analysis of extended haplotypes localized the disease gene to an approximately 12-cM interval between loci D4S1582 and D4S2397. Therefore, this kindred establishes a new dominant Stargardt-like locus, STGD4. PMID:10205271

  12. Mapping of a gene for alopecia with mental retardation syndrome (APMR3) on chromosome 18q11.2-q12.2.

    PubMed

    Wali, A; Ali, G; John, P; Lee, K; Chishti, M S; Leal, S M; Ahmad, W

    2007-09-01

    Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder characterized by total or partial absence of hair from the scalp and other parts of the body and associated with mental retardation. Previously, we have reported the mapping of two alopecia and mental retardation genes (APMR1 and APMR2) on human chromosome 3. In the present study, after excluding both of these loci through linkage analysis, a whole genome scan was performed by genotyping 396 polymorphic microsatellite markers located on 22 autosomes and the X and Y chromosomes. A disease locus was mapped to a 10.9 cM region, flanked by markers D18S866 and D18S811, on chromosome 18q11.2-q12.2. A maximum two-point LOD score of 3.03 at theta= 0.0 was obtained with marker D18S1102. Multipoint linkage analysis resulted in maximum LOD scores of 4.03 with several markers in the candidate region. According to the Rutgers combined linkage-physical map of the human genome (build 36) this region covers 12.17 Mb. DNA sequence analysis of nine candidate genes including DSC3, DSC1, DSG1, DSG4, DSG3, ZNF397, ZNF271, ZNF24 and ZNF396 did not reveal any sequence variants in the affected individuals of the family presented here.

  13. Recessive optic atrophy, sensorimotor neuropathy and cataract associated with novel compound heterozygous mutations in OPA1

    PubMed Central

    LEE, JINHO; JUNG, SUNG-CHUL; HONG, YOUNG BIN; YOO, JEONG HYUN; KOO, HEASOO; LEE, JA HYUN; HONG, HYUN DAE; KIM, SANG-BEOM; CHUNG, KI WHA; CHOI, BYUNG-OK

    2016-01-01

    Mutations in the optic atrophy 1 gene (OPA1) are associated with autosomal dominant optic atrophy and 20% of patients demonstrate extra-ocular manifestations. In addition to these autosomal dominant cases, only a few syndromic cases have been reported thus far with compound heterozygous OPA1 mutations, suggestive of either recessive or semi-dominant patterns of inheritance. The majority of these patients were diagnosed with Behr syndrome, characterized by optic atrophy, ataxia and peripheral neuropathy. The present study describes a 10-year-old boy with Behr syndrome presenting with early-onset severe optic atrophy, sensorimotor neuropathy, ataxia and congenital cataracts. He had optic atrophy and was declared legally blind at six years old. Electrophysiological, radiological, and histopathological findings were compatible with axonal sensorimotor polyneuropathy. At birth, he presented with a congenital cataract, which has not been previously described in patients with OPA1 mutations. Whole exome sequencing indicated a pair of novel compound heterozygous mutations: p.L620fs*13 (c.1857–1858delinsT) and p.R905Q (c.G2714A). Neither mutation was observed in controls (n=300), and thus, they were predicted to be pathogenic by multiple in silico analyses. The mutation sites were highly conserved throughout different vertebrate species. The patients parents did not have any ophthalmic or neurologic symptoms and the results of electrophysiological studies were normal, suggestive of an autosomal recessive pattern of inheritance. The present study identified novel compound heterozygous OPA1 mutations in a patient with recessive optic atrophy, sensorimotor neuropathy and congenital cataracts, indicating an expansion of the clinical spectrum of pathologies associated with OPA1 mutations. Thus, OPA1 gene screening is advisable in the workup of patients with recessive optic atrophy, particularly with Behr syndrome and cataracts. PMID:27150940

  14. An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans

    PubMed Central

    Gao, Ziyue; Waggoner, Darrel; Stephens, Matthew; Ober, Carole; Przeworski, Molly

    2015-01-01

    The effects of inbreeding on human health depend critically on the number and severity of recessive, deleterious mutations carried by individuals. In humans, existing estimates of these quantities are based on comparisons between consanguineous and nonconsanguineous couples, an approach that confounds socioeconomic and genetic effects of inbreeding. To overcome this limitation, we focused on a founder population that practices a communal lifestyle, for which there is almost complete Mendelian disease ascertainment and a known pedigree. Focusing on recessive lethal diseases and simulating allele transmissions, we estimated that each haploid set of human autosomes carries on average 0.29 (95% credible interval [0.10, 0.84]) recessive alleles that lead to complete sterility or death by reproductive age when homozygous. Comparison to existing estimates in humans suggests that a substantial fraction of the total burden imposed by recessive deleterious variants is due to single mutations that lead to sterility or death between birth and reproductive age. In turn, comparison to estimates from other eukaryotes points to a surprising constancy of the average number of recessive lethal mutations across organisms with markedly different genome sizes. PMID:25697177

  15. An estimate of the average number of recessive lethal mutations carried by humans.

    PubMed

    Gao, Ziyue; Waggoner, Darrel; Stephens, Matthew; Ober, Carole; Przeworski, Molly

    2015-04-01

    The effects of inbreeding on human health depend critically on the number and severity of recessive, deleterious mutations carried by individuals. In humans, existing estimates of these quantities are based on comparisons between consanguineous and nonconsanguineous couples, an approach that confounds socioeconomic and genetic effects of inbreeding. To overcome this limitation, we focused on a founder population that practices a communal lifestyle, for which there is almost complete Mendelian disease ascertainment and a known pedigree. Focusing on recessive lethal diseases and simulating allele transmissions, we estimated that each haploid set of human autosomes carries on average 0.29 (95% credible interval [0.10, 0.84]) recessive alleles that lead to complete sterility or death by reproductive age when homozygous. Comparison to existing estimates in humans suggests that a substantial fraction of the total burden imposed by recessive deleterious variants is due to single mutations that lead to sterility or death between birth and reproductive age. In turn, comparison to estimates from other eukaryotes points to a surprising constancy of the average number of recessive lethal mutations across organisms with markedly different genome sizes.

  16. The Great Recession and Mother’s Health

    PubMed Central

    Currie, Janet; Duque, Valentina; Garfinkel, Irwin

    2016-01-01

    We use longitudinal data from the Fragile Families and Child Well-being Study to investigate the impacts of the Great Recession on the health of mothers. We focus on a wide range of physical and mental health outcomes, as well as health behaviors. We find that increases in the unemployment rate decrease self-reported health status and increase smoking and drug use. We also find evidence of heterogeneous impacts. Disadvantaged mothers—African-American, Hispanic, less educated, and unmarried–experience greater deterioration in their health than advantaged mothers—those who are white, married, and college educated. PMID:27212714

  17. Campus Counseling Centers React to Recession-Related Stress among Students

    ERIC Educational Resources Information Center

    Bushong, Steven

    2009-01-01

    The recession has complicated the path in life that many students had envisioned. As a result, campus mental-health counselors say more students are expressing anxiety about the economy's effect on their future. Visits to campus counseling centers have been climbing for several years, according to the Association for University and College…

  18. Does gingival recession require surgical treatment?

    PubMed Central

    Chan, Hsun-Liang; Chun, Yong-Hee Patricia; MacEachern, Mark

    2016-01-01

    Gingival recession represents a clinical condition in adults frequently encountered in the general dental practice. It is estimated that 23% of adults in the US have one or more tooth surfaces with ≥ 3 mm gingival recession. Clinicians often time face dilemmas of whether or not to treat such a condition surgically. Therefore, we were charged by the editorial board to answer this critical question: “Does gingival recession require surgical treatment?” An initial condensed literature search was performed using a combination of gingival recession and surgery controlled terms and keywords. An analysis of the search results highlights our limited understanding of the factors that often guide the treatment of gingival recession. Understanding the etiology, prognosis and treatment of gingival recession continues to offer many unanswered questions and challenges in the field of periodontics as we strive to provide the best care possible for our patients. PMID:26427577

  19. A case of rare recessive oculopharyngeal muscular dystrophy (OPMD) coexisting with hereditary neuropathy with liability to pressure palsies (HNPP).

    PubMed

    Marsh, Eleanor A; Robinson, David O

    2008-05-01

    Oculopharyngeal muscular dystrophy (OPMD) is typically inherited in an autosomal dominant fashion and is characterized by late onset proximal muscle weakness, ptosis and difficulty swallowing. It is caused by expansion mutations in the PABPN1 gene on chromosome 14q11. There is also a rare recessive form of the disease caused by homozygosity of a very small expansion mutation in the same gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent peripheral monofocal neuropathies. In this report a patient with both recessive OPMD and HNPP is described. The presence of two genetically unlinked neurological diagnoses in the same individual is a rare event and may have delayed the diagnoses.

  20. Recess for Elementary School Students. Position Statement

    ERIC Educational Resources Information Center

    National Association for Sport and Physical Education, 2006

    2006-01-01

    It is the position of the National Association for Sport and Physical Education (NASPE) that all elementary school children should be provided with at least one daily period of recess of at least 20 minutes in length. Recess is an essential component of a comprehensive school physical activity program and of the total education experience for…

  1. The Crucial Role of Recess in Schools

    ERIC Educational Resources Information Center

    Ramstetter, Catherine L.; Murray, Robert; Garner, Andrew S.

    2010-01-01

    Background: Recess is at the heart of a vigorous debate over the role of schools in promoting optimal child development and well-being. Reallocating time to accentuate academic concerns is a growing trend and has put recess at risk. Conversely, pressure to increase activity in school has come from efforts to combat childhood obesity. The purpose…

  2. Strategies for Supporting Recess in Elementary Schools

    ERIC Educational Resources Information Center

    Centers for Disease Control and Prevention, 2014

    2014-01-01

    Recess provides students with a needed break from their structured school day. It can improve children's physical, social, and emotional well-being, and enhance learning. Recess helps children meet the goal of 60 minutes of physical activity (PA) each day, as recommended by the US Department of Health and Human Services. National…

  3. A case of non-hallopeau-siemens recessive dystrophic epidermolysis bullosa.

    PubMed

    Kang, Gyo Shin; Ko, Woo Tae; Kim, Jae Hong; Choi, Sung Min; Kim, Ae Suk; Kim, Dong Hoon; Suh, Moo Kyu

    2009-02-01

    Dystrophic epidermolysis bullosa (DEB) is a rare group of heritable mechanobullous disorders that are characterized by blistering and scarring of the skin and mucosae and these lesions are induced by minor trauma, DEB is also associated with nail dystrophy. DEB can be inherited either in an autosomal recessive or dominant fashion. Regardless of the mode of inheritance, DEB is caused by defects of the ultrastructural entity known as the anchoring fibril, which results in separation of the sublamina densa. Recessive DEB (RDEB) is classified into Hallopeau-Siemens and non-Hallopeau-Siemens. We herein report on a case of non-Hallopeau-Siemens RDEB and there was no family history of this malady, and we present the clinical, histological and electron microscopy findings.

  4. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice.

    PubMed

    Moyer, J H; Lee-Tischler, M J; Kwon, H Y; Schrick, J J; Avner, E D; Sweeney, W E; Godfrey, V L; Cacheiro, N L; Wilkinson, J E; Woychik, R P

    1994-05-27

    A line of transgenic mice was generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. Homozygotes displayed a complex phenotype that included bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker. Additionally, a candidate polycystic kidney disease (PKD) gene was identified whose structure and expression are directly associated with the mutant locus. A complementary DNA derived from this gene predicted a peptide containing a motif that was originally identified in several genes involved in cell cycle control.

  5. Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice

    SciTech Connect

    Moyer, J.H.; Lee-Tischler, M.J.; Kwon, H.Y.; Schrick, J.J. ); Avner, E.D.; Sweeney, W.E. ); Godfrey, V.L.; Cacheiro, N.L.A.; Woychik, R.P. ); Wilkinson, J.E. )

    1994-05-27

    A line of transgenic mice was generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. Homozygotes displayed a complex phenotype that included bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker. Additionally, a candidate polycystic kidney disease (PKD) gene was identified whose structure and expression are directly associated with the mutant locus. A complementary DNA derived from this gene predicted a peptide containing a motif that was originally identified in several genes involved in cell cycle control.

  6. The crucial role of recess in school.

    PubMed

    Murray, Robert; Ramstetter, Catherine

    2013-01-01

    Recess is at the heart of a vigorous debate over the role of schools in promoting the optimal development of the whole child. A growing trend toward reallocating time in school to accentuate the more academic subjects has put this important facet of a child's school day at risk. Recess serves as a necessary break from the rigors of concentrated, academic challenges in the classroom. But equally important is the fact that safe and well-supervised recess offers cognitive, social, emotional, and physical benefits that may not be fully appreciated when a decision is made to diminish it. Recess is unique from, and a complement to, physical education--not a substitute for it. The American Academy of Pediatrics believes that recess is a crucial and necessary component of a child's development and, as such, it should not be withheld for punitive or academic reasons.

  7. The KBG syndrome: confirmation of autosomal dominant inheritance and further delineation of the phenotype.

    PubMed

    Tekin, Mustafa; Kavaz, Asli; Berberoğlu, Merih; Fitoz, Suat; Ekim, Mesiha; Ocal, Gönül; Akar, Nejat

    2004-10-15

    We report on a Turkish family in which the father and his two sons were diagnosed as having the KBG syndrome. Large upper central incisors were the diagnostic finding in all three patients along with mental retardation, cryptorchidism, skeletal abnormalities, and short stature. Our report clearly confirms that the inheritance is autosomal dominant in KBG syndrome, although a high male to female ratio has been observed in published cases.

  8. Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3

    PubMed Central

    Chong, Jessica X.; Burrage, Lindsay C.; Beck, Anita E.; Marvin, Colby T.; McMillin, Margaret J.; Shively, Kathryn M.; Harrell, Tanya M.; Buckingham, Kati J.; Bacino, Carlos A.; Jain, Mahim; Alanay, Yasemin; Berry, Susan A.; Carey, John C.; Gibbs, Richard A.; Lee, Brendan H.; Krakow, Deborah; Shendure, Jay; Nickerson, Deborah A.; Bamshad, Michael J.; Shendure, Jay; Nickerson, Deborah A.; Abecasis, Gonçalo R.; Anderson, Peter; Blue, Elizabeth Marchani; Annable, Marcus; Browning, Brian L.; Buckingham, Kati J.; Chen, Christina; Chin, Jennifer; Chong, Jessica X.; Cooper, Gregory M.; Davis, Colleen P.; Frazar, Christopher; Harrell, Tanya M.; He, Zongxiao; Jain, Preti; Jarvik, Gail P.; Jimenez, Guillaume; Johanson, Eric; Jun, Goo; Kircher, Martin; Kolar, Tom; Krauter, Stephanie A.; Krumm, Niklas; Leal, Suzanne M.; Luksic, Daniel; Marvin, Colby T.; McMillin, Margaret J.; McGee, Sean; O’Reilly, Patrick; Paeper, Bryan; Patterson, Karynne; Perez, Marcos; Phillips, Sam W.; Pijoan, Jessica; Poel, Christa; Reinier, Frederic; Robertson, Peggy D.; Santos-Cortez, Regie; Shaffer, Tristan; Shephard, Cindy; Shively, Kathryn M.; Siegel, Deborah L.; Smith, Joshua D.; Staples, Jeffrey C.; Tabor, Holly K.; Tackett, Monica; Underwood, Jason G.; Wegener, Marc; Wang, Gao; Wheeler, Marsha M.; Yi, Qian; Bamshad, Michael J.

    2015-01-01

    Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development. PMID:25957469

  9. Fine localization of the locus for autosomal dominant retinitis pigmentosa on chromosome 17p

    SciTech Connect

    Goliath, R.; Janssens, P.; Beighton, P.

    1995-10-01

    The term {open_quotes}retintis pigmentosa{close_quotes} (RP) refers to a group of inherited retinal degenerative disorders. Clinical manifestations include night-blindness, with variable age of onset, followed by constriction of the visual field that may progress to total loss of sight in later life. Previous studies have shown that RP is caused by mutations within different genes and may be inherited as an X-linked recessive (XLRRP), autosomal recessive (ARRP), or autosomal dominant (ADRP) trait. The AD form of this group of conditions has been found to be caused by mutations within the rhodopsin gene in some families and the peripherin/RDS gene in others. In addition, some ADRP families have been found to be linked to anonymous markers on 8cen, 7p, 7q,19q, and, more recently, 17p. The ADRP gene locus on the short arm of chromosome 17 was identified in a large South African family (ADRP-SA) of British origin. The phenotypic expression of the disorder, which has been described elsewhere is consistent in the pedigree with an early onset of disease symptoms. In all affected subjects in the family, onset of symptoms commenced before the age of 10 years. 16 refs., 3 figs., 1 tab.

  10. Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation.

    PubMed

    Higgins, Joseph J; Hao, Jin; Kosofsky, Barry E; Rajadhyaksha, Anjali M

    2008-07-01

    A nonsense mutation (R419X) in the human cereblon gene [mutation (mut) CRBN] causes a mild type of autosomal recessive nonsyndromal mental retardation (ARNSMR). CRBN, a cytosolic protein, regulates the assembly and neuronal surface expression of large-conductance Ca(2+)-activated K(+) channels (BK(Ca)) in brain regions involved in memory and learning. Using the real-time quantitative polymerase chain reaction, we show that mut CRBN disturbs the development of adult brain BK(Ca) isoforms. These changes are predicted to result in BK(Ca) channels with a higher intracellular Ca(2+) sensitivity, faster activation, and slower deactivation kinetics. Such alterations may contribute to cognitive impairments in patients with mild ARNSMR.

  11. Autosomal dominant spondylocostal dysostosis is caused by mutation in TBX6.

    PubMed

    Sparrow, Duncan B; McInerney-Leo, Aideen; Gucev, Zoran S; Gardiner, Brooke; Marshall, Mhairi; Leo, Paul J; Chapman, Deborah L; Tasic, Velibor; Shishko, Abduhadi; Brown, Matthew A; Duncan, Emma L; Dunwoodie, Sally L

    2013-04-15

    In humans, congenital spinal defects occur with an incidence of 0.5-1 per 1000 live births. One of the most severe syndromes with such defects is spondylocostal dysostosis (SCD). Over the past decade, the genetic basis of several forms of autosomal recessive SCD cases has been solved with the identification of four causative genes (DLL3, MESP2, LFNG and HES7). Autosomal dominant forms of SCD have also been reported, but to date no genetic etiology has been described for these. Here, we have used exome capture and next-generation sequencing to identify a stoploss mutation in TBX6 that segregates with disease in two generations of one family. We show that this mutation has a deleterious effect on the transcriptional activation activity of the TBX6 protein, likely due to haploinsufficiency. In mouse, Tbx6 is essential for the patterning of the vertebral precursor tissues, somites; thus, mutation of TBX6 is likely to be causative of SCD in this family. This is the first identification of the genetic cause of an autosomal dominant form of SCD, and also demonstrates the potential of exome sequencing to identify genetic causes of dominant diseases even in small families with few affected individuals.

  12. A new autosomal dominant craniofacial deafness syndrome.

    PubMed

    Kassutto, S; Kassutto, Z; Ben-Ami, T; Goodman, R M

    1987-11-01

    A Jewish family is reported in which the proband and her father had congenital hearing loss and unusual facies consisting of facial asymmetry, temporal alopecia with frontal bossing, a broad nasal root and small nasal alae. In addition, both were born with a short frenulum of the tongue. We believe these findings represent a new autosomal dominant deafness syndrome with distinct craniofacial features.

  13. Graduated recession of the superior oblique muscle.

    PubMed Central

    Caldeira, J A

    1975-01-01

    Recession of the superior oblique was performed bilaterally in 12 patients with the A phenomenon and unilaterally in four patients with vertical imbalance. The results are discussed. Images PMID:1191613

  14. Have Employment Patterns in Recessions Changed?.

    ERIC Educational Resources Information Center

    Bowers, Norman

    1981-01-01

    A survey of postwar recessions shows that the increasing proportion of service sector jobs has moderated overall employment declines and that women in nontraditional jobs, Blacks, and youths bear a disproportionate share of job losses. (LRA)

  15. Systematic review of suicide in economic recession

    PubMed Central

    Oyesanya, Mayowa; Lopez-Morinigo, Javier; Dutta, Rina

    2015-01-01

    AIM: To provide a systematic update of the evidence concerning the relationship between economic recession and suicide. METHODS: A keyword search of Ovid Medline, Embase, Embase Classic, PsycINFO and PsycARTICLES was performed to identify studies that had investigated the association between economic recession and suicide. RESULTS: Thirty-eight studies met predetermined selection criteria and 31 of them found a positive association between economic recession and increased suicide rates. Two studies reported a negative association, two articles failed to find such an association, and three studies were inconclusive. CONCLUSION: Economic recession periods appear to increase overall suicide rates, although further research is warranted in this area, particularly in low income countries. PMID:26110126

  16. HYDRORECESSION: A toolbox for streamflow recession analysis

    NASA Astrophysics Data System (ADS)

    Arciniega, S.

    2015-12-01

    Streamflow recession curves are hydrological signatures allowing to study the relationship between groundwater storage and baseflow and/or low flows at the catchment scale. Recent studies have showed that streamflow recession analysis can be quite sensitive to the combination of different models, extraction techniques and parameter estimation methods. In order to better characterize streamflow recession curves, new methodologies combining multiple approaches have been recommended. The HYDRORECESSION toolbox, presented here, is a Matlab graphical user interface developed to analyse streamflow recession time series with the support of different tools allowing to parameterize linear and nonlinear storage-outflow relationships through four of the most useful recession models (Maillet, Boussinesq, Coutagne and Wittenberg). The toolbox includes four parameter-fitting techniques (linear regression, lower envelope, data binning and mean squared error) and three different methods to extract hydrograph recessions segments (Vogel, Brutsaert and Aksoy). In addition, the toolbox has a module that separates the baseflow component from the observed hydrograph using the inverse reservoir algorithm. Potential applications provided by HYDRORECESSION include model parameter analysis, hydrological regionalization and classification, baseflow index estimates, catchment-scale recharge and low-flows modelling, among others. HYDRORECESSION is freely available for non-commercial and academic purposes.

  17. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy

    PubMed Central

    Ceyhan-Birsoy, Ozge; Agrawal, Pankaj B.; Hidalgo, Carlos; Schmitz-Abe, Klaus; DeChene, Elizabeth T.; Swanson, Lindsay C.; Soemedi, Rachel; Vasli, Nasim; Iannaccone, Susan T.; Shieh, Perry B.; Shur, Natasha; Dennison, Jane M.; Lawlor, Michael W.; Laporte, Jocelyn; Markianos, Kyriacos; Fairbrother, William G.; Granzier, Henk

    2013-01-01

    Objective: To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes. Methods: Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest. Results: Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations. Conclusions: Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes. PMID:23975875

  18. Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1.

    PubMed

    Virtaneva, K; D'Amato, E; Miao, J; Koskiniemi, M; Norio, R; Avanzini, G; Franceschetti, S; Michelucci, R; Tassinari, C A; Omer, S; Pennacchio, L A; Myers, R M; Dieguez-Lucena, J L; Krahe, R; de la Chapelle, A; Lehesjoki, A E

    1997-04-01

    Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region. It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval, positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized. In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.

  19. Genetics Home Reference: autosomal dominant congenital stationary night blindness

    MedlinePlus

    ... stationary night blindness autosomal dominant congenital stationary night blindness Enable Javascript to view the expand/collapse boxes. ... Close All Description Autosomal dominant congenital stationary night blindness is a disorder of the retina , which is ...

  20. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract.

    PubMed

    Kohl, Stefan; Hwang, Daw-Yang; Dworschak, Gabriel C; Hilger, Alina C; Saisawat, Pawaree; Vivante, Asaf; Stajic, Natasa; Bogdanovic, Radovan; Reutter, Heiko M; Kehinde, Elijah O; Tasic, Velibor; Hildebrandt, Friedhelm

    2014-09-01

    Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.

  1. Autosomal dominant osteopetrosis associated with renal tubular acidosis is due to a CLCN7 mutation

    PubMed Central

    Piret, Sian E.; Gorvin, Caroline M.; Trinh, Anne; Taylor, John; Lise, Stefano; Taylor, Jenny C.; Ebeling, Peter R.

    2016-01-01

    The aim of this study was to identify the causative mutation in a family with an unusual presentation of autosomal dominant osteopetrosis (OPT), proximal renal tubular acidosis (RTA), renal stones, epilepsy, and blindness, a combination of features not previously reported. We undertook exome sequencing of one affected and one unaffected family member, followed by targeted analysis of known candidate genes to identify the causative mutation. This identified a missense mutation (c.643G>A; p.Gly215Arg) in the gene encoding the chloride/proton antiporter 7 (gene CLCN7, protein CLC‐7), which was confirmed by amplification refractory mutation system (ARMS)‐PCR, and to be present in the three available patients. CLC‐7 mutations are known to cause autosomal dominant OPT type 2, also called Albers–Schonberg disease, which is characterized by osteosclerosis, predominantly of the spine, pelvis and skull base, resulting in bone fragility and fractures. Albers–Schonberg disease is not reported to be associated with RTA, but autosomal recessive OPT type 3 (OPTB3) with RTA is associated with carbonic anhydrase type 2 (CA2) mutations. No mutations were detected in CA2 or any other genes known to cause proximal RTA. Neither CLCN7 nor CA2 mutations have previously been reported to be associated with renal stones or epilepsy. Thus, we identified a CLCN7 mutation in a family with autosomal dominant osteopetrosis, RTA, renal stones, epilepsy, and blindness. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. PMID:27540713

  2. Clinical Impact of Proximal Autosomal Imbalances

    PubMed Central

    Hamid, AB; Weise, A; Voigt, M; Bucksch, M; Kosyakova, N; Liehr, T; Klein, E

    2012-01-01

    Centromere-near gain of copy number can be induced by intra- or inter-chromosomal rearrangements or by the presence of a small supernumerary marker chromosome (sSMC). Interestingly, partial trisomy to hexasomy of euchromatic material may be present in clinically healthy or affected individuals, depending on origin and size of chromosomal material involved. Here we report the known minimal sizes of all centromere-near, i.e., proximal auto-somal regions in humans, which are tolerated; over 100 Mb of coding DNA are comprised in these regions. Additionally, we have summarized the typical symptoms for nine proximal autosomal regions including genes obviously sensitive to copy numbers. Overall, studying the carriers of specific chromosomal imbalances using genomics-based medicine, combined with single cell analysis can provide the genotype-phenotype correlations and can also give hints where copy-number-sensitive genes are located in the human genome. PMID:24052727

  3. Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind

    PubMed Central

    Quartier, Pierre

    2015-01-01

    All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity. PMID:25645939

  4. Weill-Marchesani syndrome - possible linkage of the autosomal dominant form to 15q21.1

    SciTech Connect

    Wirtz, M.K.; Samples, J.R.; Rust, K.

    1996-10-02

    Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait. We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals. 28 refs., 3 figs., 2 tabs.

  5. Autosomal microsatellite data from Northwestern Colombia.

    PubMed

    Palacio, Oscar Darío; Triana, Omar; Gaviria, Aníbal; Ibarra, Adriana Alexandra; Ochoa, Luz Mariela; Posada, Yeny; Maya, María Clara; Lareu, María Victoria; Brión, María; Acosta, María Amparo; Carracedo, Angel

    2006-07-13

    Allele frequencies and some forensic parameters for 12 autosomal microsatellites (CSF1PO, TPOX, THO1, VWA, D16S539, D7S820, D13S317, D5S818, F13A1, FESFPS, F13B, LPL) were estimated from three departments from Northwestern Colombia. The total number of samples analysed was 1045 individuals. Comparative analysis among the three studied departments and with other published Colombian populations were also performed and discussed.

  6. Nineteen autosomal microsatellite data from Antioquia (Colombia).

    PubMed

    Gaviria, Aníbal; Ibarra, Adriana Alexandra; Jaramillo, Nicolás; Palacio, Oscar Dario; Acosta, María Amparo; Brion, María; Carracedo, Angel

    2004-06-30

    Allele frequencies for 19 autosomal STRs (F13A01, FESFPS, F13B, LPL, D5S818, D7S820, THO1, TPOX, VWA31, CSF1P0, D16S539, D13S317, D3S1358, D8S1179, FGA, PENTA D, PENTA E, D21S11, D18S51) were estimated from a sample between 364 and 400 unrelated individuals living in the northern department of Antioquia.

  7. [How to understand the excessive lateral rectus muscle recession].

    PubMed

    Kang, Xiaoli; Wei, Yan

    2014-07-01

    Surgical treatments of intermittent exotropia include symmetric bilateral lateral rectus recession, symmetric bilateral medial rectus resection, asymmetric monocular lateral rectus recession and/or medial rectus resection, in which lateral rectus recession is the most common method. The maximum amount of lateral rectus recession, however, is still controversial. Bilateral lateral rectus recession 7-8 mm for 35(Δ)-40(Δ) exotropia and unilateral lateral rectus recession and medial rectus resection for exotropia larger than 40(Δ) are suggested by most doctor usually. But some other doctors advocated augmented bilateral lateral rectus recession (9-14 mm ) for exotropia larger than 50(Δ) or augmented unilateral lateral rectus recession for moderate angle exotropia (30(Δ)-35(Δ)), which brought confusion in practical clinical work. In this paper, we'll focus on the amount of lateral rectus recession, and discuss several common issues related to augmented lateral rectus recession, in order to provide references for the majority of clinicians.

  8. Associations between STR autosomal markers and longevity.

    PubMed

    Bediaga, N G; Aznar, J M; Elcoroaristizabal, X; Albóniga, O; Gómez-Busto, F; Artaza Artabe, I; Rocandio, Ana; de Pancorbo, M M

    2015-10-01

    Life span is a complex and multifactorial trait, which is shaped by genetic, epigenetic, environmental, and stochastic factors. The possibility that highly hypervariable short tandem repeats (STRs) associated with longevity has been largely explored by comparing the genotypic pools of long lived and younger individuals, but results so far have been contradictory. In view of these contradictory findings, the present study aims to investigate whether HUMTHO1 and HUMCSF1PO STRs, previously associated with longevity, exert a role as a modulator of life expectancy, as well as to assess the extent to which other autosomal STR markers are associated with human longevity in population from northern Spain. To that end, 21 autosomal microsatellite markers have been studied in 304 nonagenarian individuals (more than 90 years old) and 516 younger controls of European descent. Our results do not confirm the association found in previous studies between longevity and THO1 and CSF1PO loci. However, significant association between longevity and autosomal STR markers D12S391, D22S1045, and DS441 was observed. Even more, when we compared allelic frequency distribution of the 21 STR markers between cases and controls, we found that 6 out of the 21 STRs studied showed different allelic frequencies, thus suggesting that the genomic portrait of the human longevity is far complex and probably shaped by a high number of genomic loci.

  9. Identification of a second HOXA2 nonsense mutation in a family with autosomal dominant non-syndromic microtia and distinctive ear morphology.

    PubMed

    Piceci, F; Morlino, S; Castori, M; Buffone, E; De Luca, A; Grammatico, P; Guida, V

    2016-08-09

    Microtia is a congenital defect affecting external ears, which appear smaller and sometimes malformed. Here we describe a five-generation family with isolated bilateral microtia segregating as an autosomal dominant trait. Similar features have been previously observed in an autosomal dominant family with non-syndromic microtia and hearing loss segregating with a HOXA2 nonsense variant. HOXA2 biallelic mutations were also described in an inbreed family with autosomal recessive microtia, hearing impairment and incomplete cleft palate. In our family, sequence analysis detected a heterozygous protein truncating nonsense variant [c.670G>T, p.(Glu224*)] segregating in all affected individuals and absent in public databases. This study confirms the role of HOXA2 gene in dominant isolated microtia and contribute to further define the dysmorphogenetic effect of this gene on ear development.

  10. Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families.

    PubMed

    McInerney-Leo, Aideen M; Harris, Jessica E; Gattas, Michael; Peach, Elizabeth E; Sinnott, Stephen; Dudding-Byth, Tracy; Rajagopalan, Sulekha; Barnett, Christopher P; Anderson, Lisa K; Wheeler, Lawrie; Brown, Matthew A; Leo, Paul J; Wicking, Carol; Duncan, Emma L

    2016-07-01

    Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation.

  11. Large bimedial rectus recessions in congenital esotropia.

    PubMed Central

    Szmyd, S. M.; Nelson, L. B.; Calhoun, J. H.; Spratt, C.

    1985-01-01

    The success rate of large (6 and 7 mm) bimedial rectus recessions in 45 congenital esotropes with deviations of 50 prism dioptres or greater was found to be 91%. Judgment of final alignment was made six weeks postoperatively, with an average follow-up of 13 months. Large bimedial rectus recessions are an effective surgical treatment for congenital esotropia. This procedure does not significantly alter adduction, and leaves other muscles available should further surgery be necessary. These findings show that initial surgery on three or more muscles is unnecessary in congenital esotropia. PMID:3994944

  12. Glacier recession in Iceland and Austria

    SciTech Connect

    Hall, D.K.; Williams, R.S. Jr.; Bayr, K.J. USGS, Reston, VA Keene State College, NH )

    1992-03-01

    It has been possible to measure glacier recession on the basis of Landsat data, in conjunction with comparisons of the magnitude of recession of a glacier margin with in situ measurements at fixed points along the same margin. Attention is presently given to the cases of Vatnajokull ice cap, in Iceland, and the Pasterze Glacier, in Austria, on the basis of satellite data from 1973-1987 and 1984-1990, respectively. Indications of a trend toward negative mass balance are noted. Nevertheless, while most of the world's small glaciers have been receding, some are advancing either due to local climate or the tidewater glacier cycle. 21 refs.

  13. Glacier recession in Iceland and Austria

    NASA Technical Reports Server (NTRS)

    Hall, Dorothy K.; Williams, Richard S., Jr.; Bayr, Klaus J.

    1992-01-01

    It has been possible to measure glacier recession on the basis of Landsat data, in conjunction with comparisons of the magnitude of recession of a glacier margin with in situ measurements at fixed points along the same margin. Attention is presently given to the cases of Vatnajokull ice cap, in Iceland, and the Pasterze Glacier, in Austria, on the basis of satellite data from 1973-1987 and 1984-1990, respectively. Indications of a trend toward negative mass balance are noted. Nevertheless, while most of the world's small glaciers have been receding, some are advancing either due to local climate or the tidewater glacier cycle.

  14. A gene responsible for profound congenital nonsyndromal recessive deafness maps to the pericentromeric region of chromosome 17

    SciTech Connect

    Friedman, T.B.; Liang, Y.; Asher, J.H. Jr.

    1994-09-01

    Autosomal recessive deafness is the most common form of human hereditary hearing loss. Two percent of the 2,185 residents of Bengkala, Bali, Indonesia have profound congenital neurosensory nonsyndromal hereditary deafness due to a fully penetrant autosomal recessive mutation (NARD1). Families, identified through children with profound congenital deafness having hearing parents, give the expected 25% deaf progeny when corrected for ascertainment bias. Congenitally deaf individuals from Bengkala show no response to pure tone audiological examination. Obligate heterozygotes for autosomal recessive deafness in Bengkala have normal or borderline normal hearing. A chromosomal location for NARD1 was assigned directly using a linkage strategy that combines allele-frequency dependent homozygosity mapping (AHM) followed by an analysis of historical recombinants to position NARD1 relative to flanking markers. Thirteen deaf Bengkala villagers of hearing parents were typed initially for 148 STRPs distributed across the human genome and a cluster of tightly linked 17p markers with a significantly higher number of homozygotes than expected under Hardy-Weinberg and linkage equilibrium were identified. NARD1 maps closest to STRPs for D17S261 (Mfd41) and D17S805 (AFM234ta1) that are 3.2 cM apart. Recombinant genotypes for the flanking markers, D17S122 (VAW409) and D17S783 (AFM026vh7), in individuals homozygous for NARD1 place NARD1 in a 5.3 cM interval of the pericentromeric region of chromosome 17 on a refined 17p-17q12 genetic map.

  15. Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2.

    PubMed

    Tammachote, Rachaneekorn; Kingsuwannapong, Nelawat; Tongkobpetch, Siraprapa; Srichomthong, Chalurmpon; Yeetong, Patra; Kingwatanakul, Pornchai; Monico, Carla G; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk

    2012-09-01

    Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by mutations in the alanine:glyoxylate aminotransferase (AGXT) gene, located on chromosome 2q37. Mutant AGXT leads to excess production and excretion of oxalate, resulting in accumulation of calcium oxalate in the kidney, and progressive loss of renal function. Brachydactyly mental retardation syndrome (BDMR) is an autosomal dominant disorder, caused by haploinsufficiency of histone deacetylase 4 (HDAC4), also on chromosome 2q37. It is characterized by skeletal abnormalities and developmental delay. Here, we report on a girl who had phenotypes of both PH1 and BDMR. PCR-sequencing of the coding regions of AGXT showed a novel missense mutation, c.32C>G (p.Pro11Arg) inherited from her mother. Functional analyses demonstrated that it reduced the enzymatic activity to 31% of the wild-type and redirected some percentage of the enzyme away from the peroxisome. Microsatellite and array-CGH analyses indicated that the proband had a paternal de novo telomeric deletion of chromosome 2q, which included HDAC4. To our knowledge, this is the first report of PH1 and BDMR, with a novel AGXT mutation and a de novo telomeric deletion of chromosome 2q.

  16. [Periodontology and esthetics: the gingival recession].

    PubMed

    Corba, N H

    1991-06-01

    Gingival recessions are regarded by many people as an esthetical problem. Successively the etiology, the significance and the indications for therapy are discussed. Different kinds of therapy such as oral hygiene instruction, the free gingival graft and various pedicle grafts are explained. Finally it is advocated that surgical kinds of therapy have to be applied with reservedness.

  17. Weathering the Recession in College Health

    ERIC Educational Resources Information Center

    Christmas, William A.

    2010-01-01

    The current global recession has increased personal stress levels throughout our society. With dwindling resources, institutions of higher learning are especially prone to budgetary cutbacks during such periods. Based on 22 years of experience as a health service director, the author offers some personal insights in the hope that they will help…

  18. The Global Picture. Recession to Recovery

    ERIC Educational Resources Information Center

    Universities UK, 2010

    2010-01-01

    The objectives of this study were to: (1) document government and HE (higher education) sector responses to the recession within a select number of key countries which compete with the UK; and (2) compare these responses and analyse them by theme to draw out any common patterns. The focus of the work was to find, where possible, an evidence base…

  19. Gender Differences during Recess in Elementary Schools.

    ERIC Educational Resources Information Center

    Twarek, Linda S.; George, Halley S.

    A study examined the differences in what boys and girls choose, or are free to choose, to do on the playground during recess. Given the apparent problem that boys dominate the playground area, leaving girls on the perimeter, it was hypothesized that girls engage in passive, non-competitive, small group activities, whereas boys engage in…

  20. Recession curbs gas pipeline construction costs

    SciTech Connect

    Morgan, J.M.

    1983-01-24

    This paper shows how after 5 yrs. of inflation, gas pipeline construction costs have finally felt the effects of a severe building recession. First quarter (1982) construction activity, compressor equipment and drive units, and high-pressure gas-station piping are discussed. Graphs of OGJ-Morgan composite gas pipeline cost, and gas pipeline cost component indexes are presented.

  1. Naval stores markets on hold during recession

    SciTech Connect

    Layman, P.

    1982-03-22

    A review of the current state of the market and level of inventory stocks of turpentine and tall oil and its derivatives. It is concluded that pricing is soft as major markets suffer through recession, but that recovery may be quick in some areas where inventory stocks are low.

  2. Reclaiming Recess: Learning the Language of Persuasion

    ERIC Educational Resources Information Center

    Gebhard, Meg; Harman, Ruth; Seger, Wendy

    2007-01-01

    Using a case study approach, the authors describe how a teacher used the tools of systemic functional linguistics (SFL) to teach her fifth grade English Language Learners how to use academic language to challenge school policies regarding recess. In reflecting on these data, we discuss the potential of SFL to support teachers in responding to…

  3. Nevada, the Great Recession, and Education

    ERIC Educational Resources Information Center

    Verstegen, Deborah A.

    2013-01-01

    The impact of the Great Recession and its aftermath has been devastating in Nevada, especially for public education. This article discusses the budget shortfalls and the impact of the economic crisis in Nevada using case study methodology. It provides a review of documents, including Governor Gibbon's proposals for the public K-12 education system…

  4. Mutations in FKBP10 Cause Recessive Osteogenesis Imperfecta and Bruck Syndrome

    PubMed Central

    Kelley, Brian P; Malfait, Fransiska; Bonafe, Luisa; Baldridge, Dustin; Homan, Erica; Symoens, Sofie; Willaert, Andy; Elcioglu, Nursel; Van Maldergem, Lionel; Verellen-Dumoulin, Christine; Gillerot, Yves; Napierala, Dobrawa; Krakow, Deborah; Beighton, Peter; Superti-Furga, Andrea; De Paepe, Anne; Lee, Brendan

    2011-01-01

    Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique posttranslational modification of type I procollagen, that is, 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB), form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation, and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), also has been shown to be mutated in recessive OI. Here we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome, possibly Bruck syndrome Type 1 since the location on chromosome 17 has not been definitely localized. © 2011 American Society for Bone and Mineral Research. PMID:20839288

  5. Dystrophic epidermolysis bullosa with one dominant and one recessive mutation of the COL7A1 gene in a child with deafness.

    PubMed

    Weinel, Sarah; Lucky, Anne W; Uitto, Jouni; Pfendner, Ellen G; Choo, Daniel

    2008-01-01

    Dystrophic epidermolysis bullosa can be inherited in autosomal dominant and recessive forms, the former usually expressed as a milder phenotype, although mild forms of recessive dystrophic epidermolysis bullosa can occur. We present a patient who was found to be a compound heterozygote, inheriting a dominant mutation from his father and a recessive mutation from his mother, resulting in a clinically severe case of dystrophic epidermolysis bullosa. Mutations in the gene for collagen VII (COL7A1) have been documented in both types of dystrophic epidermolysis bullosa. Our patient has also been diagnosed with bilateral auditory neuropathy, a disorder coincidentally also mapped to a nearby gene on chromosome 3p21 (the transmembrane inner ear expressed gene, TMIE).

  6. Update of the spectrum of GJB2 gene mutations in 152 Moroccan families with autosomal recessive nonsyndromic hearing loss.

    PubMed

    Bakhchane, Amina; Bousfiha, Amale; Charoute, Hicham; Salime, Sara; Detsouli, Mustapha; Snoussi, Khalid; Nadifi, Sellama; Kabine, Mostafa; Rouba, Hassan; Dehbi, Hind; Roky, Rachida; Charif, Majida; Barakat, Abdelhamid

    2016-06-01

    Deafness is one of the most common genetic diseases in humans and is subject to important genetic heterogeneity. The most common cause of non syndromic hearing loss (NSHL) is mutations in the GJB2 gene. This study aims to update and evaluate the spectrum of GJB2 allele variants in 152 Moroccan multiplex families with non syndromic hearing loss. Seven different mutations were detected: c.35delG, p.V37I, p.E47X, p.G200R, p.Del120E, p.R75Q, the last three mutations were described for the first time in Moroccan deaf patients, in addition to a novel nonsense mutation, the c.385G>T which is not referenced in any database. Sixty six families (43.42%) have mutations in the coding region of GJB2, while the homozygous c.35delG mutation still to date the most represented 51/152 (33.55%). The analysis of the geographical distribution of mutations located in GJB2 gene showed more allelic heterogeneity in the north and center compared to the south of Morocco. Our results showed that the GJB2 gene is a major contributor to non syndromic hearing loss in Morocco. Thus, this report of the GJB2 mutations spectrum all over Morocco has an important implication for establishing a suitable molecular diagnosis.

  7. Linkage analysis of a new locus for autosomal recessive retinitis pigmentosa (arRP) on chromosome 6p

    SciTech Connect

    Shugart, Y.Y.; Knowles, J.A.; Banerjee, P.

    1994-09-01

    We report the localization of the arRP gene segregating in a large kindred from the Dominican Republic and the progress in refining the arRP region. The arRP gene in this family was found to be closely linked to markers D6S291, D6S273 with lod scores of 6.75, 3.08 at {theta}=0, 0.08, respectively. Since it was suggested that mutant peripherin causes arRP on 6p, we typed marker RDS1 at the peripherin-rds locus and detected four recombinants. More markers have been typed to further refine the location of arRP. Lod scores of 5.31. 5.89 and 2.05 were obtained with D6S439, UT722 and D6S426 at {theta}=0, 0, and 0.14, respectively. Some of the new markers were not included in the Genethon map, thus we used the CEPH (V7.0) data to order markers D6S273, D6S439, UT722, D6S426 and to estimate the recombination fractions as well as the ratios of female to male map distance. The best supported order is: D6S273 - D6S439 - D6S291 - UT722 - D6S426. Multipoint analyses were performed with the markers D6S273 - ({theta}{sub m}=0.0-21) - D6S439 - ({theta}{sub m}=0.066) - D6S426 with a constant sex ratio of 2.749. A maximum lod score of 9.74 was obtained at the marker D6S439. In conclusion, the most likely location for the arRP gene in the Dominican pedigree is approximately 20 centimorgans (cM) telomeric from peripherin.

  8. A Novel Splicesite Mutation in the EDAR Gene Causes Severe Autosomal Recessive Hypohydrotic (Anhidrotic) Ectodermal Dysplasia in an Iranian Family

    PubMed Central

    Torkamandi, Shahram; Gholami, Milad; Mohammadi-asl, Javad; Rezaie, Somaye; Zaimy, Mohammad Ali; Omrani, Mir Davood

    2016-01-01

    Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder arising from deficient development of ectoderm-derived structures including skin, nails, glands and teeth. The phenotype of HED is associated with mutation in EDA, EDAR, EDARADD and NEMO genes, all of them disruptingNF-κB signaling cascade necessary for initiation, formation and differentiation in the embryo and adult. Here we describe a novel acceptor splice site mutation c.730-2 A>G(IVS 8-2 A>G) in EDAR gene in homozygous form in all affected members of a family,and in heterozygous form in carriers. Bioinformatics analysis showed that this mutation can create a new broken splicing site and lead to aberrant splicing. PMID:28357203

  9. New autosomal recessive mutations in aquaporin-2 causing nephrogenic diabetes insipidus through deficient targeting display normal expression in Xenopus oocytes.

    PubMed

    Leduc-Nadeau, Alexandre; Lussier, Yoann; Arthus, Marie-Françoise; Lonergan, Michèle; Martinez-Aguayo, Alejandro; Riveira-Munoz, Eva; Devuyst, Olivier; Bissonnette, Pierre; Bichet, Daniel G

    2010-06-15

    Aquaporin-2 (AQP2), located at the luminal side of the collecting duct principal cells, is a water channel responsible for the final concentration of urine. Lack of function, often occurring through mistargeting of mutated proteins, induces nephrogenic diabetes insipidus (NDI), a condition characterized by large urinary volumes. In the present study, two new mutations (K228E and V24A) identified in NDI-affected individuals from distinct families along with the already reported R187C were analysed in comparison to the wild-type protein (AQP2-wt) using Xenopus laevis oocytes and a mouse collecting duct cell-line (mIMCD-3). Initial data in oocytes showed that all mutations were adequately expressed at reduced levels when compared to AQP2-wt. K228E and V24A were found to be properly targeted at the plasma membrane and exhibited adequate functionality similar to AQP2-wt, as opposed to R187C which was retained in internal stores and was thus inactive. In coexpression studies using oocytes, R187C impeded the functionality of all other AQP2 variants while combinations with K228E, V24A and AQP2-wt only showed additive functionalities. When expressed in mIMCD-3 cells, forskolin treatment efficiently promoted the targeting of AQP2-wt at the plasma membrane (>90%) while K228E only weakly responded to the same treatment (approximately 20%) and both V24A and R187C remained completely insensitive to the treatment. We concluded that both V24A and K228E are intrinsically functional water channels that lack a proper response to vasopressin, which leads to NDI as found in both compound mutations studied (K228E + R187C and V24A + R187C). The discrepancies in plasma membrane targeting response found in both expression systems stress the need to evaluate such data using mammalian cell systems.

  10. Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa

    PubMed Central

    Corton, M.; Avila-Fernández, A.; Campello, L.; Sánchez, M.; Benavides, B.; López-Molina, M. I.; Fernández-Sánchez, L.; Sánchez-Alcudia, R.; da Silva, L. R. J.; Reyes, N.; Martín-Garrido, E.; Zurita, O.; Fernández-San José, P.; Pérez-Carro, R.; García-García, F.; Dopazo, J.; García-Sandoval, B.; Cuenca, N.; Ayuso, C.

    2016-01-01

    Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors. PMID:27734943

  11. Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia

    PubMed Central

    Cai, Xiaodong; Chen, Xin; Wu, Song; Liu, Wenlan; Zhang, Xiejun; Zhang, Doudou; He, Sijie; Wang, Bo; Zhang, Mali; Zhang, Yuan; Li, Zongyang; Luo, Kun; Cai, Zhiming; Li, Weiping

    2016-01-01

    Dystonia is a neurological movement disorder that is clinically and genetically heterogeneous. Herein, we report the identification a novel homozygous missense mutation, c.156 C > A in VPS16, co-segregating with disease status in a Chinese consanguineous family with adolescent-onset primary dystonia by whole exome sequencing and homozygosity mapping. To assess the biological role of c.156 C > A homozygous mutation of VPS16, we generated mice with targeted mutation site of Vps16 through CRISPR-Cas9 genome-editing approach. Vps16 c.156 C > A homozygous mutant mice exhibited significantly impaired motor function, suggesting that VPS16 is a new causative gene for adolescent-onset primary dystonia. PMID:27174565

  12. Adhalin, the 50 kD dystrophin associated protein, is not the locus for severe childhood autosomal recessive dystrophy (SCARMD)

    SciTech Connect

    McNally, E.M.; Selig, S.; Kunkel, L.M.

    1994-09-01

    Mutations in the carboxyl-terminus in dystrophin are normally sufficient to produce severely dystrophic muscle. This portion of dystrophin binds a complex of dystrophin-associated glycoproteins (DAGs). The genes encoding these DAGs are candidate genes for causing neuromuscular disease. Immunoreactivity for adhalin, the 50 kD DAG, is absent in muscle biopsies from patients with SCARMD, a form of dystrophy clinically similar Duchenne muscular dystrophy. Prior linkage analysis in SCARMD families revealed that the disease gene segregates with markers on chromosome 13. To determine the molecular role that adhalin may play in SCARMD, human cDNA and genomic sequences were isolated. Primers were designed based on predicted areas of conservation in rabbit adhalin and used in RT-PCR with human skeletal and cardiac muscle. RT-PCR products were confirmed by sequence as human adhalin and then used as probes for screening human cDNA and genomic libraries. Human and rabbit adhalin are 90% identical, and among the cDNAs, a novel splice form of adhalin was seen which may encode part of the 35 kD component of the dystrophin-glycoprotein complex. To our surprise, only human/rodent hybrids containing human chromosome 17 amplified adhalin sequences in a PCR analysis. FISH analysis with three overlapping genomic sequences confirmed the chromosome 17 location and further delineated the map position to 17q21. Therefore, adhalin is excluded as the gene causing SCARMD.

  13. Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss.

    PubMed

    Riahi, Zied; Hammami, Hassen; Ouragini, Houyem; Messai, Habib; Zainine, Rim; Bouyacoub, Yosra; Romdhane, Lilia; Essaid, Donia; Kefi, Rym; Rhimi, Mohsen; Bedoui, Monia; Dhaouadi, Afef; Feldmann, Delphine; Jonard, Laurence; Besbes, Ghazi; Abdelhak, Sonia

    2013-08-01

    Hearing loss is the most frequent sensory disorder. It affects 3 in 1000 newborns. It is genetically heterogeneous with 60 causally-related genes identified to date. Mutations in GJB2 gene account for half of all cases of non-syndromic deafness. The aim of this study was to determine the relative frequency of GJB2 allele variants in Tunisia. In this study, we screened 138 patients with congenital hearing loss belonging to 131 families originating from different parts of Tunisia for mutations in GJB2 gene. GJB2 mutations were found in 39% of families (51/131). The most common mutation was c.35delG accounting for 35% of all cases (46/131). The second most frequent mutation was p.E47X present in 3.8% of families. Four identified mutations in our cohort have not been reported in Tunisia; p.V37I, c.235delC, p.G130A and the splice site mutation IVS1+1G>A (0.76%). These previously described mutations were detected only in families originating from Northern and not from other geographical regions in Tunisia. In conclusion we have confirmed the high frequency of c.35delG in Tunisia which represents 85.4% of all GJB2 mutant alleles. We have also extended the mutational spectrum of GJB2 gene in Tunisia and revealed a more pronounced allelic heterogeneity in the North compared to the rest of the country.

  14. A Homozygous Mutation in Human PRICKLE1 Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome

    PubMed Central

    Bassuk, Alexander G.; Wallace, Robyn H.; Buhr, Aimee; Buller, Andrew R.; Afawi, Zaid; Shimojo, Masahito; Miyata, Shingo; Chen, Shan; Gonzalez-Alegre, Pedro; Griesbach, Hilary L.; Wu, Shu; Nashelsky, Marcus; Vladar, Eszter K.; Antic, Dragana; Ferguson, Polly J.; Cirak, Sebahattin; Voit, Thomas; Scott, Matthew P.; Axelrod, Jeffrey D.; Gurnett, Christina; Daoud, Azhar S.; Kivity, Sara; Neufeld, Miriam Y.; Mazarib, Aziz; Straussberg, Rachel; Walid, Simri; Korczyn, Amos D.; Slusarski, Diane C.; Berkovic, Samuel F.; El-Shanti, Hatem I.

    2008-01-01

    Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy. PMID:18976727

  15. Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.

    PubMed

    Vincent, Ajoy; Audo, Isabelle; Tavares, Erika; Maynes, Jason T; Tumber, Anupreet; Wright, Thomas; Li, Shuning; Michiels, Christelle; Condroyer, Christel; MacDonald, Heather; Verdet, Robert; Sahel, José-Alain; Hamel, Christian P; Zeitz, Christina; Héon, Elise

    2016-05-05

    Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.

  16. Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness

    PubMed Central

    Vincent, Ajoy; Audo, Isabelle; Tavares, Erika; Maynes, Jason T.; Tumber, Anupreet; Wright, Thomas; Li, Shuning; Michiels, Christelle; Banin, Eyal; Bocquet, Beatrice; De Baere, Elfride; Casteels, Ingele; Defoort-Dhellemmes, Sabine; Drumare, Isabelle; Friedburg, Christoph; Gottlob, Irene; Jacobson, Samuel G.; Kellner, Ulrich; Koenekoop, Robert; Kohl, Susanne; Leroy, Bart P.; Lorenz, Birgit; McLean, Rebecca; Meire, Francoise; Meunier, Isabelle; Munier, Francis; de Ravel, Thomy; Reiff, Charlotte M.; Mohand-Saïd, Saddek; Sharon, Dror; Schorderet, Daniel; Schwartz, Sharon; Zanlonghi, Xavier; Condroyer, Christel; MacDonald, Heather; Verdet, Robert; Sahel, José-Alain; Hamel, Christian P.; Zeitz, Christina; Héon, Elise

    2016-01-01

    Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339∗]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339∗]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling. PMID:27063057

  17. Autosomal dominant cerebellar ataxia deafness and narcolepsy.

    PubMed

    Melberg, A; Hetta, J; Dahl, N; Nennesmo, I; Bengtsson, M; Wibom, R; Grant, C; Gustavson, K H; Lundberg, P O

    1995-12-01

    A new autosomal dominant syndrome in a Swedish pedigree is described. Five patients were affected with cerebellar ataxia and sensorineural deafness. Four of these patients had symptoms of narcolepsy. Optic atrophy, other neurological abnormalities and psychiatric symptoms developed with increasing disease duration. Three patients had non-neurological disease in addition, including diabetes mellitus in two and hypertrophic cardiomyopathy in one. Autopsy with neuropathological examination was performed in one case. Molecular studies focused on the short arm of chromosome 6, including the HLA DR2 locus associated with narcolepsy and the (CAG)n repeat at the spinocerebellar ataxia type 1 (SCA1) locus. Biochemical investigation of muscle biopsy of one case indicated mitochondrial dysfunction with selective decrease in ATP production for substrates that normally give the highest rates. The activity of glutamate dehydrogenase was reduced, indicating a low mitochondrial density. We postulate an autosomal dominant genetic factor responsible for this syndrome. Linkage was excluded to HLA DR2, and a normal sized SCA1 repeat was observed. We conclude that a locus predisposing to ataxia, deafness and narcolepsy exists outside this region of chromosome 6.

  18. [Treatment of autosomal dominant polycystic kidney disease].

    PubMed

    Torra, Roser

    2014-01-21

    Autosomal dominant polycystic kidney disease is the most frequent hereditary kidney disease. However it lacks a specific treatment. Its prevalence is 1/800 and causes the need for renal replacement therapy in 8-10% of patients on dialysis or kidney transplant. It is caused by mutations in the PKD1 and PKD2 genes, which cause a series of alterations in the polycystic cells, which have become therapeutic targets. There are many molecules that are being tested to counteract the alterations of these therapeutic targets. There are studies in all phases of research, from phase i to phase iv. Some of the molecules being tested are tolvaptan, mTOR inhibitors and, among many other, somatostatin analogues. These drugs are extensively reviewed in this article. Based on the accumulated experience the primary objective of the trials is the slowing of the increase in renal volume. Yet other renal end points such as renal function and hypertension are necessary. It is expected that in the coming years we can have specific, well tolerated, effective and affordable drugs for the treatment of autosomal dominant polycystic kidney disease.

  19. Autosomal dominant familial spastic paraplegia; Linkage analysis and evidence for linkage to chromosome 2p

    SciTech Connect

    Figlewicz, D.A.; Dube, M.P.; Rouleau, G.A.

    1994-09-01

    Familial spastic paraplegia (FSP) is a degenerative disorder of the motor system characterized by progressive weakness and spasticity of the lower limbs. Little is known about the pathophysiology of this disorder. FSP can be inherited as an autosomal dominant (AD), autosomal recessive, or X-linked trait. We have undertaken linkage analysis for a group of 36 AD FSP families from which we have collected blood samples from 427 individuals, including 148 affected individuals. Typing of polymorphic markers has allowed us to exclude more than 50% of the genome. Recently, linkage for AD FSP to a locus on chromosome 14q was reported. Our AD FSP kindreds were tested for linkage to markers spanning the 20 cM region between D14S69 and D14S66; however, we were not able to establish linkage for any of our families to chromosome 14. Lod scores suggestive of linkage for some AD FSP kindreds have been obtained for markers on chromosome 2p. We have tested seven polymorphic markers spanning the region between D2S405 and D2S177. Our highest aggregate lod score, including all families tested, was obtained at the locus D2S352: 2.4 at 20 cM. Results from HOMOG analysis for linkage heterogeneity will be reported.

  20. Autosomal dominant congenital fibre type disproportion: a clinicopathological and imaging study of a large family.

    PubMed

    Sobrido, M J; Fernández, J M; Fontoira, E; Pérez-Sousa, C; Cabello, A; Castro, M; Teijeira, S; Alvarez, S; Mederer, S; Rivas, E; Seijo-Martínez, M; Navarro, C

    2005-07-01

    Congenital fibre type disproportion (CFTD) is considered a non-progressive or slowly progressive muscle disease with relative smallness of type 1 fibres on pathological examination. Although generally benign, CFTD has a variable natural course and severe progression has been observed in some patients. The pathogenesis of the disorder is unknown and many authors consider CFTD a syndrome with multiple aetiologies rather than a separate clinical entity. A positive family history has been reported in about 40% of cases, but the inheritance pattern is not clear. Both autosomal recessive and dominant modes of inheritance have been suggested. The present paper describes a large, multigenerational kindred that has an inherited myopathy fulfilling the histological criteria of CFTD, with autosomal dominant transmission and high penetrance. The clinical picture, remarkably similar in all affected family members, started in early infancy with mild limb muscle weakness. There was slow progression of symptoms into adulthood, with moderate to severe, mainly proximal, muscle weakness without loss of ambulation. Muscle biopsy from two affected individuals demonstrated predominance of small type 1 muscle fibres without other significant findings. Nerve conduction studies were normal and needle electromyography showed a myopathic pattern. MRI examination performed on three patients from successive generations showed involvement of proximal limb and paraspinal muscles. The clinical and pathological homogeneity in the present family, together with the lack of additional histological abnormalities after decades of disease progression in two affected individuals, supports this being a distinct myopathy with fibre type disproportion. Whether the disease in this family can be regarded as a form of the congenital myopathy known as CFTD or rather a unique condition sharing histological features with CFTD needs further investigation. This is, to our knowledge, the largest kindred with muscle

  1. Linkage of the late onset autosomal dominant familial spastic paraplegia (DFSPII) to chromosome 2p markers

    SciTech Connect

    Hentati, A.; Wasserman, B.; Siddique, T.

    1994-09-01

    Pure familial spastic paraplegias (FSP) is a neurodegenerative disease characterized by spasticity of lower limbs. FSP in inherited as an autosomal dominant (DFSP) or an autosomal recessive (RFSP) trait. DFSP has been classified into early onset (DFSPI) and late onset (DFSPII) based on the mean age of onset in families. A locus for RFSP has been mapped to chromosome 8, while a locus for DFSPI has been mapped to chromosome 14q. Genetic locus heterogeneity was observed in both of these forms. The location of DFSPII locus (or loci) is unknown. We collected DNA samples from 81 individuals including 26 affecteds from three DFSPII families (9998, 840, 581). The mean age of onset of systems was 26.5, 42.5, and 35.2 years, respectively. We first tested 156 DNA markers distributed throughout the human 22 autosomes with family 9998 and positive lod scores were obtained with chromosome 2p markers D2S174 (Z({theta})=2.93 at {theta}=0.00), D2S146 (Z({theta})=1.03 at {theta}=0.00) and D2S177 (Z({theta})=1.04 at {theta}=0.00). Analysis of the 2 additional families confirmed the linkage with a peak lod score of Z({theta})=4.62 at {theta}=0.105 with D2S174. The multipoint linkage analysis using the map D2S175-10cM-D2S174-14cM-D2DS177 suggested that the DFSPII locus most likely maps between D2S174 and D2S177 with Z({theta})=6.11. There was no evidence in our data supporting genetic locus heterogeneity for the DFSPII.

  2. Recessive Mutations in COL25A1 Are a Cause of Congenital Cranial Dysinnervation Disorder

    PubMed Central

    Shinwari, Jameela M.A.; Khan, Arif; Awad, Salma; Shinwari, Zakia; Alaiya, Ayodele; Alanazi, Mohamad; Tahir, Asma; Poizat, Coralie; Al Tassan, Nada

    2015-01-01

    Abnormal ocular motility is a common clinical feature in congenital cranial dysinnervation disorder (CCDD). To date, eight genes related to neuronal development have been associated with different CCDD phenotypes. By using linkage analysis, candidate gene screening, and exome sequencing, we identified three mutations in collagen, type XXV, alpha 1 (COL25A1) in individuals with autosomal-recessive inheritance of CCDD ophthalmic phenotypes. These mutations affected either stability or levels of the protein. We further detected altered levels of sAPP (neuronal protein involved in axon guidance and synaptogenesis) and TUBB3 (encoded by TUBB3, which is mutated in CFEOM3) as a result of null mutations in COL25A1. Our data suggest that lack of COL25A1 might interfere with molecular pathways involved in oculomotor neuron development, leading to CCDD phenotypes. PMID:25500261

  3. New Recessive Syndrome of Microcephaly, Cerebellar Hypoplasia, and Congenital Heart Conduction Defect

    PubMed Central

    Zaki, Maha S; Salam, Ghada M H Abdel; Saleem, Sahar N; Dobyns, William B; Issa, Mahmoud Y; Sattar, Shifteh; Gleeson, Joseph G

    2011-01-01

    We identified a two-branch consanguineous family in which four affected members (three females and one male) presented with constitutive growth delay, severe psychomotor retardation, microcephaly, cerebellar hypoplasia, and second-degree heart block. They also shared distinct facial features and similar appearance of their hands and feet. Childhood-onset insulin-dependent diabetes mellitus developed in one affected child around the age of 9 years. Molecular analysis excluded mutations in potentially related genes such as PTF1A, EIF2AK3, EOMES, and WDR62. This condition appears to be unique of other known conditions, suggesting a unique clinical entity of autosomal recessive mode of inheritance. © 2011 Wiley Periodicals, Inc. PMID:22002884

  4. Semiconductor structure and recess formation etch technique

    DOEpatents

    Lu, Bin; Sun, Min; Palacios, Tomas Apostol

    2017-02-14

    A semiconductor structure has a first layer that includes a first semiconductor material and a second layer that includes a second semiconductor material. The first semiconductor material is selectively etchable over the second semiconductor material using a first etching process. The first layer is disposed over the second layer. A recess is disposed at least in the first layer. Also described is a method of forming a semiconductor structure that includes a recess. The method includes etching a region in a first layer using a first etching process. The first layer includes a first semiconductor material. The first etching process stops at a second layer beneath the first layer. The second layer includes a second semiconductor material.

  5. Cutting Symmetrical Recesses In Soft Ceramic Tiles

    NASA Technical Reports Server (NTRS)

    Nesotas, Tony C.; Tyler, Brent

    1989-01-01

    Simple tool cuts hemispherical recesses in soft ceramic tiles. Designed to expose wires of thermocouples embedded in tiles without damaging leads. Creates neat, precise holes around wires. End mill includes axial hole to accommodate thermocouple wires embedded in material to be cut. Wires pass into hole without being bent or broken. Dimensions in inches. Used in place of such tools as dental picks, tweezers, spatulas, and putty knives.

  6. Recession trims third-quarter building costs

    SciTech Connect

    Morgan, J.M.

    1983-05-09

    The composite cost index for building oil pipelines during the third quarter of 1982 showed a decrease of 0.96%. This decrease was due to a steady drop in the rate of inflation for most pipeline construction materials during the first 9 months of the year. The major thrust behind the pipeline materials decline was a sharp 5.3% drop in the average price of steel line pipe. However, the pipeline construction recession has failed to deter escalating pipeline labor rates.

  7. Semiconductor devices having a recessed electrode structure

    DOEpatents

    Palacios, Tomas Apostol; Lu, Bin; Matioli, Elison de Nazareth

    2015-05-26

    An electrode structure is described in which conductive regions are recessed into a semiconductor region. Trenches may be formed in a semiconductor region, such that conductive regions can be formed in the trenches. The electrode structure may be used in semiconductor devices such as field effect transistors or diodes. Nitride-based power semiconductor devices are described including such an electrode structure, which can reduce leakage current and otherwise improve performance.

  8. Posterior peritoneal recesses: assessment using CT

    SciTech Connect

    Rubenstein, W.A.; Auh, Y.H.; Zirinsky, K.; Kneeland, J.B.; Whalen, J.P.; Kazam, E.

    1985-08-01

    Intraperitoneal compartments may extend posteriorly to the level of known retroperitoneal structures at several locations within the abdomen. These locations include the posterior subhepatic or hepatorenal space, the splenorenal space, the retropancreatic recess, the paracolic gutters, and the pararectal fossae. Because of their posterior location, fluid collections within these compartments may be mistaken radiologically for retroperitoneal masses. The sectional anatomy of these spaces and particularly their appearance on computed tomographic scans, are illustrated in this paper.

  9. Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development

    PubMed Central

    Kwasniewska, Alexandra; Sadighi Akha, Elham; Parolin Schnekenberg, Ricardo; Suminaite, Daumante; Hope, Jilly; Baker, Ian; Gregory, Lorna; Green, Angie; Allan, Chris; Lamble, Sarah; Jayawant, Sandeep; Quaghebeur, Gerardine; Cader, M. Zameel; Hughes, Sarah; Armstrong, Richard J. E.; Kanapin, Alexander; Rimmer, Andrew; Lunter, Gerton; Mathieson, Iain; Cazier, Jean-Baptiste; Buck, David; Taylor, Jenny C.; Bentley, David; McVean, Gilean; Donnelly, Peter; Knight, Samantha J. L.; Jackson, Mandy; Ragoussis, Jiannis; Németh, Andrea H.

    2012-01-01

    β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome. PMID:23236289

  10. Etiology and occurrence of gingival recession - An epidemiological study

    PubMed Central

    Mythri, Sarpangala; Arunkumar, Suryanarayan Maiya; Hegde, Shashikanth; Rajesh, Shanker Kashyap; Munaz, Mohamed; Ashwin, Devasya

    2015-01-01

    Objectives: Gingival recession is the term used to characterize the apical shift of the marginal gingiva from its normal position on the crown of the tooth. It is frequently observed in adult subjects. The occurrence and severity of the gingival recession present considerable differences between populations. To prevent gingival recession from occurring, it is essential to detect the underlying etiology. The aim of the present study was to determine the occurrence of gingival recession and to identify the most common factor associated with the cause of gingival recession. Methods: A total of 710 subjects aged between 15 years to 60 years were selected. Data were collected by an interview with the help of a proforma and then the dental examination was carried out. The presence of gingival recession was recorded using Miller's classification of gingival recession. The Silness and Loe Plaque Index, Loe and Silness gingival index, community periodontal index were recorded. The data thus obtained were subjected to statistical analysis using Chi-square test and Student's unpaired t-test. Results: Of 710 subjects examined, 291 (40.98%) subjects exhibited gingival recession. The frequency of gingival recession was found to increase with age. High frequency of gingival recession was seen in males (60.5%) compared to females (39.5%). Gingival recession was commonly seen in mandibular incisors (43.0%). Miller's class I gingival recession was more commonly seen. The most common cause for gingival recession was dental plaque accumulation (44.1%) followed by faulty toothbrushing (42.7%). Conclusion: Approximately half of the subjects examined exhibited gingival recession. The etiology of gingival recession is multifactorial, and its appearance is always the result of more than one factor acting together. PMID:26941519

  11. Evidence for increased levels of positive and negative selection on the X chromosome versus autosomes in humans.

    PubMed

    Veeramah, Krishna R; Gutenkunst, Ryan N; Woerner, August E; Watkins, Joseph C; Hammer, Michael F

    2014-09-01

    Partially recessive variants under positive selection are expected to go to fixation more quickly on the X chromosome as a result of hemizygosity, an effect known as faster-X. Conversely, purifying selection is expected to reduce substitution rates more effectively on the X chromosome. Previous work in humans contrasted divergence on the autosomes and X chromosome, with results tending to support the faster-X effect. However, no study has yet incorporated both divergence and polymorphism to quantify the effects of both purifying and positive selection, which are opposing forces with respect to divergence. In this study, we develop a framework that integrates previously developed theory addressing differential rates of X and autosomal evolution with methods that jointly estimate the level of purifying and positive selection via modeling of the distribution of fitness effects (DFE). We then utilize this framework to estimate the proportion of nonsynonymous substitutions fixed by positive selection (α) using exome sequence data from a West African population. We find that varying the female to male breeding ratio (β) has minimal impact on the DFE for the X chromosome, especially when compared with the effect of varying the dominance coefficient of deleterious alleles (h). Estimates of α range from 46% to 51% and from 4% to 24% for the X chromosome and autosomes, respectively. While dependent on h, the magnitude of the difference between α values estimated for these two systems is highly statistically significant over a range of biologically realistic parameter values, suggesting faster-X has been operating in humans.

  12. Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus.

    PubMed Central

    Howard, T D; Guttmacher, A E; McKinnon, W; Sharma, M; McKusick, V A; Jabs, E W

    1997-01-01

    We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome. Images Figure 1 PMID:9399901

  13. Autosomal dominant polycystic kidney disease diagnosed in utero. Review.

    PubMed

    Nowak, Magdalena; Huras, Hubert; Wiecheć, Marcin; Jach, Robert; Radoń-Pokracka, Małgorzata; Górecka, Joanna

    2016-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is one of most common inherited renal diseases. It is estimated that very early onset ADPKD affects even 2% patients. The purpose of this article is to provide a comprehensive review of genetics, prenatal diagnosis and prognosis in very early onset autosomal dominant polycystic kidney disease.

  14. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia.

    PubMed

    Hardies, Katia; de Kovel, Carolien G F; Weckhuysen, Sarah; Asselbergh, Bob; Geuens, Thomas; Deconinck, Tine; Azmi, Abdelkrim; May, Patrick; Brilstra, Eva; Becker, Felicitas; Barisic, Nina; Craiu, Dana; Braun, Kees P J; Lal, Dennis; Thiele, Holger; Schubert, Julian; Weber, Yvonne; van 't Slot, Ruben; Nürnberg, Peter; Balling, Rudi; Timmerman, Vincent; Lerche, Holger; Maudsley, Stuart; Helbig, Ingo; Suls, Arvid; Koeleman, Bobby P C; De Jonghe, Peter

    2015-11-01

    The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.

  15. The difficult nosology of blepharophimosis-mental retardation syndromes: report on two siblings.

    PubMed

    Dentici, Maria Lisa; Mingarelli, Rita; Dallapiccola, Bruno

    2011-03-01

    Blepharophimosis-mental retardation syndromes (BMRS) include a group of clinically and etiologically heterogeneous conditions, which can occur as isolated features or as part of distinct disorders displaying multiple congenital anomalies. We report on two siblings, a 6-year-old girl and an 18-month-old male, presenting with overlapping clinical findings. Major characteristics included facial dysmorphisms with upward slanted palpebral fissures, blepharophimosis, telecanthus, hypertelorism, posteriorly rotated and abnormal ears, and micrognathia. Ectodermal abnormalities consisted of fine hair, sparse eyebrows, and thin skin. Both patients had feeding difficulties with gastro-esophageal reflux and growth retardation. Psychomotor skills were severely delayed with no verbal capacity. The male sib also displayed low growth hormone (GH) levels, while the older sister had low cholesterol and mildly elevated TSH levels. Numerous metabolic/genetic investigations, including cholesterol precursors, dosage, and high-resolution array-CGH, were negative. BMR syndromes, including Dubowitz syndrome, Marden-Walker syndrome, Ohdo/Ohdo-like syndromes, and the cholesterol storage disorders were considered. We concluded that these two patients are affected by a possible autosomal recessive condition within the heterogeneous clinical spectrum of BMRS, fitting with the Young-Simpson syndrome subtype.

  16. Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia.

    PubMed

    Romero, Norma Beatriz; Monnier, Nicole; Viollet, Louis; Cortey, Anne; Chevallay, Martine; Leroy, Jean Paul; Lunardi, Joël; Fardeau, Michel

    2003-11-01

    We studied seven patients (fetuses/infants) from six unrelated families affected by central core disease (CCD) and presenting with a fetal akinesia syndrome. Two fetuses died before birth (at 31 and 32 weeks) and five infants presented severe symptoms at birth (multiple arthrogryposis, congenital dislocation of the hips, severe hypotonia and hypotrophy, skeletal and feet deformities, kyphoscoliosis, etc.). Histochemical and ultrastructural studies of muscle biopsies confirmed the diagnosis of CCD showing unique large eccentric cores. Molecular genetic investigations led to the identification of mutations in the ryanodine receptor (RYR1) gene in three families, two with autosomal recessive (AR) and one with autosomal dominant (AD) inheritance. RYR1 gene mutations were located in the C-terminal domain in two families (AR and AD) and in the N-terminal domain of the third one (AR). This is the first report of mutations in the RYR1 gene involved in a severe form of CCD presenting as a fetal akinesia syndrome with AD and AR inheritances.

  17. Defective Lipid Transport and Biosynthesis in Recessive and Dominant Stargardt Macular Degeneration

    PubMed Central

    Molday, Robert S.; Zhang, Kang

    2010-01-01

    Stargardt disease is a common inherited macular degeneration characterized by a significant loss in central vision in the first or second decade of life, bilateral atrophic changes in the central retina associated with degeneration of photoreceptors and underlying retinal pigment epithelial cells, and the presence of yellow flecks extending from the macula. Autosomal recessive Stargardt disease, the most common macular dystrophy, is caused by mutations in the gene encoding ABCA4, a photoreceptor ATP binding cassette (ABC) transporter. Biochemical studies together with analysis of abca4 knockout mice and Stargardt patients have implicated ABCA4 as a lipid transporter that facilitates the removal of potentially toxic retinal compounds from photoreceptors following photoexcitation. An autosomal dominant form of Stargardt disease also known as Stargardt-like dystrophy is caused by mutations in a gene encoding ELOVL4, an enzyme that catalyzes the elongation of very long chain fatty acids in photoreceptors and other tissues. This review focuses on the molecular characterization of ABCA4 and ELOVL4 and their role in photoreceptor cell biology and the pathogenesis of Stargardt disease. PMID:20633576

  18. Event-scale power law recession analysis: quantifying methodological uncertainty

    NASA Astrophysics Data System (ADS)

    Dralle, David N.; Karst, Nathaniel J.; Charalampous, Kyriakos; Veenstra, Andrew; Thompson, Sally E.

    2017-01-01

    The study of single streamflow recession events is receiving increasing attention following the presentation of novel theoretical explanations for the emergence of power law forms of the recession relationship, and drivers of its variability. Individually characterizing streamflow recessions often involves describing the similarities and differences between model parameters fitted to each recession time series. Significant methodological sensitivity has been identified in the fitting and parameterization of models that describe populations of many recessions, but the dependence of estimated model parameters on methodological choices has not been evaluated for event-by-event forms of analysis. Here, we use daily streamflow data from 16 catchments in northern California and southern Oregon to investigate how combinations of commonly used streamflow recession definitions and fitting techniques impact parameter estimates of a widely used power law recession model. Results are relevant to watersheds that are relatively steep, forested, and rain-dominated. The highly seasonal mediterranean climate of northern California and southern Oregon ensures study catchments explore a wide range of recession behaviors and wetness states, ideal for a sensitivity analysis. In such catchments, we show the following: (i) methodological decisions, including ones that have received little attention in the literature, can impact parameter value estimates and model goodness of fit; (ii) the central tendencies of event-scale recession parameter probability distributions are largely robust to methodological choices, in the sense that differing methods rank catchments similarly according to the medians of these distributions; (iii) recession parameter distributions are method-dependent, but roughly catchment-independent, such that changing the choices made about a particular method affects a given parameter in similar ways across most catchments; and (iv) the observed correlative relationship

  19. What mainly controls recession flows in river basins?

    NASA Astrophysics Data System (ADS)

    Biswal, Basudev; Nagesh Kumar, D.

    2014-03-01

    The ubiquity of the power law relationship between dQ/dt and Q for recession periods (-dQ/dt=kQα,Q being discharge at the basin outlet at time t) clearly hints at the existence of a dominant recession flow process that is common to all real basins. It is commonly assumed that a basin, during recession events, functions as a single phreatic aquifer resting on a impermeable horizontal bed or the Dupuit-Boussinesq (DB) aquifer, and with time different aquifer geometric conditions arise that give different values of α and k. The recently proposed alternative model, geomorphological recession flow model, however, suggests that recession flows are controlled primarily by the dynamics of the active drainage network (ADN). In this study we use data for several basins and compare the above two contrasting recession flow models in order to understand which of the above two factors dominates during recession periods in steep basins. Particularly, we do the comparison by selecting three key recession flow properties: (1) power law exponent α, (2) dynamic dQ/dt-Q relationship (characterized by k) and (3) recession timescale (time period for which a recession event lasts). Our observations suggest that neither drainage from phreatic aquifers nor evapotranspiration significantly controls recession flows. Results show that the value of α and recession timescale are not modeled well by DB aquifer model. However, the above mentioned three recession curve properties can be captured satisfactorily by considering the dynamics of the ADN as described by geomorphological recession flow model, possibly indicating that the ADN represents not just phreatic aquifers but the organization of various sub-surface storage systems within the basin.

  20. Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation and growth delay: clinical report and review of the literature.

    PubMed

    de Ru, M H; Gille, J J P; Nieuwint, A W M; Bijlsma, J B; van der Blij, J F; van Hagen, J M

    2005-08-15

    We present a boy with blepharophimosis, ptosis, epicanthus inversus, microcephaly, mild mental retardation, and growth delay. Chromosomal analysis revealed a male karyotype with an interstitial deletion in the long arm of chromosome 3. DNA-analysis showed that the deletion is of maternal origin and encompasses the region between markers D3S1535 and D3S1593. The deletion contains not only the FOXL2 gene, but also the gene encoding ataxia-telangiectasia and Rad3-related protein (ATR). Mutations in FOXL2 have been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). ATR has been identified as a candidate gene for Seckel syndrome, an autosomal recessive syndrome that comprises growth retardation, microcephaly, and mental retardation. We hypothesize that our patient has a contiguous gene syndrome and that the non-BPES-associated abnormalities (microcephaly, mild mental retardation, and growth delay) are the result of the deletion of the maternal ATR gene. However, it has not yet been excluded that haploinsufficiency of some other gene in this region plays a role.

  1. Compound Heterozygosity of Dominant and Recessive COL7A Alleles in a Severely Affected Patient with a Family History of Dystrophic Epidermolysis Bullosa: Clinical Findings, Genetic Testing, and Treatment Implications.

    PubMed

    Watson, Kendra D; Schoch, Jennifer J; Beek, Geoffrey J; Hand, Jennifer L

    2017-03-01

    An 8-year-old girl born to a family with more than three generations of dominant dystrophic epidermolysis bullosa (DDEB) presented with life-threatening confluent skin erosions, mitten hand deformity, and failure to thrive. Reassessment of her family history and genetic testing showed compound heterozygous COL7A mutations, one inherited from her DDEB-affected mother and one from her unaffected, healthy father. This family illustrates the risk of unexpected, severe, autosomal recessive epidermolysis bullosa (EB) in a family with milder, multigenerational autosomal dominant EB. Clinicians should recognize the clinical spectrum of dystrophic EB and recommend genetic consultation when the phenotype conflicts with family history.

  2. Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

    PubMed Central

    Angebault, Claire; Guichet, Pierre-Olivier; Talmat-Amar, Yasmina; Charif, Majida; Gerber, Sylvie; Fares-Taie, Lucas; Gueguen, Naig; Halloy, François; Moore, David; Amati-Bonneau, Patrizia; Manes, Gael; Hebrard, Maxime; Bocquet, Béatrice; Quiles, Mélanie; Piro-Mégy, Camille; Teigell, Marisa; Delettre, Cécile; Rossel, Mireille; Meunier, Isabelle; Preising, Markus; Lorenz, Birgit; Carelli, Valerio; Chinnery, Patrick F.; Yu-Wai-Man, Patrick; Kaplan, Josseline; Roubertie, Agathe; Barakat, Abdelhamid; Bonneau, Dominique; Reynier, Pascal; Rozet, Jean-Michel; Bomont, Pascale; Hamel, Christian P.; Lenaers, Guy

    2015-01-01

    Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation. PMID:26593267

  3. Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia.

    PubMed

    Zech, Michael; Lam, Daniel D; Francescatto, Ludmila; Schormair, Barbara; Salminen, Aaro V; Jochim, Angela; Wieland, Thomas; Lichtner, Peter; Peters, Annette; Gieger, Christian; Lochmüller, Hanns; Strom, Tim M; Haslinger, Bernhard; Katsanis, Nicholas; Winkelmann, Juliane

    2015-06-04

    Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.

  4. Autosomal Trisomies and Partial Trisomy Syndromes

    PubMed Central

    Zaleski, W. A.

    1963-01-01

    The establishing of 46 chromosomes as the normal complement in man and the report of the sex chromatin bodies in buccal smears were followed by reports of trisomies and other abnormal patterns of the X and Y chromosomes in Klinefelter's and Turner's syndromes. Abnormal autosomal complements were described in mongolism, in the E-trisomy syndrome, the D-trisomy syndrome, in the Sturge-Weber syndrome, Waldenstrom's macroglobulinemia, benign congenital hypotonia, atrial septal defect and in the schizoid personality. Certain of these conditions, as well as the “oral-facial-digital” syndrome, were also found to exist as partial trisomies. The mechanism of a trisomy is one of non-disjunction and of partial trisomy translocation or insertion. Two cases of the partial trisomy in the E group are described; these are of especial interest because of the familial incidence, longer survival and male sex occurrence, features which are rarely seen in the full E-trisomy syndrome. ImagesFig. 4Fig. 5Fig. 6 PMID:20327419

  5. Autosomal dominant polycystic kidney disease in children

    PubMed Central

    Cadnapaphornchai, Melissa A.

    2015-01-01

    Purpose of review Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting one in 500 individuals. The cardinal manifestation of ADPKD is progressive cystic dilatation of renal tubules with kidney enlargement and progression to end-stage renal disease in approximately half of cases by 60 years of age. Although previously considered a condition of adults, it is clear that children and young adults are subject to the complications of ADPKD. Recent findings It has been increasingly recognized that interventions early in life are necessary in order to confer the best long-term outcome in this common condition. Therefore, it is imperative for pediatricians to recognize the manifestations and complications of this disease. Until recently ADPKD management focused on general principles of chronic kidney disease. However, several recent clinical trials in children and adults with ADPKD have focused on disease-specific therapies. Summary This review will highlight the clinical manifestations, diagnosis, and appropriate management of ADPKD in childhood and will review recent relevant clinical trials in children and adults with this condition. PMID:25635587

  6. CFLs in Recessed Downlights: Technical Challenges

    SciTech Connect

    Ledbetter, Marc R.; McCullough, Jeffrey J.; Dillon, Heather E.; Sandahl, Linda J.; Gordon, Kelly L.

    2005-05-09

    Recessed downlights are the most popular residential lighting fixture in the United States representing about 12 percent of installed residential lighting fixtures and 15 percent of total lighting energy use nationwide. We estimate 400 million recessed downlights are currently installed in American homes, almost all using incandescent light sources. In the year 2000, only 0.44 percent of recessed cans sold were hard-wired for using pin-based CFLs. Recessed downlights consume energy in three ways. First, their incandescent light sources use energy directly, drawing 65 to 150 watts. Second, they consume energy indirectly by adding heat from their light sources to air-conditioning loads. Third, since most are not airtight, they also consume energy indirectly by allowing conditioned air to escape into unconditioned areas above the downlights, such as attics. PNNL calculated potential energy savings and found that if a 65W incandescent non-airtight downlight is replaced with a 26W CFL ICAT downlight operated at 3 hrs per day savings will be 126 kWh/yr. Early reflector CFLs have had high return rates primarily because of failure due to thermal related stress. A PNNL laboratory test of ten commercially available R-CFLs selected from retail store shelves showed almost all operated above their manufacturer rated maximum operating temperatures when they were installed and tested in ICAT downlights in a simulated insulated ceiling apparatus. DOE asked PNNL to investigate the development and introduction of both pin-based and screw-based CFLs for use in ICAT fixtures. PNNL invited manufacturers to submit lamps to a procurement program. PNNL conducted short- and long-term thermal testing of the lamps to measure performance parameters affected by elevated temperatures. 8 out of 10 R-CFLs (secrew-based lamps) failed the long-tem testing. Five out of nine CFL-ICAT (pin-based CFL) fixtures passed the long-term test, surviving a full year of operation in a simulated insulated

  7. X chromosome regulation of autosomal gene expression in bovine blastocysts.

    PubMed

    Itoh, Yuichiro; Arnold, Arthur P

    2014-10-01

    Although X chromosome inactivation in female mammals evolved to balance the expression of X chromosome and autosomal genes in the two sexes, female embryos pass through developmental stages in which both X chromosomes are active in somatic cells. Bovine blastocysts show higher expression of many X genes in XX than XY embryos, suggesting that X inactivation is not complete. Here, we reanalyzed bovine blastocyst microarray expression data from a network perspective with a focus on interactions between X chromosome and autosomal genes. Whereas male-to-female ratios of expression of autosomal genes were distributed around a mean of 1, X chromosome genes were clearly shifted towards higher expression in females. We generated gene coexpression networks and identified a major module of genes with correlated gene expression that includes female-biased X genes and sexually dimorphic autosomal genes for which the sexual dimorphism is likely driven by the X genes. In this module, expression of X chromosome genes correlates with autosome genes, more than the expression of autosomal genes with each other. Our study identifies correlated patterns of autosomal and X-linked genes that are likely influenced by the sexual imbalance of X gene expression when X inactivation is inefficient.

  8. Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33-q27.3.

    PubMed

    John, Peter; Ali, Ghazanfar; Chishti, Muhammad S; Naqvi, Syed Muhammad S; Leal, Suzanne M; Ahmad, Wasim

    2006-01-01

    Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33-q27.3. A maximum two-point LOD score of 3.05 (theta = 0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33-q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.

  9. A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31.

    PubMed

    Wali, A; John, P; Gul, A; Lee, K; Chishti, M S; Ali, G; Hassan, M J; Leal, S M; Ahmad, W

    2006-09-01

    Congenital alopecia may occur either alone or in association with ectodermal and other abnormalities. On the bases of such associations, several different syndromes featuring congenital alopecia can be distinguished. Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder, clinically characterized by total or partial hair loss and mental retardation. In the present study, a five-generation Pakistani family with multiple affected individuals with APMR was ascertained. Patients in this family exhibited typical features of APMR syndrome. The disease locus was mapped to chromosome 3q26.2-q26.31 by carrying out a genome scan followed by fine mapping. A maximum two-point logarithm of odds (LOD) score of 2.93 at theta=0.0 was obtained at markers D3S3053 and D3S2309. Multipoint linkage analysis resulted in a maximum LOD score of 4.57 with several markers, which supports the linkage. The disease locus was flanked by markers D3S1564 and D3S2427, which corresponds to 9.6-cM region according to the Rutgers combined linkage-physical map of the human genome (build 35) and contains 5.6 Mb. The linkage interval of the APMR locus identified here does not overlap with the one described previously; therefore, this locus has been designated as APMR2.

  10. Autosomal dominant hearing loss resulting from p.R75Q mutation in the GJB2 gene: nonsyndromic presentation in a South Indian family.

    PubMed

    Pavithra, Amritkumar; Selvakumari, Mathiyalagan; Nityaa, Venkatesan; Sharanya, Narasimhan; Ramakrishnan, Rajagopalan; Narasimhan, Murali; Srisailapathy, C R Srikumari

    2015-01-01

    Mutations in the GJB2 gene encoding the gap junction protein Connexin 26 have been associated with autosomal recessive as well as dominant nonsyndromic hearing loss. Owing to the involvement of connexins in skin homeostasis, GJB2 mutations have also been associated with syndromic forms of hearing loss showing various skin manifestations. We report an assortatively mating hearing impaired family of south Indian origin with three affected members spread over two generations, having p.R75Q mutation in the GJB2 gene in the heterozygous condition. The inheritance pattern was autosomal dominant with mother and son being affected. Dermatological and histopathologic examinations showed absence of palmoplantar keratoderma. To the best of our knowledge, this is the first report from India on p.R75Q mutation in the GJB2 gene with nonsyndromic hearing loss.

  11. Cultural transmission of a sign language when deafness is caused by recessive alleles at two independent loci.

    PubMed

    Aoki, K; Feldman, M W

    1994-02-01

    Two unlinked autosomal loci are assumed to affect the ability to hear in such a way that homozygosity for the recessive allele at either locus causes deafness. The five deaf genotypes are subject to the same negative selection due to a lower likelihood of marriage, but unmarried deaf persons remain socially active and participate in the cultural transmission of sign languages. Marriages are assortative for deafness or for hearing, and mutation occurs irreversibly from the dominant to recessive allele at each locus at the same rate. At mutation-selection balance, the fully polymorphic equilibrium is symmetrical. Based on this genetic model, we consider the relative importance of various forms of cultural transmission as they affect the persistence of sign languages. Horizontal transmission is shown to be effective when deaf children are able to interact with many peers. This observation is especially pertinent if assortative meeting of deaf children occurs, for example, at schools for the deaf. Oblique transmission can also be effective, but the literature suggests that this kind of transmission plays only a minor role. It is necessary, however, that some form of cultural transmission occur between generations. Thus, vertical transmission is a critical factor, despite the fact that parent-child transmission is often interrupted due to the recessive inheritance of deafness. In particular, the contribution of vertical transmission is enhanced by assortative mating for deafness.

  12. The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate.

    PubMed

    Hwang, Vicki J; Kim, Jeffrey; Rand, Amy; Yang, Chaozhe; Sturdivant, Steve; Hammock, Bruce; Bell, P Darwin; Guay-Woodford, Lisa M; Weiss, Robert H

    2015-09-15

    Since polycystic kidney disease (PKD) was first noted over 30 years ago to have neoplastic parallels, there has been a resurgent interest in elucidating neoplasia-relevant pathways in PKD. Taking a nontargeted metabolomics approach in the B6(Cg)-Cys1(cpk/)J (cpk) mouse model of recessive PKD, we have now characterized metabolic reprogramming in these tissues, leading to a glutamine-dependent TCA cycle shunt toward total 2-hydroxyglutarate (2-HG) production in cpk compared with B6 wild-type kidney tissue. After confirmation of increased 2-HG expression in immortalized collecting duct cpk cells as well as in human autosomal recessive PKD tissue using targeted analysis, we show that the increase in 2-HG is likely due to glutamine-sourced α-ketoglutarate. In addition, cpk cells require exogenous glutamine for growth such that inhibition of glutaminase-1 decreases cell viability as well as proliferation. This study is a demonstration of the striking parallels between recessive PKD and cancer metabolism. Our data, once confirmed in other PKD models, suggest that future therapeutic approaches targeting this pathway, such as using glutaminase inhibitors, have the potential to open novel treatment options for renal cystic disease.

  13. Mental Disorders

    MedlinePlus

    Mental disorders include a wide range of problems, including Anxiety disorders, including panic disorder, obsessive-compulsive disorder, post- ... disorders, including schizophrenia There are many causes of mental disorders. Your genes and family history may play a ...

  14. Mental Health

    MedlinePlus

    Mental health includes our emotional, psychological, and social well-being. It affects how we think, feel and act as ... stress, relate to others, and make choices. Mental health is important at every stage of life, from ...

  15. Hypertension in Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Chapman, Arlene B.; Stepniakowski, Konrad; Rahbari-Oskoui, Frederic

    2010-01-01

    Hypertension is common and occurs in a majority of autosomal dominant polycystic kidney disease (ADPKD) patients prior to loss of kidney function. Hypertension relates to progressive kidney enlargement, and is a significant independent risk factor for progression to end stage renal disease. The pathogenesis of hypertension in ADPKD is complex and dependent on many factors that influence each other. Pkd1 and Pkd2 expression levels are highest in the major vessels and are present in the cilia of endothelial cells and in vascular smooth muscle cells. Decreased or absent polycystin 1 or 2 expression is associated with abnormal vascular structure and function. Pkd1/Pkd2 deficiency results in reduced nitric oxide (NO) levels, altered endothelial response to shear stress with attenuation in vascular relaxation. 10–20% of ADPKD children demonstrate hypertension and the majority of adults are hypertensive before any loss of kidney function. Cardiac abnormalities such as left ventricular hypertrophy and carotid intimal wall thickening are present prior to the development of hypertension in ADPKD. Activation of the renin-angiotensin-aldosterone system occurs in ADPKD due to decreased NO production as well as bilateral cyst expansion and intra-renal ischemia. With increasing cyst size, further activation of the RAAS occurs, blood pressure increases and a vicious cycle ensues with enhanced cyst growth and hypertension ultimately leading to ESRD. Inhibition of the angiotensin aldosterone system is possible with angiotensin converting enzyme inhibitors and angiotensin receptor blockers. However, interventional studies have not yet demonstrated benefit in slowing progression to renal failure in ADPKD. Currently, large multicenter studies are being performed to determine the beneficial effects of RAAS inhibition both early and late in ADPKD. PMID:20219618

  16. Prediction of the start of next recession using latent factors

    NASA Astrophysics Data System (ADS)

    Pooi, Ah-Hin; Soo, Huei-Ching; Pan, Wei-Yeing

    2016-10-01

    The data on the binary recession variable and the latent factors extracted from a large set of economic variables are fitted with a multivariate power-normal distribution. A conditional distribution for the recession variable is obtained from the fitted multivariate distribution. The results based on the US economic data show that the 2.5% point of the conditional distribution provides a good indicator for the start of the next recession.

  17. A gene defect causing a novel progressive epilepsy with mental retardation, EPMR, maps to chromosome 8p

    SciTech Connect

    Ranta, S.; Tahvanainen, E.; Karila, E.

    1994-09-01

    EPMR (progressive epilepsy with mental retardation) is a newly discovered autosomal recessively inherited disorder which occurs with high frequency in an isolated rural population in Finland. So far 25 patients have been identified, 21 of whom are alive. Twenty-three patients share a common ancestor from the 18th century. The main features of EPMR are: normal early development, tonic-clonic seizures with onset between ages 5 and 10, and mental retardation which begins approximately 2 years after the onset of epilepsy and soon leads to deepening mental retardation. Adult patients do not manage their daily life without help. The EEG is normal at the onset of epilepsy but later progressive slowing of the background activity occurs. The etiology and pathogenesis of EPMR remain known. As this is a novel disease entity without any definitive diagnostic marker we wished to begin its elucidation by first defining its gene locus. A random search for linkage in four multiplex families (only 20 individuals tested) resulted in the finding of linkage to marker D8S264 with a lod score of 4.45 at zero recombination. The EPMR gene resides in a 7 centimorgan interval between marker loci AFM185xb2 and D8S262 with a maximum multipoint lod score of 7.03 at 1.8 centimorgans proximal to D8S264. Physically this region is very distal on 8p. Of the sixteen EPMR chromosomes haplotyped 15 were identical or almost identical. One chromosome, however, had a distinctly different haplotype raising the possibility of there being two different mutations or one very old mutation. These findings are a starting point toward isolating and characterizing the gene and its protein product. Physical mapping has been initiated by isolating nine YACs from the region.

  18. A visual basic spreadsheet macro for recession curve analysis.

    PubMed

    Posavec, Kristijan; Bacani, Andrea; Nakić, Zoran

    2006-01-01

    A Visual Basic program for an Excel spreadsheet was written to construct a master recession curve (MRC), using the adapted matching strip method, for recession analysis of ground water level time series. The program uses five different linear/nonlinear regression models to adjust individual recession segments to their proper positions in the MRC. The program can also be used to analyze the recession segments of other time series, such as daily stream discharge or stage. Some examples of field data from Croatia are used to illustrate the usefulness of its application.

  19. X Chromosome and Autosome Dosage Responses in Drosophila melanogaster Heads.

    PubMed

    Chen, Zhen-Xia; Oliver, Brian

    2015-04-07

    X chromosome dosage compensation is required for male viability in Drosophila. Dosage compensation relative to autosomes is two-fold, but this is likely to be due to a combination of homeostatic gene-by-gene regulation and chromosome-wide regulation. We have baseline values for gene-by-gene dosage compensation on autosomes, but not for the X chromosome. Given the evolutionary history of sex chromosomes, these baseline values could differ. We used a series of deficiencies on the X and autosomes, along with mutations in the sex-determination gene transformer-2, to carefully measure the sex-independent X-chromosome response to gene dosage in adult heads by RNA sequencing. We observed modest and indistinguishable dosage compensation for both X chromosome and autosome genes, suggesting that the X chromosome is neither inherently more robust nor sensitive to dosage change.

  20. Genetics Home Reference: autosomal dominant hyper-IgE syndrome

    MedlinePlus

    ... Facebook Share on Twitter Your Guide to Understanding Genetic Conditions Search MENU Toggle navigation Home Page Search ... Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Home Health Conditions autosomal dominant hyper-IgE syndrome ...

  1. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome

    PubMed Central

    Burrage, Lindsay C.; Charng, Wu-Lin; Eldomery, Mohammad K.; Willer, Jason R.; Davis, Erica E.; Lugtenberg, Dorien; Zhu, Wenmiao; Leduc, Magalie S.; Akdemir, Zeynep C.; Azamian, Mahshid; Zapata, Gladys; Hernandez, Patricia P.; Schoots, Jeroen; de Munnik, Sonja A.; Roepman, Ronald; Pearring, Jillian N.; Jhangiani, Shalini; Katsanis, Nicholas; Vissers, Lisenka E.L.M.; Brunner, Han G.; Beaudet, Arthur L.; Rosenfeld, Jill A.; Muzny, Donna M.; Gibbs, Richard A.; Eng, Christine M.; Xia, Fan; Lalani, Seema R.; Lupski, James R.; Bongers, Ernie M.H.F.; Yang, Yaping

    2015-01-01

    Meier-Gorlin syndrome (MGS)