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Sample records for 8-oxoguanine-repair-deficient mutator phenotype

  1. The new mutation theory of phenotypic evolution

    PubMed Central

    Nei, Masatoshi

    2007-01-01

    Recent studies of developmental biology have shown that the genes controlling phenotypic characters expressed in the early stage of development are highly conserved and that recent evolutionary changes have occurred primarily in the characters expressed in later stages of development. Even the genes controlling the latter characters are generally conserved, but there is a large component of neutral or nearly neutral genetic variation within and between closely related species. Phenotypic evolution occurs primarily by mutation of genes that interact with one another in the developmental process. The enormous amount of phenotypic diversity among different phyla or classes of organisms is a product of accumulation of novel mutations and their conservation that have facilitated adaptation to different environments. Novel mutations may be incorporated into the genome by natural selection (elimination of preexisting genotypes) or by random processes such as genetic and genomic drift. However, once the mutations are incorporated into the genome, they may generate developmental constraints that will affect the future direction of phenotypic evolution. It appears that the driving force of phenotypic evolution is mutation, and natural selection is of secondary importance. PMID:17640887

  2. Wolfram Syndrome: New Mutations, Different Phenotype

    PubMed Central

    Pasquali, Lorenzo; Lugani, Francesca; Perri, Katia; Russo, Chiara; Tallone, Ramona; Ghiggeri, Gian Marco; Lorini, Renata; d'Annunzio, Giuseppe

    2012-01-01

    Background Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. Methodology/Principal Findings We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. Conclusions/Significance Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA). PMID:22238590

  3. A multiple phenotype predator-prey model with mutation

    NASA Astrophysics Data System (ADS)

    Abernethy, Gavin M.; Mullan, Rory; Glass, David H.; McCartney, Mark

    2017-01-01

    An existing multiple phenotype predator-prey model is expanded to include mutation amongst the predator phenotypes. Two unimodal maps are used for the underlying dynamics of the prey. A predation strategy is also defined which differs for each of the predators in the model. Results show that the introduction of predator mutation enhances predator survival both in terms of the number of phenotypes and total population for a range of values of the predation rate. In general, the dominant predator phenotype is the one which is most focused on the prey phenotype with the largest population.

  4. Cardiac sodium channel mutations: why so many phenotypes?

    PubMed Central

    Liu, Man; Yang, Kai-Chien; Dudley, Samuel C.

    2016-01-01

    Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype–phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype–phenotype correlations and lead to new therapeutic strategies. PMID:24958080

  5. IDH mutations: genotype-phenotype correlation and prognostic impact.

    PubMed

    Wang, Xiao-Wei; Ciccarino, Pietro; Rossetto, Marta; Boisselier, Blandine; Marie, Yannick; Desestret, Virginie; Gleize, Vincent; Mokhtari, Karima; Sanson, Marc; Labussière, Marianne

    2014-01-01

    IDH1/2 mutation is the most frequent genomic alteration found in gliomas, affecting 40% of these tumors and is one of the earliest alterations occurring in gliomagenesis. We investigated a series of 1305 gliomas and showed that IDH mutation is almost constant in 1p19q codeleted tumors. We found that the distribution of IDH1(R132H) , IDH1(nonR132H) , and IDH2 mutations differed between astrocytic, mixed, and oligodendroglial tumors, with an overrepresentation of IDH2 mutations in oligodendroglial phenotype and an overrepresentation of IDH1(nonR132H) in astrocytic tumors. We stratified grade II and grade III gliomas according to the codeletion of 1p19q and IDH mutation to define three distinct prognostic subgroups: 1p19q and IDH mutated, IDH mutated--which contains mostly TP53 mutated tumors, and none of these alterations. We confirmed that IDH mutation with a hazard ratio = 0.358 is an independent prognostic factor of good outcome. These data refine current knowledge on IDH mutation prognostic impact and genotype-phenotype associations.

  6. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

    PubMed

    Tatton-Brown, Katrina; Murray, Anne; Hanks, Sandra; Douglas, Jenny; Armstrong, Ruth; Banka, Siddharth; Bird, Lynne M; Clericuzio, Carol L; Cormier-Daire, Valerie; Cushing, Tom; Flinter, Frances; Jacquemont, Marie-Line; Joss, Shelagh; Kinning, Esther; Lynch, Sally Ann; Magee, Alex; McConnell, Vivienne; Medeira, Ana; Ozono, Keiichi; Patton, Michael; Rankin, Julia; Shears, Debbie; Simon, Marleen; Splitt, Miranda; Strenger, Volker; Stuurman, Kyra; Taylor, Clare; Titheradge, Hannah; Van Maldergem, Lionel; Temple, I Karen; Cole, Trevor; Seal, Sheila; Rahman, Nazneen

    2013-12-01

    Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

  7. Atypical phenotype in two patients with LAMA2 mutations.

    PubMed

    Marques, Joana; Duarte, Sofia T; Costa, Sónia; Jacinto, Sandra; Oliveira, Jorge; Oliveira, Márcia E; Santos, Rosário; Bronze-da-Rocha, Elsa; Silvestre, Ana Rita; Calado, Eulália; Evangelista, Teresinha

    2014-05-01

    Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene, which encodes the α2-chain of laminin. We report two patients with partial laminin-α2 deficiency and atypical phenotypes, one with almost exclusive central nervous system involvement (cognitive impairment and refractory epilepsy) and the second with marked cardiac dysfunction, rigid spine syndrome and limb-girdle weakness. Patients underwent clinical, histopathological, imaging and genetic studies. Both cases have two heterozygous LAMA2 variants sharing a potentially pathogenic missense mutation c.2461A>C (p.Thr821Pro) located in exon 18. Brain MRI was instrumental for the diagnosis, since muscular examination and motor achievements were normal in the first patient and there was a severe cardiac involvement in the second. The clinical phenotype of the patients is markedly different which could in part be explained by the different combination of mutations types (two missense versus a missense and a truncating mutation).

  8. PhenCode: connecting ENCODE data with mutations and phenotype.

    PubMed

    Giardine, Belinda; Riemer, Cathy; Hefferon, Tim; Thomas, Daryl; Hsu, Fan; Zielenski, Julian; Sang, Yunhua; Elnitski, Laura; Cutting, Garry; Trumbower, Heather; Kern, Andrew; Kuhn, Robert; Patrinos, George P; Hughes, Jim; Higgs, Doug; Chui, David; Scriver, Charles; Phommarinh, Manyphong; Patnaik, Santosh K; Blumenfeld, Olga; Gottlieb, Bruce; Vihinen, Mauno; Väliaho, Jouni; Kent, Jim; Miller, Webb; Hardison, Ross C

    2007-06-01

    PhenCode (Phenotypes for ENCODE; http://www.bx.psu.edu/phencode) is a collaborative, exploratory project to help understand phenotypes of human mutations in the context of sequence and functional data from genome projects. Currently, it connects human phenotype and clinical data in various locus-specific databases (LSDBs) with data on genome sequences, evolutionary history, and function from the ENCODE project and other resources in the UCSC Genome Browser. Initially, we focused on a few selected LSDBs covering genes encoding alpha- and beta-globins (HBA, HBB), phenylalanine hydroxylase (PAH), blood group antigens (various genes), androgen receptor (AR), cystic fibrosis transmembrane conductance regulator (CFTR), and Bruton's tyrosine kinase (BTK), but we plan to include additional loci of clinical importance, ultimately genomewide. We have also imported variant data and associated OMIM links from Swiss-Prot. Users can find interesting mutations in the UCSC Genome Browser (in a new Locus Variants track) and follow links back to the LSDBs for more detailed information. Alternatively, they can start with queries on mutations or phenotypes at an LSDB and then display the results at the Genome Browser to view complementary information such as functional data (e.g., chromatin modifications and protein binding from the ENCODE consortium), evolutionary constraint, regulatory potential, and/or any other tracks they choose. We present several examples illustrating the power of these connections for exploring phenotypes associated with functional elements, and for identifying genomic data that could help to explain clinical phenotypes.

  9. Genotypes and phenotypes of 162 families with a glomulin mutation.

    PubMed

    Brouillard, P; Boon, L M; Revencu, N; Berg, J; Dompmartin, A; Dubois, J; Garzon, M; Holden, S; Kangesu, L; Labrèze, C; Lynch, S A; McKeown, C; Meskauskas, R; Quere, I; Syed, S; Vabres, P; Wassef, M; Mulliken, J B; Vikkula, M

    2013-04-01

    A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling.

  10. Genotypes and Phenotypes of 162 Families with a Glomulin Mutation

    PubMed Central

    Brouillard, P.; Boon, L.M.; Revencu, N.; Berg, J.; Dompmartin, A.; Dubois, J.; Garzon, M.; Holden, S.; Kangesu, L.; Labrèze, C.; Lynch, S.A.; McKeown, C.; Meskauskas, R.; Quere, I.; Syed, S.; Vabres, P.; Wassef, M.; Mulliken, J.B.; Vikkula, M.

    2013-01-01

    A decade ago, we identified a novel gene, glomulin (GLMN) in which mutations cause glomuvenous malformations (GVMs). GVMs are bluish-purple cutaneous vascular lesions with characteristic glomus cells in the walls of distended venous channels. The discovery of the genetic basis for GVMs allowed the definition of clinical features to distinguish GVMs from other venous anomalies. The variation in phenotype was also highlighted: from a single punctate blue dot to a large plaque-like lesion. In this study, we screened GLMN in a large cohort of patients to broaden the spectrum of mutations, define their frequency and search for possible genotype-phenotype correlations. Taking into account 6 families published by others, a mutation in GLMN has been found in 162 families. This represents 40 different mutations; the most frequent one being present in almost 45% of them. Expressivity varies largely, without a genotype/phenotype relationship. Among 381 individuals with a mutation, we discovered 37 unaffected carriers, implying a penetrance of 90%. As nonpenetrant individuals may transmit the disease to their descendants, knowledge on the mutational status is needed for appropriate genetic counseling. PMID:23801931

  11. CMT4D (NDRG1 mutation): genotype-phenotype correlations.

    PubMed

    Ricard, Emilie; Mathis, Stéphane; Magdelaine, Corinne; Delisle, Marie-Bernadette; Magy, Laurent; Funalot, Benoît; Vallat, Jean-Michel

    2013-09-01

    Charcot-Marie-Tooth (CMT) disease is a heterogeneous condition with a large number of clinical, electrophysiological and pathological phenotypes. More than 40 genes are involved. We report a child of gypsy origin with an autosomal recessive demyelinating phenotype. Clinical data, familial history, and electrophysiological studies were in favor of a CMT4 sub-type. The characteristic N-Myc downstream-regulated gene 1 (NDRG1) mutation responsible for this CMT4D phenotype was confirmed: p.R148X. The exact molecular function of the NDRG1 protein has yet to be elucidated.

  12. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.

    PubMed

    Zimoń, M; Baets, J; Fabrizi, G M; Jaakkola, E; Kabzińska, D; Pilch, J; Schindler, A B; Cornblath, D R; Fischbeck, K H; Auer-Grumbach, M; Guelly, C; Huber, N; De Vriendt, E; Timmerman, V; Suter, U; Hausmanowa-Petrusewicz, I; Niemann, A; Kochański, A; De Jonghe, P; Jordanova, A

    2011-08-09

    Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling.

  13. Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations.

    PubMed

    Emery, Edward C; Habib, Abdella M; Cox, James J; Nicholas, Adeline K; Gribble, Fiona M; Woods, C Geoffrey; Reimann, Frank

    2015-05-20

    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.

  14. FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-Phenotype Correlation

    PubMed Central

    De Baere, Elfride; Beysen, Diane; Oley, Christine; Lorenz, Birgit; Cocquet, Julie; De Sutter, Paul; Devriendt, Koen; Dixon, Michael; Fellous, Marc; Fryns, Jean-Pierre; Garza, Arturo; Jonsrud, Christoffer; Koivisto, Pasi A.; Krause, Amanda; Leroy, Bart P.; Meire, Françoise; Plomp, Astrid; Van Maldergem, Lionel; De Paepe, Anne; Veitia, Reiner; Messiaen, Ludwine

    2003-01-01

    Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5′ untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations. PMID:12529855

  15. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.

    PubMed

    De Baere, Elfride; Beysen, Diane; Oley, Christine; Lorenz, Birgit; Cocquet, Julie; De Sutter, Paul; Devriendt, Koen; Dixon, Michael; Fellous, Marc; Fryns, Jean-Pierre; Garza, Arturo; Jonsrud, Christoffer; Koivisto, Pasi A; Krause, Amanda; Leroy, Bart P; Meire, Françoise; Plomp, Astrid; Van Maldergem, Lionel; De Paepe, Anne; Veitia, Reiner; Messiaen, Ludwine

    2003-02-01

    Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations.

  16. Novel SCN9A Mutations Underlying Extreme Pain Phenotypes: Unexpected Electrophysiological and Clinical Phenotype Correlations

    PubMed Central

    Emery, Edward C.; Habib, Abdella M.; Cox, James J.; Nicholas, Adeline K.; Gribble, Fiona M.

    2015-01-01

    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype–phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies. PMID:25995458

  17. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.

    PubMed

    Gripp, Karen W; Lin, Angela E; Stabley, Deborah L; Nicholson, Linda; Scott, Charles I; Doyle, Daniel; Aoki, Yoko; Matsubara, Yoichi; Zackai, Elaine H; Lapunzina, Pablo; Gonzalez-Meneses, Antonio; Holbrook, Jennifer; Agresta, Cynthia A; Gonzalez, Iris L; Sol-Church, Katia

    2006-01-01

    Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

  18. Fragile X mutation and FG syndrome-like phenotype

    SciTech Connect

    Piussan, C.; Mathieu, M.; Berquin, P.

    1996-08-09

    We present data on 4 mentally retarded brothers, 2 of whom were dizygotic twins with congenital hypotonia, constipation, head size disproportionately large for length or height, and a combination of minor anomalies suggestive of FG syndrome. These brothers have a mentally retarded full sister with similar minor anomalies and an older half-brother with the Martin-Bell syndrome. The mother is mentally retarded; 4 of 7 individuals are positive for fragile X, but all have a CGG expansion ranging from 0.2-2 to 4 kb. Although the phenotype is not completely typical of the FG syndrome and the coincidence of the FMR1 mutation and segregation of the MCA/MR phenotype are highly unlikely, the FMR1 mutation may affect morphogenesis more extensively and differently than the Martin-Bell syndrome does to effect an FG syndrome-like phenotype in certain families. This phenotype does not appear to be a contiguous gene syndrome, but an effect of the FMR1 mutation on an adjacent gene must be considered. 18 refs., 4 figs.

  19. FKRP mutations, including a founder mutation, cause phenotype variability in Chinese patients with dystroglycanopathies.

    PubMed

    Fu, Xiaona; Yang, Haipo; Wei, Cuijie; Jiao, Hui; Wang, Shuo; Yang, Yanling; Han, Chunxi; Wu, Xiru; Xiong, Hui

    2016-12-01

    Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2. Two known and 13 novel mutations were identified in our single center cohort. Interestingly, the c.545A>G mutation was found in eight of the nine LGMD2I patients as a founder mutation and this founder mutation in Chinese patients differs from the one seen in European patients. Moreover, patients homozygous for the c.545A>G mutation were clinically asymptomatic, a less severe phenotype than in compound heterozygous patients with the c.545A>G mutation. The 13 novel mutations of FKRP significantly expanded the mutation spectrum of MDC1C and LGMD2I, and the different founder mutations indicate the ethnic difference in FKRP mutations.

  20. Polk Mutant Mice Have a Spontaneous Mutator Phenotype

    PubMed Central

    Stancel, J. Nicole Kosarek; McDaniel, Lisa D.; Velasco, Susana; Richardson, James; Guo, Caixia; Friedberg, Errol C.

    2009-01-01

    Mice defective in the Polk gene (which encodes DNA polymerase kappa) are viable and do not manifest obvious phenotypes. The present studies document a spontaneous mutator phenotype in Polk−/− mice. The initial indication of enhanced spontaneous mutations in these mice came from the serendipitous observation of a postulated founder mutation that manifested in multiple disease states among a cohort of mice comprising all three possible Polk genotypes. Polk−/− and isogenic wild type controls carrying a reporter transgene (the λ-phage cII gene) were used for subsequent quantitative and qualitative studies on mutagenesis in various tissues. We observed significantly increased mutation frequencies in the kidney, liver, and lung of Polk−/− mice, but not in the spleen or testis. G:C base pairs dominated the mutation spectra of the kidney, liver, and lung. These results are consistent with the notion that Polκ is required for accurate translesion DNA synthesis past naturally occurring polycyclic guanine adducts, possibly generated by cholesterol and/or its metabolites. PMID:19783230

  1. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum.

    PubMed

    Moutton, Sébastien; Fergelot, Patricia; Naudion, Sophie; Cordier, Marie-Pierre; Solé, Guilhem; Guerineau, Elodie; Hubert, Christophe; Rooryck, Caroline; Vuillaume, Marie-Laure; Houcinat, Nada; Deforges, Julie; Bouron, Julie; Devès, Sylvie; Le Merrer, Martine; David, Albert; Geneviève, David; Giuliano, Fabienne; Journel, Hubert; Megarbane, André; Faivre, Laurence; Chassaing, Nicolas; Francannet, Christine; Sarrazin, Elisabeth; Stattin, Eva-Lena; Vigneron, Jacqueline; Leclair, Danielle; Abadie, Caroline; Sarda, Pierre; Baumann, Clarisse; Delrue, Marie-Ange; Arveiler, Benoit; Lacombe, Didier; Goizet, Cyril; Coupry, Isabelle

    2016-08-01

    Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.

  2. Phenotypic effect of mutations in evolving populations of RNA molecules

    PubMed Central

    2010-01-01

    Background The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework. Results We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population) in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population), and the behavior under periodic population bottlenecks (perturbed population). Conclusions The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate μ at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of μ, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto distribution. These results

  3. Diverse phenotypic expression of NPHP4 mutations in four siblings.

    PubMed

    Bakkaloğlu, Sevcan A; Kandur, Yaşar; Bedir-Demirdağ, Tuğba; Işık-Gönül, İpek; Hildebrandt, Friedhelm

    2014-01-01

    Nephronophthisis (NPHP) is an autosomal recessive disease characterized by renal tubular basement membrane disruption, interstitial fibrosis and tubular cysts that progresses to end-stage kidney disease (ESKD). There are also characteristic extrarenal manifestations. Mutations of more than thirteen genes that can cause NPHP have been identified. We herein report four siblings from a consanguineous family, who carried the same NPHP4 mutations but presented with different disease phenotypes ranging from enuresis nocturna to ESKD. Diluted urine and echogenic kidneys in ultrasound examination were consistent, which is typical for 100% of the NPHP cases that have been described. Chronic kidney disease developed in the older two brothers. The observed phenotypic differences are likely to be related to environmental and epigenetic factors, oligogenic inheritance and modifier genes affecting the age of presentation of signs and symptoms. NPHP should be considered as an important cause of CKD in children, which insidiously progresses to ESKD, with no specific therapy available.

  4. Genotype-Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers.

    PubMed

    Bayraktar, Soley; Jackson, Michelle; Gutierrez-Barrera, Angelica M; Liu, Diane; Meric-Bernstam, Funda; Brandt, Amanda; Woodson, Ashley; Litton, Jennifer; Lu, Karen H; Valero, Vicente; Arun, Banu K

    2015-01-01

    The genotype-phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi-ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi-Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0-12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation-specific counseling and be more aggressively managed for risk reduction.

  5. Mutator phenotype of MUTYH-null mouse embryonic stem cells.

    PubMed

    Hirano, Seiki; Tominaga, Yohei; Ichinoe, Akimasa; Ushijima, Yasuhiro; Tsuchimoto, Daisuke; Honda-Ohnishi, Yoko; Ohtsubo, Toshio; Sakumi, Kunihiko; Nakabeppu, Yusaku

    2003-10-03

    To evaluate the antimutagenic role of a mammalian mutY homolog, namely the Mutyh gene, which encodes adenine DNA glycosylase excising adenine misincorporated opposite 8-oxoguanine in the template DNA, we generated MUTYH-null mouse embryonic stem (ES) cells. In the MUTYH-null cells carrying no adenine DNA glycosylase activity, the spontaneous mutation rate increased 2-fold in comparison with wild type cells. The expression of wild type mMUTYH or mutant mMUTYH protein with amino acid substitutions at the proliferating cell nuclear antigen binding motif restored the increased spontaneous mutation rates of the MUTYH-null ES cells to the wild type level. The expression of a mutant mMUTYH protein with an amino acid substitution (G365D) that corresponds to a germ-line mutation (G382D) found in patients with multiple colorectal adenomas could not suppress the elevated spontaneous mutation rate of the MUTYH-null ES cells. Although the recombinant mMUTYH(G365D) purified from Escherichia coli cells had a substantial level of adenine DNA glycosylase activity as did wild type MUTYH, no adenine DNA glycosylase activity was detected in the MUTYH-null ES cells expressing the mMUTYH(G365D) mutant protein. The germ-line mutation (G382D) of the human MUTYH gene is therefore likely to be responsible for the occurrence of a mutator phenotype in these patients.

  6. Refining the phenotype associated with CASC5 mutation.

    PubMed

    Saadi, Abdelkrim; Verny, Florine; Siquier-Pernet, Karine; Bole-Feysot, Christine; Nitschke, Patrick; Munnich, Arnold; Abada-Dendib, Myriam; Chaouch, Malika; Abramowicz, Marc; Colleaux, Laurence

    2016-01-01

    Autosomal recessive primary microcephaly is a neurodevelopmental disorder characterized by congenitally reduced head circumference by at least two standard deviations (SD) below the mean for age and gender. It is associated with nonprogressive mental retardation of variable degree, minimal neurological deficit with no evidence of architectural anomalies of the brain. So far, 12 genetic loci (MCPH1-12) and corresponding genes have been identified. Most of these encode centrosomal proteins. CASC5 is one the most recently unravelled genes responsible for MCPH with mutations reported in three consanguineous families of Moroccan origin, all of whom harboured the same CASC5 homozygous mutation (c.6125G>A; p.Met2041Ile). Here, we report the identification, by whole exome sequencing, of the same missense mutation in a consanguineous Algerian family. All patients exhibited a similar clinical phenotype, including congenital microcephaly with head circumferences ranging from -3 to -4 standard deviations (SD) after age 5 years, moderate to severe cognitive impairment, short stature (adult height -3 SD), dysmorphic features included a sloping forehead, thick eyebrows, synophris and a low columella. Severe vermis hypoplasia and a large cyst of the posterior fossa were observed in one patient. Close microsatellite markers showed identical alleles in the Algerian the previously and Moroccan patients. This study confirms the involvement of CASC5 in autosomal recessive microcephaly and supports the hypothesis of a founder effect of the c.6125G>A mutation. In addition, this report refines the phenotype of this newly recognized form of primary microcephaly.

  7. Disruption of mutated BRAF signaling modulates thyroid cancer phenotype.

    PubMed

    Hanly, Elyse K; Rajoria, Shilpi; Darzynkiewicz, Zbigniew; Zhao, Hong; Suriano, Robert; Tuli, Neha; George, Andrea L; Bednarczyk, Robert; Shin, Edward J; Geliebter, Jan; Tiwari, Raj K

    2014-03-28

    Thyroid cancer is the most common endocrine-related cancer in the United States and its incidence is rising rapidly. Since among various genetic lesions identified in thyroid cancer, the BRAFV600E mutation is found in 50% of papillary thyroid cancers and 25% of anaplastic thyroid cancers, this mutation provides an opportunity for targeted drug therapy. Our laboratory evaluated cellular phenotypic effects in response to treatment with PLX4032, a BRAFV600E-specific inhibitor, in normal BRAF-wild-type thyroid cells and in BRAFV600E-positive papillary thyroid cancer cells. Normal BRAF-wild-type thyroid cells and BRAFV600E-mutated papillary thyroid cancer cells were subjected to proliferation assays and analyzed for cell death by immunofluorescence. Cell cycle status was determined using an EdU uptake assay followed by laser scanning cytometry. In addition, expression of proteins within the MAPK signal transduction pathway was analyzed by Western blot. PLX4032 has potent anti-proliferative effects selectively in BRAF-mutated thyroid cancer cells. These effects appear to be mediated by the drug's activity of inhibiting phosphorylation of signaling molecules downstream of BRAF within the pro-survival MAPK pathway. Interestingly, PLX4032 promotes the phosphorylation of these signaling molecules in BRAF-wild-type thyroid cells. These findings support further evaluation of combinational therapy that includes BRAFV600E inhibitors in thyroid cancer patients harboring the BRAFV600E mutation.

  8. Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap

    PubMed Central

    Chen, Guangbo; Rubinstein, Boris; Li, Rong

    2012-01-01

    Despite its wide existence, the adaptive role of aneuploidy (the abnormal state of having unequal number of different chromosomes) has been a subject of debate. Cellular aneuploidy has been associated with enhanced resistance to stress, whereas on the organismal level it is detrimental to multi-cellular species. Certain aneuploid karyotypes are deleterious for specific environments, but karyotype diversity in a population potentiates adaptive evolution. To reconcile these paradoxical observations, this review distinguishes the role of aneuploidy in cellular versus organismal evolution. Further, it proposes a population genetics perspective to examine the behavior of aneuploidy on a populational versus individual level. By altering the copy number of a significant portion of the genome, aneuploidy introduces large phenotypic leap that enables small cell populations to explore a wide phenotypic landscape, from which adaptive traits can be selected. The production of chromosome number variation can be further increased by stress- or mutation-induced chromosomal instability, fueling rapid cellular adaptation. PMID:22926916

  9. EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations

    PubMed Central

    2014-01-01

    Background Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. Methods We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. Results EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. Conclusions EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly

  10. Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.

    PubMed

    Prasad, M K; Laouina, S; El Alloussi, M; Dollfus, H; Bloch-Zupan, A

    2016-12-01

    Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis.

  11. The neuropathology and clinical phenotype of FTD with progranulin mutations.

    PubMed

    Mackenzie, Ian R A

    2007-07-01

    Mutations in the progranulin gene (PGRN), on chromosome 17q21, have recently been identified as a major cause of familial frontotemporal dementia (FTD). These cases have a characteristic pattern of neuropathology that is a distinct subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), with lentiform neuronal intranuclear inclusions being a consistent feature. There is no abnormal accumulation of PGRN protein in the brain and immunohistochemical and biochemical analysis indicates that the ubiquitinated pathological protein is TDP-43. In these families, FTD is inherited in an autosomal dominant fashion with high penetrance. The clinical phenotype is usually a combination of behavioural abnormality and language disturbance that is most often a form of primary progressive aphasia. Mild parkinsonism is common but motor neuron disease is notably rare. Marked variation in the disease course and clinical features are common, not only between families with different mutations, but also within individual families. This degree of clinical variability makes it difficult to predict which cases of familial FTD will turn out to have a PGRN mutation.

  12. Frameshift mutations in dentin phosphoprotein and dependence of dentin disease phenotype on mutation location.

    PubMed

    Nieminen, Pekka; Papagiannoulis-Lascarides, Lisa; Waltimo-Siren, Janna; Ollila, Päivi; Karjalainen, Sara; Arte, Sirpa; Veerkamp, Jaap; Tallon Walton, Victoria; Chimenos Küstner, Eduard; Siltanen, Tarja; Holappa, Heidi; Lukinmaa, Pirjo-Liisa; Alaluusua, Satu

    2011-04-01

    We describe results from a mutational analysis of the region of the dentin sialophosphoprotein (DSPP) gene encoding dentin phosphoprotein (DPP) in 12 families with dominantly inherited dentin diseases. In eight families (five mutations in the N-terminal third of DPP), the clinical and radiologic features were uniform and compatible with dentin dysplasia type II (DD-II) with major clinical signs in the deciduous dentition. In the other families (four mutations in the more C-terminal part), the permanent teeth also were affected, and the diseases could be classified as variants of dentinogenesis imperfecta. Attrition was not prominent, but periapical infections were common. Discoloring with varying intensity was evident, and pulps and root canals were obliterated in the permanent dentition. All mutations caused a frameshift that replaced the Ser-Ser-Asx repeat by a code for a hydrophobic downstream sequence of approximately original length. We conclude that frameshift mutations in DSPP explain a significant part of dentin diseases. Furthermore, we propose that the location of the mutation is reflected in the phenotypic features as a gradient from DD-II to more severe disease that does not conform to the classic definitions of DI-II. Copyright © 2011 American Society for Bone and Mineral Research.

  13. COMP and Col9A3 mutations and their relationship to the pseudoachondroplasia phenotype.

    PubMed

    Jung, Woon-Won; Balce, Gracia Cielo; Cho, Jae-Woo; Jung, Sung-Chul; Hong, Suk-Joo; Song, Hae-Ryong

    2010-12-01

    While pseudoachondroplasia (PSACH) is almost exclusively caused by cartilage oligomeric matrix protein (COMP) mutations, many patients identified with the PSACH phenotype do not have this mutation, suggesting gene and locus heterogeneity. In order to further characterize this entity, we studied 32 clinically and radiographically diagnosed PSACH patients, among 19 families. COMP and collagen (Col) IX (A1, A2 and A3) mutations, were determined. Patients who tested negative for pathological gene mutations but who were identified with the PSACH phenotype, were included. The phenotypes were characterized according to height deviation (cm) from normal, lower extremity mechanical axis deviation (MAD), cervical and thoracolumbar spine involvement, pelvic index, as well as hip, knee, ankle and hand involvement. We report an 81% mutation detection rate for PSACH, of which COMP+Col9A3 mutations were more prevalent (61%) than COMP mutations alone (30%). Of our PSACH patients, 19% tested negative for both COMP and Col9A3 mutations, and they presented with the greatest mean height deviations, but the least mean MADs. While all the PSACH mutations consistently produced the severe phenotype, the V426A mutation in Col9A3 produced the most severe. Mother-daughter and father-son phenotypic similarities were noted in the COMP+Col9A3 families. Col9A3 and gender play confounding roles in the phenotypic severity of PSACH. The presence of the PSACH phenotype in patients who tested negative for known mutations further confirms the genetic heterogeneity of this condition.

  14. Cardiopulmonary phenotype associated with human PHD2 mutation.

    PubMed

    Talbot, Nick P; Smith, Thomas G; Balanos, George M; Dorrington, Keith L; Maxwell, Patrick H; Robbins, Peter A

    2017-04-01

    Oxygen-dependent regulation of the erythropoietin gene is mediated by the hypoxia-inducible factor (HIF) family of transcription factors. When oxygen is plentiful, HIF undergoes hydroxylation by a family of oxygen-dependent prolyl hydroxylase domain (PHD) proteins, promoting its association with the von Hippel-Lindau (VHL) ubiquitin E3 ligase and subsequent proteosomal degradation. When oxygen is scarce, the PHD enzymes are inactivated, leading to HIF accumulation and upregulation not only of erythropoietin expression, but also the expression of hundreds of other genes, including those coordinating cardiovascular and ventilatory adaptation to hypoxia. Nevertheless, despite the identification of over 50 mutations in the PHD-HIF-VHL pathway in patients with previously unexplained congenital erythrocytosis, there are very few reports of associated cardiopulmonary abnormalities. We now report exaggerated pulmonary vascular and ventilatory responses to acute hypoxia in a 35-year-old man with erythrocytosis secondary to heterozygous mutation in PHD2, the most abundant of the PHD isoforms. We compare this phenotype with that reported in patients with the archetypal disorder of cellular oxygen sensing, Chuvash polycythemia, and discuss the possible clinical implications of our findings, particularly in the light of the emerging role for small molecule PHD inhibitors in clinical practice.

  15. 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

  16. POMT2 mutation in a patient with 'MEB-like' phenotype.

    PubMed

    Mercuri, E; D'Amico, A; Tessa, A; Berardinelli, A; Pane, M; Messina, S; van Reeuwijk, J; Bertini, E; Muntoni, F; Santorelli, F M

    2006-07-01

    Mutations in POMT2 have so far only been reported in patients with Walker-Warburg phenotype. We report heterozygous POMT2 mutations in an a girl with a milder phenotype characterized by mental retardation, microcephaly, hypertrophy of the quadriceps and calf muscles, and structural brain changes mostly affecting the posterior fossa. Our findings suggest that, as previously reported for POMT1 and FKRP, mutations in the POMT2 can also be associated with clinical heterogeneity.

  17. Complex phenotype in an Italian family with a novel mutation in SPG3A.

    PubMed

    de Leva, Maria Fulvia; Filla, Alessandro; Criscuolo, Chiara; Tessa, Alessandra; Pappatà, Sabina; Quarantelli, Mario; Bilo, Leonilda; Peluso, Silvio; Antenora, Antonella; Longo, Dario; Santorelli, Filippo M; De Michele, Giuseppe

    2010-03-01

    Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations.

  18. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    ERIC Educational Resources Information Center

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  19. Alzheimer's Disease Phenotypes and Genotypes Associated with Mutations in Presenilin 2

    ERIC Educational Resources Information Center

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D.

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11…

  20. X-linked adrenoleukodystrophy: genes, mutations, and phenotypes.

    PubMed

    Smith, K D; Kemp, S; Braiterman, L T; Lu, J F; Wei, H M; Geraghty, M; Stetten, G; Bergin, J S; Pevsner, J; Watkins, P A

    1999-04-01

    X-linked adrenoleukodystrophy (X-ALD) is a complex and perplexing neurodegenerative disorder. The metabolic abnormality, elevated levels of very long-chain fatty acids in tissues and plasma, and the biochemical defect, reduced peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity, are ubiquitous features of the disease. However, clinical manifestations are highly variable with regard to time of onset, site of initial pathology and rate of progression. In addition, the abnormal gene in X-ALD is not the gene for VLCS. Rather, it encodes a peroxisomal membrane protein with homology to the ATP-binding cassette (ABC) transmembrane transporter superfamily of proteins. The X-ALD protein (ALDP) is closely related to three other peroxisomal membrane ABC proteins. In this report we summarize all known X-ALD mutations and establish the lack of an X-ALD genotype/phenotype correlation. We compare the evolutionary relationships among peroxisomal ABC proteins, demonstrate that ALDP forms homodimers with itself and heterodimers with other peroxisomal ABC proteins and present cDNA complementation studies suggesting that the peroxisomal ABC proteins have overlapping functions. We also establish that there are at least two peroxisomal VLCS activities, one that is ALDP dependent and one that is ALDP independent. Finally, we discuss variable expression of the peroxisomal ABC proteins and ALDP independent VLCS in relation to the variable clinical presentations of X-ALD.

  1. On genetic information uncertainty and the mutator phenotype in cancer.

    PubMed

    Chan, Jason Yongsheng

    2012-01-01

    Recent evidence supports the existence of a mutator phenotype in cancer cells, although the mechanistic basis remains unknown. In this paper, it is shown that this enhanced genetic instability is generated by an amplified measurement uncertainty on genetic information during DNA replication. At baseline, an inherent measurement uncertainty implies an imprecision of the recognition, replication and transfer genetic information, and forms the basis for an intrinsic genetic instability in all biological cells. Genetic information is contained in the sequence of DNA bases, each existing due to proton tunnelling, as a coherent superposition of quantum states composed of both the canonical and rare tautomeric forms until decoherence by interaction with DNA polymerase. The result of such a quantum measurement process may be interpreted classically as akin to a Bernoulli trial, whose outcome X is random and can be either of two possibilities, depending on whether the proton is tunnelled (X=1) or not (X=0). This inherent quantum uncertainty is represented by a binary entropy function and quantified in terms of Shannon information entropy H(X)=-P(X=1)log(2)P(X=1)-P(X=0)log(2)P(X=0). Enhanced genetic instability may either be directly derived from amplified uncertainty induced by increases in quantum and thermodynamic fluctuation, or indirectly arise from the loss of natural uncertainty reduction mechanisms.

  2. Induction of phenotype modifying cytokines by FERMT1 mutations.

    PubMed

    Heinemann, Anja; He, Yinghong; Zimina, Elena; Boerries, Melanie; Busch, Hauke; Chmel, Nadja; Kurz, Thorsten; Bruckner-Tuderman, Leena; Has, Cristina

    2011-04-01

    Kindler syndrome (KS) is a progressive skin disorder caused by FERMT1 mutations. Early in life, KS manifests as a mechanobullous disease reflecting diminished cell adhesion, but the mechanisms of its later phenotypic features, progressive poikiloderma, and mucocutaneous fibrosis, remain elusive. The FERMT1 gene product and KS protein, kindlin-1, is an epithelial-specific phosphoprotein involved in integrin beta-1 activation, without an obvious link to dermal connective tissue. Here we show how lack of intracellular kindlin-1 in epidermal keratinocytes leads to profound changes in another skin compartment, the dermis. Kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of cytokines such as IL-20, IL-24, TGF-β2, IL1F5, PDGFB, and CTGF. These launch-via paracrine communication-an inflammatory response in the dermis, accompanied by the presence of TGF-β, IL-6, and CTGF, activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. These data are concordant with a model wherein repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie mucocutaneous fibrosis in KS. © 2011 Wiley-Liss, Inc.

  3. UNSTABLE MUTATIONS IN THE FMR1 GENE AND THE PHENOTYPES

    PubMed Central

    Loesch, Danuta; Hagerman, Randi

    2014-01-01

    Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable (‘dynamic’) mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS. However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed ‘premutations’, which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed. The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile X-associated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct

  4. Bias and Evolution of the Mutationally Accessible Phenotypic Space in a Developmental System

    PubMed Central

    Braendle, Christian; Baer, Charles F.; Félix, Marie-Anne

    2010-01-01

    Genetic and developmental architecture may bias the mutationally available phenotypic spectrum. Although such asymmetries in the introduction of variation may influence possible evolutionary trajectories, we lack quantitative characterization of biases in mutationally inducible phenotypic variation, their genotype-dependence, and their underlying molecular and developmental causes. Here we quantify the mutationally accessible phenotypic spectrum of the vulval developmental system using mutation accumulation (MA) lines derived from four wild isolates of the nematodes Caenorhabditis elegans and C. briggsae. The results confirm that on average, spontaneous mutations degrade developmental precision, with MA lines showing a low, yet consistently increased, proportion of developmental defects and variants. This result indicates strong purifying selection acting to maintain an invariant vulval phenotype. Both developmental system and genotype significantly bias the spectrum of mutationally inducible phenotypic variants. First, irrespective of genotype, there is a developmental bias, such that certain phenotypic variants are commonly induced by MA, while others are very rarely or never induced. Second, we found that both the degree and spectrum of mutationally accessible phenotypic variation are genotype-dependent. Overall, C. briggsae MA lines exhibited a two-fold higher decline in precision than the C. elegans MA lines. Moreover, the propensity to generate specific developmental variants depended on the genetic background. We show that such genotype-specific developmental biases are likely due to cryptic quantitative variation in activities of underlying molecular cascades. This analysis allowed us to identify the mutationally most sensitive elements of the vulval developmental system, which may indicate axes of potential evolutionary variation. Consistent with this scenario, we found that evolutionary trends in the vulval system concern the phenotypic characters that

  5. Do cell junction protein mutations cause an airway phenotype in mice or humans?

    PubMed

    Chang, Eugene H; Pezzulo, Alejandro A; Zabner, Joseph

    2011-08-01

    Cell junction proteins connect epithelial cells to each other and to the basement membrane. Genetic mutations of these proteins can cause alterations in some epithelia leading to varied phenotypes such as deafness, renal disease, skin disorders, and cancer. This review examines if genetic mutations in these proteins affect the function of lung airway epithelia. We review cell junction proteins with examples of disease mutation phenotypes in humans and in mouse knockout models. We also review which of these genes are expressed in airway epithelium by microarray expression profiling and immunocytochemistry. Last, we present a comprehensive literature review to find the lung phenotype when cell junction and adhesion genes are mutated or subject to targeted deletion. We found that in murine models, targeted deletion of cell junction and adhesion genes rarely result in a lung phenotype. Moreover, mutations in these genes in humans have no obvious lung phenotype. Our research suggests that simply because a cell junction or adhesion protein is expressed in an organ does not imply that it will exhibit a drastic phenotype when mutated. One explanation is that because a functioning lung is critical to survival, redundancy in the system is expected. Therefore mutations in a single gene might be compensated by a related function of a similar gene product. Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described.

  6. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice

    PubMed Central

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-01-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10−9 (95% confidence interval = 4.6 × 10−9–6.5 × 10−9) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population. PMID:26129709

  7. Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice.

    PubMed

    Uchimura, Arikuni; Higuchi, Mayumi; Minakuchi, Yohei; Ohno, Mizuki; Toyoda, Atsushi; Fujiyama, Asao; Miura, Ikuo; Wakana, Shigeharu; Nishino, Jo; Yagi, Takeshi

    2015-08-01

    The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10(-9) (95% confidence interval = 4.6 × 10(-9)-6.5 × 10(-9)) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population.

  8. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

    PubMed

    Bertolini, Stefano; Pisciotta, Livia; Rabacchi, Claudio; Cefalù, Angelo B; Noto, Davide; Fasano, Tommaso; Signori, Alessio; Fresa, Raffaele; Averna, Maurizio; Calandra, Sebastiano

    2013-04-01

    To determine the spectrum of gene mutations and the genotype-phenotype correlations in patients with Autosomal Dominant Hypercholesterolemia (ADH) identified in Italy. The resequencing of LDLR, PCSK9 genes and a selected region of APOB gene were conducted in 1018 index subjects clinically heterozygous ADH and in 52 patients clinically homozygous ADH. The analysis was also extended to 1008 family members of mutation positive subjects. Mutations were detected in 832 individuals: 97.4% with LDLR mutations, 2.2% with APOB mutations and 0.36% with PCSK9 mutations. Among the patients with homozygous ADH, 51 were carriers of LDLR mutations and one was an LDLR/PCSK9 double heterozygote. We identified 237 LDLR mutations (45 not previously reported), 4 APOB and 3 PCSK9 mutations. The phenotypic characterization of 1769 LDLR mutation carriers (ADH-1) revealed that in both sexes independent predictors of the presence of tendon xanthomas were age, the quintiles of LDL cholesterol, the presence of coronary heart disease (CHD) and of receptor negative mutations. Independent predictors of CHD were male gender, age, the presence of arterial hypertension, smoking, tendon xanthomas, the scalar increase of LDL cholesterol and the scalar decrease of HDL cholesterol. We identified 13 LDLR mutation clusters, which allowed us to compare the phenotypic impact of different mutations. The LDL cholesterol raising potential of these mutations was found to vary over a wide range. This study confirms the genetic and allelic heterogeneity of ADH and underscores that the variability in phenotypic expression of ADH-1 is greatly affected by the type of LDLR mutation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation.

    PubMed

    Boutoleau-Bretonnière, Claire; Camuzat, Agnès; Le Ber, Isabelle; Bouya-Ahmed, Kawtar; Guerreiro, Rita; Deruet, Anne-Laure; Evrard, Christelle; Bras, José; Lamy, Estelle; Auffray-Calvier, Elisabeth; Pallardy, Amandine; Hardy, John; Brice, Alexis; Derkinderen, Pascal; Vercelletto, Martine

    2015-01-01

    SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.

  10. Novel MBTPS2 missense mutation causes a keratosis follicularis spinulosa decalvans phenotype: mutation update and review of the literature.

    PubMed

    Zhang, J; Wang, Y; Cheng, R; Ni, C; Liang, J; Li, M; Yao, Z

    2016-10-01

    Keratosis follicularis spinulosa decalvans (KFSD) is an X-linked condition characterized by keratotic follicular papules and progressive alopecia, which is caused by mutations in the MBTPS2 gene. We carried out a genetic study on a child who was suspected clinically to have KFSD. Sanger sequencing was performed to detect mutations in the entire coding region of MBTPS2. A novel missense mutation (c.599C>T) was identified in the patient, confirming a diagnosis of KFSD. We reviewed related cases with MBTPS2 mutations for evidence of genotype-phenotype correlations.

  11. [Correlation between degree of mitochondrial DNA 1555 mutation and clinical phenotype of nonsyndromic hearing loss].

    PubMed

    Cheng, Zu-jian; Zhang, Rong; Yang, Bin; Liu, Qi-cai; Jiang, Ling; Chen, Jing; Chen, Yong; Ou, Qi-shui

    2009-09-29

    To study the correlation between the number of mtDNA (mitochondrial DNA) copies containing mtDNA A1555G mutation site and phenotype and further elucidate the molecular genetic basis of phenotype diversity of nonsyndromic hearing loss. Real time-amplification refractory mutation system-quantitative PCR was employed to detect the number of mtDNA copies in mild type and mutant type of mtDNA 1555. In the sporadic group, there was no significant correlation between mtDNA A1555G homogeneity mutation copies and phenotype (R = 0.001, P = 0.997) while significant correlation existed between mtDNA A1555G heteroplasmic mutations and phenotype (R = 0.771, P = 0.003). In the familial group there was significant correlation mtDNA 1555 homogeneity mutation copies and phenotype (R = 0.341, P = 0.022) and significant correlation existed between mtDNA 1555 heterogenicity mutation copies and phenotype (R = 0.85, P = 0.015). There is significant correlation between the mtDNA A1555G mutation copies and the severity of hearing loss.

  12. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations

    PubMed Central

    Johnston, Jennifer J.; Sapp, Julie C.; Turner, Joyce T.; Amor, David; Aftimos, Salim; Aleck, Kyrieckos A.; Bocian, Maureen; Bodurtha, Joann N.; Cox, Gerald F.; Curry, Cynthia J.; Day, Ruth; Donnai, Dian; Field, Michael; Fujiwara, Ikuma; Gabbett, Michael; Gal, Moran; Graham, John M.; Hedera, Peter; Hennekam, Raoul C.M.; Hersh, Joseph H.; Hopkin, Robert J.; Kayserili, Hülya; Kidd, Alexa M.J.; Kimonis, Virginia; Lin, Angela E.; Lynch, Sally Ann; Maisenbacher, Melissa; Mansour, Sahar; McGaughran, Julie; Mehta, Lakshmi; Murphy, Helen; Raygada, Margarita; Robin, Nathaniel H.; Rope, Alan F.; Rosenbaum, Kenneth N.; Schaefer, G. Bradley; Shealy, Amy; Smith, Wendy; Soller, Maria; Sommer, Annmarie; Stalker, Heather J.; Steiner, Bernhard; Stephan, Mark J.; Tilstra, David; Tomkins, Susan; Trapane, Pamela; Tsai, Anne Chun-Hui; Van Allen, Margot I.; Vasudevan, Pradeep C.; Zabel, Bernhard; Zunich, Janice; Black, Graeme C.M.; Biesecker, Leslie G.

    2010-01-01

    A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining ninety-three probands here. This includes nineteen probands (twelve mutations) who fulfilled clinical criteria for GCPS or PHS, forty-eight probands (sixteen mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), twenty-one probands (six mutations) with features of PHS or GCPS and oral-facial-digital syndrome and five probands (one mutation) with non-syndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the phenotype-genotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria. PMID:20672375

  13. Phenotypic conservation in patients with X-linked retinitis pigmentosa caused by RPGR mutations.

    PubMed

    Zahid, Sarwar; Khan, Naheed; Branham, Kari; Othman, Mohammad; Karoukis, Athanasios J; Sharma, Nisha; Moncrief, Ashley; Mahmood, Mahdi N; Sieving, Paul A; Swaroop, Anand; Heckenlively, John R; Jayasundera, Thiran

    2013-08-01

    For patients with X-linked retinitis pigmentosa and clinicians alike, phenotypic variability can be challenging because it complicates counseling regarding patients' likely visual prognosis. To evaluate the clinical findings from patients with X-linked retinitis pigmentosa with 13 distinct RPGR mutations and assess for phenotypic concordance or variability. Retrospective medical record review of data collected from 1985 to 2011. Kellogg Eye Center, University of Michigan. A total of 42 patients with X-linked retinitis pigmentosa with mutations in RPGR. Age at first visit ranged from 4 to 53 years, with follow-up ranging from 1 to 11 visits (median follow-up time, 5.5 years; range, 1.4-32.7 years, for 23 patients with >1 visit). Clinical data assessed for concordance included visual acuity (VA), Goldmann visual fields (GVFs), and full-field electroretinography (ERG). Electroretinography phenotype (cone-rod vs rod-cone dysfunction) was defined by the extent of photopic vs scotopic abnormality. Qualitative GVF phenotype was determined by the GVF pattern, where central or peripheral loss suggested cone or rod dysfunction, respectively. Goldmann visual fields were also quantified and compared among patients. Each mutation was detected in 2 or more related or unrelated patients. Five mutations in 11 patients displayed strong concordance of VA, while 4 mutations in 16 patients revealed moderate concordance of VA. A definitive cone-rod or rod-cone ERG pattern consistent among patients was found in 6 of 13 mutations (46.2%); the remaining mutations were characterized by patients demonstrating both phenotypes or who had limited data or nonrecordable ERG values. Concordant GVF phenotypes (7 rod-cone pattern vs 4 cone-rod pattern) were seen in 11 of 13 mutations (84.6%). All 6 mutations displaying a constant ERG pattern within the mutation group revealed a GVF phenotype consistent with the ERG findings. While VA and ERG phenotypes are concordant in only some patients carrying

  14. A Novel Missense Mutation in POMT1 Modulates the Severe Congenital Muscular Dystrophy Phenotype Associated with POMT1 Nonsense Mutations

    PubMed Central

    Wallace, Stephanie E.; Conta, Jessie H.; Winder, Thomas L.; Willer, Tobias; Eskuri, Jamie M.; Haas, Richard; Patterson, Kathleen; Campbell, Kevin P.; Moore, Steven A.; Gospe, Sidney M.

    2014-01-01

    Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles. PMID:24491487

  15. Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum.

    PubMed

    Gervasini, Cristina; Russo, Silvia; Cereda, Anna; Parenti, Ilaria; Masciadri, Maura; Azzollini, Jacopo; Melis, Daniela; Aravena, Teresa; Doray, Bérénice; Ferrarini, Alessandra; Garavelli, Livia; Selicorni, Angelo; Larizza, Lidia

    2013-11-01

    We report on the clinical and molecular characterization of eight patients, one male and seven females, with clinical diagnosis of Cornelia de Lange syndrome (CdLS), who were found to carry distinct mutations of the SMC1A gene. Five of the eight mutations are novel, with two involving amino acid residues previously described as altered in a different way. The other three have been reported each in a single case. Comparison of pairs of individuals with the same mutation indicates only partial overlap of their clinical phenotypes. The following novel missense mutations, all affecting highly conserved amino acid residues, were found: p.R398G in the N-terminal coiled-coil domain, p.V651M in the C-terminal coiled-coil/hinge junction, p.R693G in the C-terminal coiled-coil, and p.N1166T and p.L1189F in the C-terminal ABC cassette. The latter is localized in the H-loop, and represents the first mutation involving a functional motif of SMC1A protein. The effect of the mutations on SMC1A protein function has been predicted using four bioinformatic tools. All mutations except p.V651M were scored as pathogenic by three or four of the tools. p.V651M was found in the only male individual of our cohort, who presented with the most severe phenotype. This raises the issue of gender effect when addressing mutation-phenotype correlation for genes such as SMC1A, which incompletely escapes X-inactivation. Our clinical and molecular findings expand the total number of characterized SMC1A-mutated patients (from 44 to 52) and the restricted repertoire of SMC1A mutations (from 29 to 34), contributing to the molecular and clinical signature of SMC1A-based CdLS. © 2013 Wiley Periodicals, Inc.

  16. Phenotype-optimized sequence ensembles substantially improve prediction of disease-causing mutation in cystic fibrosis.

    PubMed

    Masica, David L; Sosnay, Patrick R; Cutting, Garry R; Karchin, Rachel

    2012-08-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) mutation is associated with a phenotypic spectrum that includes cystic fibrosis (CF). The disease liability of some common CFTR mutations is known, but rare mutations are seen in too few patients to categorize unequivocally, making genetic diagnosis difficult. Computational methods can predict the impact of mutation, but prediction specificity is often below that required for clinical utility. Here, we present a novel supervised learning approach for predicting CF from CFTR missense mutation. The algorithm begins by constructing custom multiple sequence alignments called phenotype-optimized sequence ensembles (POSEs). POSEs are constructed iteratively, by selecting sequences that optimize predictive performance on a training set of CFTR mutations of known clinical significance. Next, we predict CF disease liability from a different set of CFTR mutations (test-set mutations). This approach achieves improved prediction performance relative to popular methods recently assessed using the same test-set mutations. Of clinical significance, our method achieves 94% prediction specificity. Because databases such as HGMD and locus-specific mutation databases are growing rapidly, methods that automatically tailor their predictions for a specific phenotype may be of immediate utility. If the performance achieved here generalizes to other systems, the approach could be an excellent tool to help establish genetic diagnoses.

  17. Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors.

    PubMed

    Gasparre, Giuseppe; Porcelli, Anna Maria; Bonora, Elena; Pennisi, Lucia Fiammetta; Toller, Matteo; Iommarini, Luisa; Ghelli, Anna; Moretti, Massimo; Betts, Christine M; Martinelli, Giuseppe Nicola; Ceroni, Alberto Rinaldi; Curcio, Francesco; Carelli, Valerio; Rugolo, Michela; Tallini, Giovanni; Romeo, Giovanni

    2007-05-22

    Oncocytic tumors are a distinctive class of proliferative lesions composed of cells with a striking degree of mitochondrial hyperplasia that are particularly frequent in the thyroid gland. To understand whether specific mitochondrial DNA (mtDNA) mutations are associated with the accumulation of mitochondria, we sequenced the entire mtDNA in 50 oncocytic lesions (45 thyroid tumors of epithelial cell derivation and 5 mitochondrion-rich breast tumors) and 52 control cases (21 nononcocytic thyroid tumors, 15 breast carcinomas, and 16 gliomas) by using recently developed technology that allows specific and reliable amplification of the whole mtDNA with quick mutation scanning. Thirteen oncocytic lesions (26%) presented disruptive mutations (nonsense or frameshift), whereas only two samples (3.8%) presented such mutations in the nononcocytic control group. In one case with multiple thyroid nodules analyzed separately, a disruptive mutation was found in the only nodule with oncocytic features. In one of the five mitochondrion-rich breast tumors, a disruptive mutation was identified. All disruptive mutations were found in complex I subunit genes, and the association between these mutations and the oncocytic phenotype was statistically significant (P=0.001). To study the pathogenicity of these mitochondrial mutations, primary cultures from oncocytic tumors and corresponding normal tissues were established. Electron microscopy and biochemical and molecular analyses showed that primary cultures derived from tumors bearing disruptive mutations failed to maintain the mutations and the oncocytic phenotype. We conclude that disruptive mutations in complex I subunits are markers of thyroid oncocytic tumors.

  18. Autism Spectrum Phenotype in Males and Females with Fragile X Full Mutation and Premutation

    ERIC Educational Resources Information Center

    Clifford, Sally; Dissanayake, Cheryl; Bui, Quang M.; Huggins, Richard; Taylor, Annette K.; Loesch, Danuta Z.

    2007-01-01

    The behavioural phenotype of autism was assessed in individuals with full mutation and premutation fragile X syndrome (FXS) using the Autism Diagnostic Observation Scale-Generic (ADOS-G) and the Autism Diagnostic Interview (ADI-R). The participants, aged 5-80 years, comprised 33 males and 31 females with full mutation, 7 males and 43 females with…

  19. Autism Spectrum Phenotype in Males and Females with Fragile X Full Mutation and Premutation

    ERIC Educational Resources Information Center

    Clifford, Sally; Dissanayake, Cheryl; Bui, Quang M.; Huggins, Richard; Taylor, Annette K.; Loesch, Danuta Z.

    2007-01-01

    The behavioural phenotype of autism was assessed in individuals with full mutation and premutation fragile X syndrome (FXS) using the Autism Diagnostic Observation Scale-Generic (ADOS-G) and the Autism Diagnostic Interview (ADI-R). The participants, aged 5-80 years, comprised 33 males and 31 females with full mutation, 7 males and 43 females with…

  20. Novel PRRT2 mutations in paroxysmal dyskinesia patients with variant inheritance and phenotypes.

    PubMed

    Liu, X-R; Wu, M; He, N; Meng, H; Wen, L; Wang, J-L; Zhang, M-P; Li, W-B; Mao, X; Qin, J-M; Li, B-M; Tang, B; Deng, Y-H; Shi, Y-W; Su, T; Yi, Y-H; Tang, B-S; Liao, W-P

    2013-03-01

    Paroxysmal dyskinesias (PDs) are a group of episodic movement disorders with marked variability in clinical manifestation and potential association with epilepsy. PRRT2 has been identified as a causative gene for PDs, but the phenotypes and inheritance patterns of PRRT2 mutations need further clarification. In this study, 10 familial and 21 sporadic cases with PDs and PDs-related phenotypes were collected. Genomic DNA was screened for PRRT2 mutations by direct sequencing. Seven PRRT2 mutations were identified in nine (90.0%) familial cases and in six (28.6%) sporadic cases. Five mutations are novel: two missense mutations (c.647C>G/p.Pro216Arg and c.872C>T/p.Ala291Val) and three truncating mutations (c.117delA/p.Val41TyrfsX49, c.510dupT/p.Leu171SerfsX3 and c.579dupA/p.Glu194ArgfsX6). Autosomal dominant inheritance with incomplete penetrance was observed in most of the familial cases. In the sporadic cases, inheritance was heterogeneous including recessive inheritance with compound heterozygous mutations, inherited mutations with incomplete parental penetrance and de novo mutation. Variant phenotypes associated with PRRT2 mutations, found in 36.0% of the affected cases, included febrile convulsions, epilepsy, infantile non-convulsive seizures (INCS) and nocturnal convulsions (NC). All patients with INCS or NC, not reported previously, displayed abnormalities on electroencephalogram (EEG). No EEG abnormalities were recorded in patients with classical infantile convulsions and paroxysmal choreoathetosis (ICCA)/paroxysmal kinesigenic dyskinesia (PKD). Our study further confirms that PRRT2 mutations are the most common cause of familial PDs, displaying both dominant and recessive inheritance. Epilepsy may occasionally occur in ICCA/PKD patients with PRRT2 mutations. Variant phenotypes INCS or NC differ from classical ICCA/PKD clinically and electroencephalographically. They have some similarities with, but not identical to epilepsy, possibly represent an overlap between

  1. Strong mutator phenotype drives faster adaptation from growth on glucose to growth on acetate in Salmonella.

    PubMed

    Le Bars, Hervé; Bonnaure-Mallet, Martine; Barloy-Hubler, Frédérique; Jolivet-Gougeon, Anne; Bousarghin, Latifa

    2014-10-01

    The metabolic adaptation of strong mutator strains was studied to better understand the link between the strong mutator phenotype and virulence. Analysis of the growth curves of isogenic strains of Salmonella, which were previously grown in M63 glucose media, revealed that the exponential phase of growth was reached earlier in an M63 acetate medium with strong mutator strains (mutated in mutS or in mutL) than with normomutator strains (P<0.05). Complemented strains confirmed the direct role of the strong mutator phenotype in this faster metabolic adaptation to the assimilation of acetate. In a mixed cell population, proliferation of strong mutators over normomutators was observed when the carbon source was switched from glucose to acetate. These results add to the sparse body of knowledge about strong mutators and highlight the selective advantage conferred by the strong mutator phenotype to adapt to a switch of carbon source in the environment. This work may provide clinically useful information given that there is a high prevalence of strong mutators among pathogenic strains of Salmonella and that acetate is the principal short chain fatty acid of the human terminal ileum and colon where Salmonella infection is localized.

  2. Evidence of a Mild Mutator Phenotype in Cambodian Plasmodium falciparum Malaria Parasites.

    PubMed

    Lee, Andrew H; Fidock, David A

    2016-01-01

    Malaria control efforts have been continuously stymied by drug-resistant strains of Plasmodium falciparum, which typically originate in Southeast Asia prior to spreading into high-transmission settings in Africa. One earlier proposed explanation for Southeast Asia being a hotbed of resistance has been the hypermutability or "Accelerated Resistance to Multiple Drugs" (ARMD) phenotype, whereby multidrug-resistant Southeast Asian parasites were reported to exhibit 1,000-fold higher rates of resistance to unrelated antimalarial agents when compared to drug-sensitive parasites. However, three recent studies do not recapitulate this hypermutability phenotype. Intriguingly, genome sequencing of recently derived multidrug-resistant Cambodian isolates has identified a high proportion of DNA repair gene mutations in multidrug-resistant parasites, suggesting their potential role in shaping local parasite evolution. By adapting fluctuation assays for use in P. falciparum, we have examined the in vitro mutation rates of five recent Cambodian isolates and three reference laboratory strains. For these studies we also generated a knockout parasite line lacking the DNA repair factor Exonuclease I. In these assays, parasites were typed for their ability to acquire resistance to KAE609, currently in advanced clinical trials, yielding 13 novel mutations in the Na+/H+-ATPase PfATP4, the primary resistance determinant. We observed no evidence of hypermutability. Instead, we found evidence of a mild mutator (up to a 3.4-fold increase in mutation rate) phenotype in two artemisinin-resistant Cambodian isolates, which carry DNA repair gene mutations. We observed that one such mutation in the Mismatch Repair protein Mlh1 contributes to the mild mutator phenotype when modeled in yeast (scmlh1-P157S). Compared to basal rates of mutation, a mild mutator phenotype may provide a greater overall benefit for parasites in Southeast Asia in terms of generating drug resistance without incurring

  3. A missense mutation in PAX9 in a family with distinct phenotype of oligodontia.

    PubMed

    Lammi, Laura; Halonen, Katri; Pirinen, Sinikka; Thesleff, Irma; Arte, Sirpa; Nieminen, Pekka

    2003-11-01

    Mutations in PAX9 have been described for families in which inherited oligodontia characteristically involves permanent molars. Our study analysed one large family with dominantly inherited oligodontia clinically and genetically. In addition to permanent molars, some teeth were congenitally missing in the premolar, canine, and incisor regions. Measurements of tooth size revealed the reduced size of the proband's and his father's deciduous and permanent teeth. This phenotype is distinct from oligodontia phenotypes associated with mutations in PAX9. Sequencing of the PAX9 gene revealed a missense mutation in the beginning of the paired domain of the molecule, an arginine-to-tryptophan amino-acid change occurring in a position absolutely conserved in all sequenced paired box genes. A mutation of the homologous arginine of PAX6 has been shown to affect the target DNA specificity of PAX6. We suggest that a similar mechanism explains these distinct oligodontia phenotypes.

  4. A FBN1 mutation association with different phenotypes of Marfan syndrome in a Chinese family.

    PubMed

    Li, Yapeng; Xu, Jianhua; Chen, Mingjie; Du, Binbin; Li, Qiaoli; Xing, Qinghe; Zhang, Yanzhou

    2016-09-01

    Previous studies demonstrated that patients with different FBN1 mutations often present more considerable phenotypic variation compared to different members of the related family carrying a same mutation. The purpose of our study was to identify pathogenic mutation and provide more information about genotype-phenotypic correlations in a large Chinese family with Marfan syndrome. 15 related family members from a Chinese 4-generation pedigree with Marfan syndrome underwent physical, ophthalmologic, radiological and cardiovascular examinations. The propositus has De Bakey III aortic dissection and didn't fulfill the revised Ghent criteria for Marfan syndrome. Nine family members have ectopia lentis and their echocardiogram was normal. Five other family members have no evidence of Marfan syndrome. Genomic DNA was isolated from blood leukocytes. The exome sequencing was employed on the propositus, then the Sanger sequencing was conducted for mutation verification in other 14 participants of this family. The causative mutation in FBN1 discovered in the propositus was a known heterozygous missense mutation, c.1633T>G (p.R545C), in exon 14 (NM 000138). This same mutation was also identified in all 9 ectopia lentis patients and one unaffected 8-year-old girl. However, the same mutation was not discovered in other 4 unaffected family members. Our data enhance the information of genotype-phenotype correlation owing to FBN1 mutations. To our current knowledge, we firstly reported that the same FBN1 mutation, c. 1633C>T (Arg545Cys), was detected simultaneously in three different cardinal phenotypes (ectopia lentis, aortic dissection and unaffected) within one family. The unaffected girl with FBN1 mutation may presumably represent a rare case of nonpenetrance. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease

    PubMed Central

    Jin, Meiling; Xie, Yuansheng; Chen, Zhiqiang; Liao, Yujie; Li, Zuoxiang; Hu, Panpan; Qi, Yan; Yin, Zhiwei; Li, Qinggang; Fu, Ping; Chen, Xiangmei

    2016-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder mainly caused by mutation in PKD1/PKD2. However, ethnic differences in mutations, the association between mutation genotype/clinical phenotype, and the clinical applicable value of mutation detection are poorly understood. We made systematically analysis of Chinese ADPKD patients based on a next-generation sequencing platform. Among 148 ADPKD patients enrolled, 108 mutations were detected in 127 patients (85.8%). Compared with mutations in Caucasian published previously, the PKD2 mutation detection rate was lower, and patients carrying the PKD2 mutation invariably carried the PKD1 mutation. The definite pathogenic mutation detection rate was lower, whereas the multiple mutations detection rate was higher in Chinese patients. Then, we correlated PKD1/PKD2 mutation data and clinical data: patients with mutation exhibited a more severe phenotype; patients with >1 mutations exhibited a more severe phenotype; patients with pathogenic mutations exhibited a more severe phenotype. Thus, the PKD1/PKD2 mutation status differed by ethnicity, and the PKD1/PKD2 genotype may affect the clinical phenotype of ADPKD. Furthermore, it makes sense to detect PKD1/PKD2 mutation status for early diagnosis and prognosis, perhaps as early as the embryo/zygote stage, to facilitate early clinical intervention and family planning. PMID:27782177

  6. The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations.

    PubMed

    Frédéric, Melissa Yana; Monino, Christine; Marschall, Christoph; Hamroun, Dalil; Faivre, Laurence; Jondeau, Guillaume; Klein, Hanns-Georg; Neumann, Luitgard; Gautier, Elodie; Binquet, Christine; Maslen, Cheryl; Godfrey, Maurice; Gupta, Prateek; Milewicz, Dianna; Boileau, Catherine; Claustres, Mireille; Béroud, Christophe; Collod-Béroud, Gwenaëlle

    2009-02-01

    Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin-2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective-tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved. In 1995 we created a locus-specific database (LSDB) for FBN1 mutations with the Universal Mutation Database (UMD) tool. To facilitate comparison of identified mutations in these two genes and search for specific functional areas, we created an LSDB for the FBN2 gene: the UMD-FBN2 database. This database lists 26 published and six newly identified mutations that mainly comprise missense and splice-site mutations. Although the number of described FBN2 mutations was low, the frequency of joint dislocation was significantly higher with missense mutations when compared to splice site mutations. (c) 2008 Wiley-Liss, Inc.

  7. Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes

    PubMed Central

    du Montcel, S Tezenas; Clot, F; Vidailhet, M; Roze, E; Damier, P; Jedynak, C P; Camuzat, A; Lagueny, A; Vercueil, L; Doummar, D; Guyant‐Maréchal, L; Houeto, J‐L; Ponsot, G; Thobois, S; Cournelle, M‐A; Durr, A; Durif, F; Echenne, B; Hannequin, D; Tranchant, C; Brice, A

    2006-01-01

    Background Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon‐sarcoglycan gene (SGCE) on chromosome 7q21. Methods We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M‐D), essential myoclonus (E‐M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested. Results Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M‐D and five E‐M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non‐carriers. None of the patients had severe psychiatric disorders. Conclusion This large cohort of index patients shows that SGCE mutations are primarily found in patients with M‐D and to a lesser extent E‐M, but are present in only 30% of these patients combined (M‐D and E‐M). PMID:16227522

  8. Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype.

    PubMed

    Vuillaumier-Barrot, S; Quijano-Roy, S; Bouchet-Seraphin, C; Maugenre, S; Peudenier, S; Van den Bergh, P; Marcorelles, P; Avila-Smirnow, D; Chelbi, M; Romero, N B; Carlier, R Y; Estournet, B; Guicheney, P; Seta, N

    2009-03-01

    Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker-Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.

  9. Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial dwarfism type I.

    PubMed

    Abdel-Salam, Ghada M H; Abdel-Hamid, Mohamed S; Issa, Mahmoud; Magdy, Ahmed; El-Kotoury, Ahmed; Amr, Khalda

    2012-06-01

    Mutations in the RNU4ATAC gene cause microcephalic osteodysplastic primordial dwarfism type I. It encodes U4atac, a small nuclear RNA that is a component of the minor spliceosome. Six distinct mutations in 30 patients diagnosed as microcephalic osteodysplastic primordial dwarfism type I have been described. We report on three additional patients from two unrelated families presenting with a milder phenotype of microcephalic osteodysplastic primordial dwarfism type I and metopic synostosis. Patient 1 had two novel heterozygous mutations in the 3' prime stem-loop, g.66G > C and g.124G > A while Patients 2 and 3 had a homozygous mutation g.55G > A in the 5' prime stem-loop. Although they manifested the known spectrum of clinical features of microcephalic osteodysplastic primordial dwarfism type I, they lacked evidence of severe developmental delay and neurological symptoms. These findings expand the mutational and phenotypic spectrum of this syndrome.

  10. Novel TMEM67 Mutations and Genotype-phenotype Correlates in Meckelin-related Ciliopathies

    PubMed Central

    Iannicelli, Miriam; Brancati, Francesco; Mougou-Zerelli, Soumaya; Mazzotta, Annalisa; Thomas, Sophie; Elkhartoufi, Nadia; Travaglini, Lorena; Gomes, Céline; Ardissino, Gian Luigi; Bertini, Enrico; Boltshauser, Eugen; Castorina, Pierangela; D'Arrigo, Stefano; Fischetto, Rita; Leroy, Brigitte; Loget, Philippe; Bonnière, Maryse; Starck, Lena; Tantau, Julia; Gentilin, Barbara; Majore, Silvia; Swistun, Dominika; Flori, Elizabeth; Lalatta, Faustina; Pantaleoni, Chiara; Johannes.Penzien; Grammatico, Paola; Dallapiccola, Bruno; Gleeson, Joseph G.; Attie-Bitach, Tania; Valente, Enza Maria

    2010-01-01

    Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin. PMID:20232449

  11. Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia

    PubMed Central

    Stoll, Marion; Teoh, Hooiling; Lee, James; Reddel, Stephen; Zhu, Ying; Buckley, Michael; Sampaio, Hugo; Roscioli, Tony; Farrar, Michelle

    2016-01-01

    Objective: To describe the phenotypes in 2 families with vaccinia-related kinase 1 (VRK1) mutations including one novel VRK1 mutation. Methods: VRK1 mutations were found by whole exome sequencing in patients presenting with motor neuron disorders. Results: We identified pathogenic mutations in the VRK1 gene in the affected members of 2 families. In family 1, compound heterozygous mutations were identified in VRK1, c.356A>G; p.H119R, and c.1072C>T; p.R358*, in 2 siblings with adult onset distal spinal muscular atrophy (SMA). In family 2, a novel VRK1 mutation, c.403G>A; p.G135R and c.583T>G; p.L195V, were identified in a child with motor neuron disease. Conclusions: VRK1 mutations can produce adult-onset SMA and motor neuron disease in children without pontocerebellar hypoplasia. PMID:27281532

  12. Colorectal Adenomatous Polyposis: Heterogeneity of Susceptibility Gene Mutations and Phenotypes in a Cohort of Italian Patients.

    PubMed

    Marabelli, Monica; Molinaro, Valeria; Abou Khouzam, Raefa; Berrino, Enrico; Panero, Mara; Balsamo, Antonella; Venesio, Tiziana; Ranzani, Guglielmina Nadia

    2016-12-01

    Colorectal adenomatous polyposis entailing cancer predisposition is caused by constitutional mutations in different genes. APC is associated with the familial adenomatous polyposis (FAP/AFAP) and MUTYH with the MUTYH-associated polyposis (MAP), while POLE and POLD1 mutations cause the polymerase proofreading-associated polyposis (PPAP). We screened for mutations in patients with multiple adenomas/FAP: 121 patients were analyzed for APC and MUTYH mutations, and 36 patients were also evaluated for POLE and POLD1 gene mutations. We found 20 FAP/AFAP, 15 MAP, and no PPAP subjects: pathogenic mutations proved to be heterogeneous, and included 5 APC and 1 MUTYH novel mutations. The mutation detection rate was significantly different between patients with 5-100 polyps and those with >100 polyps (p = 8.154 × 10(-7)), with APC mutations being associated with an aggressive phenotype (p = 1.279 × 10(-9)). Mean age at diagnosis was lower in FAP/AFAP compared to MAP (p = 3.055 × 10(-4)). Mutation-negative probands showed a mean age at diagnosis that was significantly higher than FAP/AFAP (p = 3.46986 × 10(-7)) and included 45.3% of patients with <30 polyps and 70.9% of patients with no family history. This study enlarges the APC and MUTYH mutational spectra, and also evaluated variants of uncertain significance, including the MUTYH p.Gln338His mutation. Moreover this study underscores the phenotypic heterogeneity and genotype-phenotype correlations in a cohort of Italian patients.

  13. Microarray-based mutation detection and phenotypic characterization in Korean patients with retinitis pigmentosa

    PubMed Central

    Kim, Cinoo; Kim, Kwang Joong; Bok, Jeong; Lee, Eun-Ju; Kim, Dong-Joon; Oh, Ji Hee; Park, Sung Pyo; Shin, Joo Young; Lee, Jong-Young

    2012-01-01

    Purpose To evaluate microarray-based genotyping technology for the detection of mutations responsible for retinitis pigmentosa (RP) and to perform phenotypic characterization of patients with pathogenic mutations. Methods DNA from 336 patients with RP and 360 controls was analyzed using the GoldenGate assay with microbeads containing 95 previously reported disease-associated mutations from 28 RP genes. Mutations identified by microarray-based genotyping were confirmed by direct sequencing. Segregation analysis and phenotypic characterization were performed in patients with mutations. The disease severity was assessed by visual acuity, electroretinography, optical coherence tomography, and kinetic perimetry. Results Ten RP-related mutations of five RP genes (PRP3 pre-mRNA processing factor 3 homolog [PRPF3], rhodopsin [RHO], phosphodiesterase 6B [PDE6B], peripherin 2 [PRPH2], and retinitis pigmentosa 1 [RP1]) were identified in 26 of the 336 patients (7.7%) and in six of the 360 controls (1.7%). The p.H557Y mutation in PDE6B, which was homozygous in four patients and heterozygous in nine patients, was the most frequent mutation (2.5%). Mutation segregation was assessed in four families. Among the patients with missense mutations, the most severe phenotype occurred in patients with p.D984G in RP1; less severe phenotypes occurred in patients with p.R135W in RHO; a relatively moderate phenotype occurred in patients with p.T494M in PRPF3, p.H557Y in PDE6B, or p.W316G in PRPH2; and a mild phenotype was seen in a patient with p.D190N in RHO. Conclusions The results reveal that the GoldenGate assay may not be an efficient method for molecular diagnosis in RP patients with rare mutations, although it has proven to be reliable and efficient for high-throughput genotyping of single-nucleotide polymorphisms. The clinical features varied according to the mutations. Continuous effort to identify novel RP genes and mutations in a population is needed to improve the efficiency and

  14. An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

    PubMed

    Liu, Pengfei; Yuan, Bo; Carvalho, Claudia M B; Wuster, Arthur; Walter, Klaudia; Zhang, Ling; Gambin, Tomasz; Chong, Zechen; Campbell, Ian M; Coban Akdemir, Zeynep; Gelowani, Violet; Writzl, Karin; Bacino, Carlos A; Lindsay, Sarah J; Withers, Marjorie; Gonzaga-Jauregui, Claudia; Wiszniewska, Joanna; Scull, Jennifer; Stankiewicz, Paweł; Jhangiani, Shalini N; Muzny, Donna M; Zhang, Feng; Chen, Ken; Gibbs, Richard A; Rautenstrauss, Bernd; Cheung, Sau Wai; Smith, Janice; Breman, Amy; Shaw, Chad A; Patel, Ankita; Hurles, Matthew E; Lupski, James R

    2017-02-23

    De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.

  15. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia.

    PubMed

    Pisciotta, Livia; Priore Oliva, Claudio; Cefalù, Angelo Baldassare; Noto, Davide; Bellocchio, Antonella; Fresa, Raffaele; Cantafora, Alfredo; Patel, Dilip; Averna, Maurizio; Tarugi, Patrizia; Calandra, Sebastiano; Bertolini, Stefano

    2006-06-01

    Patients homozygous or compound heterozygous for LDLR mutations or double heterozygous for LDLR and apo B R3500Q mutation have higher LDL-C levels, more extensive xanthomatosis and more severe premature coronary disease (pCAD) than simple heterozygotes for mutations in either these genes or for missense mutations in PCSK9 gene. It is not known whether combined mutations in LDLR and PKCS9 are associated with such a severe phenotype. We sequenced Apo B and PCSK9 genes in two patients with the clinical diagnosis of homozygous FH who were heterozygous for LDLR gene mutations. Proband Z.P. (LDL-C 13.39 mmol/L and pCAD) was heterozygous for an LDLR mutation (p.E228K) inherited from her father (LDL-C 8.07 mmol/L) and a PCSK9 mutation (p.R496W) from her mother (LDL-C 5.58 mmol/L). Proband L.R. and her sister (LDL-C 11.51 and 10.47 mmol/L, xanthomatosis and carotid atherosclerosis) were heterozygous for an LDLR mutation (p.Y419X) inherited from their mother (LDL-C 6.54 mmol/L) and a PCSK9 mutation (p.N425S) probably from their deceased father. The LDL-C levels in double heterozygotes of these two families were 56 and 44% higher than those found in simple heterozygotes for the two LDLR mutations, respectively. The two PCSK9 mutations are novel and were not found in 110 controls and 80 patients with co-dominant hypercholesterolemia. These observations indicate that rare missense mutations of PCSK9 may worsen the clinical phenotype of patients carrying LDLR mutations.

  16. Surfactant Protein C-associated interstitial lung disease; three different phenotypes of the same SFTPC mutation.

    PubMed

    Salerno, Teresa; Peca, Donatella; Menchini, Laura; Schiavino, Alessandra; Boldrini, Renata; Esposito, Fulvio; Danhaive, Olivier; Cutrera, Renato

    2016-02-29

    Monoallelic mutations of the Surfactant Protein C gene (SFTPC) are associated with Interstitial Lung Disease in children. I73T is the most common mutation, accounting for 30 % of all cases reported. We describe three patients carrying the same I73T SPC mutation with very different phenotypes, clinical course (ranging from mild respiratory symptoms to death for respiratory failure) and outcome. The disease mechanisms associated with SP-C mutations suggest that the combination of individual genetic background and environmental factors contribute largely to the wide variability of clinical expression. Infants, children and adults with ILD of unknown etiology should be investigated for SP-C genetic abnormalities.

  17. Second site mutations specifically suppress the Fix- phenotype of Rhizobium meliloti ndvF mutations on alfalfa: identification of a conditional ndvF-dependent mucoid colony phenotype.

    PubMed

    Oresnik, I J; Charles, T C; Finan, T M

    1994-04-01

    Rhizobium meliloti mutants carrying ndvF insertion or deletion mutations induce nodules on alfalfa which contain very few infected cells and fail to fix N2 (Fix-). We have characterized five independent second site mutations (designated sfx) which completely suppress the Fix- phenotype of ndvF mutants on Medicago sativa but not on another R. meliloti host Melilotus alba. Genetic mapping and phenotypic analysis revealed that the suppressor mutations sfx-1, sfx-4 and sfx-5 mapped to a single locus which was distinct from another locus defined by the sfx-2 and sfx-3 mutations. Tn5-mob-mediated conjugal mapping experiments showed that the sfx-1 locus was located clockwise from trp-33 on the R. meliloti chromosome and a detailed cotransduction map of this region was generated. To clone the sfx-1 locus, we prepared a cosmid library from total DNA obtained from an sfx-1, ndvF deletion strain. From this library, a cosmid pTH56, which converted Fix- ndvF mutants to Fix+, was isolated. Southern blot analysis provided direct physical evidence that the insert DNA in plasmid pTH56 was contiguous with the sfx-1 region. On low osmolarity glutamate-yeast extract-mannitol-salts medium (GYM) agar medium, ndvF insertion and deletion mutants were found to have a mucoid colony phenotype, as opposed to the dry colony phenotype of the wild-type strain. This phenotype was shown to be dependent on the exoB and expE genes required for synthesis of exopolysaccharide II in R. meliloti but not to be dependent on genes required exclusively for the synthesis of the succinoglycan or exopolysaccharide I. Transduction of either sfx-1 or sfx-2 or transfer of the cosmid pTH56 into the ndvF mutants restored them to a wild-type dry colony phenotype. The mucoid phenotype is not responsible for the Fix- phenotype of ndvF mutants as the Fix-, ndvF exp double mutants can be complemented to Fix+ by introducing plasmids which carry only the wild-type ndvF genes.

  18. Second Site Mutations Specifically Suppress the Fix(-) Phenotype of Rhizobium Meliloti Ndvf Mutations on Alfalfa: Identification of a Conditional Ndvf-Dependent Mucoid Colony Phenotype

    PubMed Central

    Oresnik, I. J.; Charles, T. C.; Finan, T. M.

    1994-01-01

    Rhizobium meliloti mutants carrying ndvF insertion or deletion mutations induce nodules on alfalfa which contain very few infected cells and fail to fix N(2) (Fix(-)). We have characterized five independent second site mutations (designated sfx) which completely suppress the Fix(-) phenotype of ndvF mutants on Medicago sativa but not on another R. meliloti host Melilotus alba. Genetic mapping and phenotypic analysis revealed that the suppressor mutations sfx-1, sfx-4 and sfx-5 mapped to a single locus which was distinct from another locus defined by the sfx-2 and sfx-3 mutations. Tn5-mob-mediated conjugal mapping experiments showed that the sfx-1 locus was located clockwise from trp-33 on the R. meliloti chromosome and a detailed cotransduction map of this region was generated. To clone the sfx-1 locus, we prepared a cosmid library from total DNA obtained from an sfx-1, ndvF deletion strain. From this library, a cosmid pTH56, which converted Fix(-) ndvF mutants to Fix(+), was isolated. Southern blot analysis provided direct physical evidence that the insert DNA in plasmid pTH56 was contiguous with the sfx-1 region. On low osmolarity glutamate-yeast extract-mannitol-salts medium (GYM) agar medium, ndvF insertion and deletion mutants were found to have a mucoid colony phenotype, as opposed to the dry colony phenotype of the wild-type strain. This phenotype was shown to be dependent on the exoB and expE genes required for synthesis of exopolysaccharide II in R. meliloti but not to be dependent on genes required exclusively for the synthesis of the succinoglycan or exopolysaccharide I. Transduction of either sfx-1 or sfx-2 or transfer of the cosmid pTH56 into the ndvF mutants restored them to a wild-type dry colony phenotype. The mucoid phenotype is not responsible for the Fix(-) phenotype of ndvF mutants as the Fix(-), ndvF exp double mutants can be complemented to Fix(+) by introducing plasmids which carry only the wild-type ndvF genes. PMID:8013901

  19. New insights into genotype-phenotype correlation for GLI3 mutations.

    PubMed

    Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent-Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

    2015-01-01

    The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

  20. New insights into genotype–phenotype correlation for GLI3 mutations

    PubMed Central

    Démurger, Florence; Ichkou, Amale; Mougou-Zerelli, Soumaya; Le Merrer, Martine; Goudefroye, Géraldine; Delezoide, Anne-Lise; Quélin, Chloé; Manouvrier, Sylvie; Baujat, Geneviève; Fradin, Mélanie; Pasquier, Laurent; Megarbané, André; Faivre, Laurence; Baumann, Clarisse; Nampoothiri, Sheela; Roume, Joëlle; Isidor, Bertrand; Lacombe, Didier; Delrue, Marie-Ange; Mercier, Sandra; Philip, Nicole; Schaefer, Elise; Holder, Muriel; Krause, Amanda; Laffargue, Fanny; Sinico, Martine; Amram, Daniel; André, Gwenaelle; Liquier, Alain; Rossi, Massimiliano; Amiel, Jeanne; Giuliano, Fabienne; Boute, Odile; Dieux-Coeslier, Anne; Jacquemont, Marie-Line; Afenjar, Alexandra; Van Maldergem, Lionel; Lackmy-Port-Lis, Marylin; Vincent- Delorme, Catherine; Chauvet, Marie-Liesse; Cormier-Daire, Valérie; Devisme, Louise; Geneviève, David; Munnich, Arnold; Viot, Géraldine; Raoul, Odile; Romana, Serge; Gonzales, Marie; Encha-Razavi, Ferechte; Odent, Sylvie; Vekemans, Michel; Attie-Bitach, Tania

    2015-01-01

    The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister–Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype–phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype–phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues. PMID:24736735

  1. Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes

    PubMed Central

    Romani, Marta; Isrie, Mala; Rosti, Rasim Ozgur; Micalizzi, Alessia; Musaev, Damir; Mazza, Tommaso; Al-gazali, Lihadh; Altunoglu, Umut; Boltshauser, Eugen; D'Arrigo, Stefano; De Keersmaecker, Bart; Kayserili, Hülya; Brandenberger, Sarah; Kraoua, Ichraf; Mark, Paul R; McKanna, Trudy; Van Keirsbilck, Joachim; Moerman, Philippe; Poretti, Andrea; Puri, Ratna; Van Esch, Hilde; Gleeson, Joseph G; Valente, Enza Maria

    2016-01-01

    Background Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. Methods Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. Results We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. Conclusion Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype–phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies. PMID:27208211

  2. Single amino acid mutations in the capsid switch the neutralization phenotype of porcine circovirus 2.

    PubMed

    Saha, Dipongkor; Lefebvre, David J; Ooms, Karen; Huang, Liping; Delputte, Peter L; Van Doorsselaere, Jan; Nauwynck, Hans J

    2012-07-01

    Porcine circovirus 2 (PCV2) is the causative agent of porcine circovirus-associated diseases in pigs. Previously, it was demonstrated that mAbs 16G12, 38C1, 63H3 and 94H8 directed against the PCV2 capsid protein recognize PCV2 strains Stoon-1010 (PCV2a), 48285 (PCV2b), 1121 (PCV2a), 1147 (PCV2b) and II9F (PCV2b), but only neutralize Stoon-1010 and 48285. This points to the existence of two distinct PCV2 neutralization phenotypes: phenotype α (mAb recognition with neutralization; Stoon-1010 and 48285) and phenotype β (mAb recognition without neutralization; 1121, 1147 and II9F). In the present study, amino acids that are important in determining the neutralization phenotype were identified in the capsid. Mutation of T at position 190 to A in strain 48285 (phenotype α) resulted in a capsid resembling that of strain 1147 (phenotype β) and caused a loss of neutralization (switch from α to β). Mutations of P at position 151 to T and A at position 190 to T in strain II9F (phenotype β) resulted in a capsid resembling that of strain 48285 (phenotype α) and gave a gain of neutralization (switch from β to α). Mutations of T at position 131 to P and of E at position 191 to R in Stoon-1010 (phenotype α) changed the capsid into that of 1121 (phenotype β) and reduced neutralization (switch from α to β). This study demonstrated that single amino acid changes in the capsid result in a phenotypic switch from α to β or β to α.

  3. Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.

    PubMed

    Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina; Krantz, Ian D; Musio, Antonio

    2013-12-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype. © 2013 WILEY PERIODICALS, INC.

  4. Mutation Spectrum and Genotype–Phenotype Correlation in Cornelia de Lange Syndrome

    PubMed Central

    Mannini, Linda; Cucco, Francesco; Quarantotti, Valentina; Krantz, Ian D.; Musio, Antonio

    2013-01-01

    Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype. PMID:24038889

  5. A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing.

    PubMed

    Poulter, James A; Smith, Claire E L; Murrillo, Gina; Silva, Sandra; Feather, Sally; Howell, Marianella; Crinnion, Laura; Bonthron, David T; Carr, Ian M; Watson, Christopher M; Inglehearn, Chris F; Mighell, Alan J

    2015-11-01

    Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation-positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase-PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild-type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.

  6. A structure-function study of MID1 mutations associated with a mild Opitz phenotype.

    PubMed

    Mnayer, Laila; Khuri, Sawsan; Merheby, Hassan Al-Ali; Meroni, Germana; Elsas, Louis J

    2006-03-01

    The X-linked form of Opitz syndrome (OS) affects midline structures and produces a characteristic, but heterogeneous, phenotype that may include severe mental retardation, hypertelorism, broad nasal bridge, widow's peak, cleft lip/cleft palate, congenital heart disease, laryngotracheal defects, and hypospadias. The MID1 gene was implicated in OS by linkage to Xp22. It encodes a 667 amino acid protein that contains a RING finger motif, two B-box zinc fingers, a coiled-coil, a fibronectin type III (FNIII) domain, and a B30.2 domain. Several mutations in MID1 are associated with severe OS. Here, we describe an intelligent male with a milder phenotype characterized by hypertelorism, broad nasal bridge, widow's peak, mild hypospadias, pectus excavatum, and a surgically corrected tracheo-esophageal fistula. He has an above average intelligence and no cleft lip/palate or heart disease. We identified a novel mutation in MID1 (P441L) which is in exon 8 and functionally associated with the FNIII domain. While OS phenotypes have been attributed to mutations in the C-terminal part of MID1, little is currently known about the structure-function relationships of MID1 mutations, and how they affect phenotype. We find from a literature review that missense mutations within the FNIII domain of MID1 are associated with a milder presentation of OS than missense mutations elsewhere in MID1. All truncating mutations (frameshift, insertions/deletions) lead to severe OS. We used homology analysis of the MID1 FNIII domain to investigate structure-function changes caused by our missense mutation. This and other missense mutations probably cause disruption of protein-protein interactions, either within MID1 or between MID1 and other proteins. We correlate these protein structure-function findings to the absence of CNS or palatal changes and conclude that the FNIII domain of the MID1 protein may be involved in midline differentiation after neural tube and palatal structures are completed.

  7. Somatic mosaicism and the phenotypic expression of COL2A1 mutations.

    PubMed

    Nagendran, Sonali; Richards, Allan J; McNinch, Annie; Sandford, Richard N; Snead, Martin P

    2012-05-01

    Mutations in COL2A1, the gene for type II-collagen, can result in a wide variety of phenotypes depending upon the nature of the mutation. Dominant negative mutations tend to result in severe and often lethal skeletal dysplasias such as achondrogenesis type 2, Kniest dysplasia, and spondyloepiphyseal dysplasia congenita. Stickler syndrome, a condition characterized by ophthalmological and orofacial features, deafness and arthritis, usually, but not exclusively, results from haploinsufficiency. Overlapping features of all these disorders can also be seen in the same family. Rare reports have demonstrated that phenotypic variability can be explained in some families by somatic mosaicism. Here, we describe five further examples of somatic mosaicism of COL2A1 mutations illustrating the importance of detailed clinical evaluation and molecular testing even in clinically normal parents of affected individuals.

  8. De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

    PubMed

    Hara, Munetsugu; Ohba, Chihiro; Yamashita, Yushiro; Saitsu, Hirotomo; Matsumoto, Naomichi; Matsuishi, Toyojiro

    2015-07-01

    Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability.

  9. Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain.

    PubMed

    Sivera, Rafael; Frasquet, Marina; Lupo, Vincenzo; García-Sobrino, Tania; Blanco-Arias, Patricia; Pardo, Julio; Fernández-Torrón, Roberto; de Munain, Adolfo López; Márquez-Infante, Celedonio; Villarreal, Liliana; Carbonell, Pilar; Rojas-García, Ricard; Segovia, Sonia; Illa, Isabel; Frongia, Anna Lia; Nascimento, Andrés; Ortez, Carlos; García-Romero, María Del Mar; Pascual, Samuel Ignacio; Pelayo-Negro, Ana Lara; Berciano, José; Guerrero, Antonio; Casasnovas, Carlos; Camacho, Ana; Esteban, Jesús; Chumillas, María José; Barreiro, Marisa; Díaz, Carmen; Palau, Francesc; Vílchez, Juan Jesús; Espinós, Carmen; Sevilla, Teresa

    2017-07-27

    Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.

  10. Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1

    PubMed Central

    van den Elzen, M E P; Twigg, S R F; Goos, J A C; Hoogeboom, A J M; van den Ouweland, A M W; Wilkie, A O M; Mathijssen, I M J

    2014-01-01

    Craniofrontonasal syndrome (CFNS) is an X-linked developmental malformation, caused by mutations in the EFNB1 gene, which have only been described since 2004. A genotype–phenotype correlation seems not to be present. As it is of major importance to adequately counsel patients with EFNB1 mutations and their parents, and to improve diagnosis of new patients, more information about the phenotypic features is needed. This study included 23 patients (2 male, 21 female) with confirmed EFNB1 mutations. All patients underwent a thorough physical examination and photographs were taken. If available, radiological images were also consulted. Hypertelorism, longitudinal ridging and/or splitting of nails, a (mild) webbed neck and a clinodactyly of one or more toes were the only consistent features observed in all patients. Frequently observed phenotypic features were bifid tip of the nose (91%), columellar indentation (91%) and low implantation of breasts (90%). In comparison with anthropometric data of facial proportions, patients with CFNS had a significantly different face in multiple respects. An overview of all phenotypic features is shown. Patients with EFNB1 mutations have a clear phenotype. This study will facilitate genetic counseling of parents and patients, and contribute to the diagnostic and screening process of patients with suspected CFNS. PMID:24281372

  11. Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

    PubMed

    Bercovich, Dani; Elimelech, Arava; Zlotogora, Joel; Korem, Sigal; Yardeni, Tal; Gal, Nurit; Goldstein, Nurit; Vilensky, Bela; Segev, Roni; Avraham, Smadar; Loewenthal, Ron; Schwartz, Gerard; Anikster, Yair

    2008-01-01

    The aims of our research were to define the genotype-phenotype correlations of mutations in the phenylalanine hydroxylase (PAH) gene that cause phenylketonuria (PKU) among the Israeli population. The mutation spectrum of the PAH gene in PKU patients in Israel is described, along with a discussion on genotype-phenotype correlations. By using polymerase chain reaction/denaturing high-performance liquid chromatography (PCR/dHPLC) and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes [classic PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia (MHP)]. In 63.2% of patient genotypes, the metabolic phenotype could be predicted, though evidence is also found for both phenotypic inconsistencies among subjects with more than one type of mutation in the PAH gene. Data analysis revealed that about 25% of patients could participate in the future in (6R)-L: -erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) treatment trials according to their mutation genotypes. This study enables us to construct a national database in Israel that will serve as a valuable tool for genetic counseling and a prognostic evaluation of future cases of PKU.

  12. Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1).

    PubMed

    Zenaty, Delphine; Bretones, Patricia; Lambe, Cécile; Guemas, Isabelle; David, Michel; Léger, Juliane; de Roux, Nicolas

    2006-07-25

    Kallmann syndrome characterised by hypogonadotropic hypogonadism (HH) and anosmia is genetically heterogeneous with X-linked, autosomal dominant and autosomal recessive forms. The autosomal dominant form due to loss of function mutation in the fibroblast growth factor receptor 1 (FGFR1) accounts for about 10% of cases. We report here three paediatric cases of Kallmann syndrome with unusual phenotype in two unrelated patients with severe ear anomalies (hypoplasia or agenesis of external ear) associated with classical features, such as cleft palate, dental agenesis, syndactylia, micropenis and cryptorchidism. We found de novo mutation in these two patients (Cys178Ser and Arg622Gly, respectively), and one inherited Arg622Gln mutation with intrafamilial variable phenotype. These genotype-phenotype correlations indicate that paediatric phenotypic expression of FGFR1 loss of function mutations is highly variable, the severity of the oro-facial malformations at birth does not predict gonadotropic function at the puberty and that de novo mutations of FGFR1 are relatively frequent.

  13. The phenotypic variance within plastic traits under migration-mutation-selection balance.

    PubMed

    Zhang, Xu-Sheng

    2006-06-01

    How phenotypic variances of quantitative traits are influenced by the heterogeneity in environment is an important problem in evolutionary biology. In this study, both genetic and environmental variances in a plastic trait under migration-mutation-stabilizing selection are investigated. For this, a linear reaction norm is used to approximate the mapping from genotype to phenotype, and a population of clonal inheritance is assumed to live in a habitat consisting of many patches in which environmental conditions vary among patches and generations. The life cycle is assumed to be selection-reproduction-mutation-migration. Analysis shows that phenotypic plasticity is adaptive if correlations between the optimal phenotype and environment have become established in both space and/or time, and it is thus possible to maintain environmental variance (V(E)) in the plastic trait. Under the special situation of no mutation but maximum migration such that separate patches form an effective single-site habitat, the genotype that maximizes the geometric mean fitness will come to fixation and thus genetic variance (V(G)) cannot be maintained. With mutation and/or restricted migration, V(G) can be maintained and it increases with mutation rate but decreases with migration rate; whereas VE is little affected by them. Temporal variation in environmental quality increases V(G) while its spatial variance decreases V(G). Variation in environmental conditions may decrease the environmental variance in the plastic trait.

  14. DLX3 mutation in a new family and its phenotypic variations.

    PubMed

    Lee, S-K; Lee, Z H; Lee, S-J; Ahn, B-D; Kim, Y-J; Lee, S-H; Kim, J-W

    2008-04-01

    Tricho-dento-osseous syndrome (TDO) is an autosomal-dominant disease characterized by curly hair at birth, enamel hypoplasia, taurodontism, and a thick cortical bone. A common DLX3 gene mutation (c.571_574delGGGG) has been identified in multiple families with variable clinical phenotypes. Recently, another DLX3 gene mutation (c.561_562delCT) was reported to cause amelogenesis imperfecta with taurodontism (AIHHT). We identified a Korean family with overlapping phenotypes of TDO and AIHHT. We performed mutational analysis to discover its genetic etiology. The identified mutation was c.561_562delCT mutation in the DLX3 gene. The enamel was hypomature and hypoplastic. The characteristic taurodontic features were not identified. Increased bone density or thickness could not be revealed by cephalometric, hand-wrist, and panoramic radiographs. Affected individuals reported that their nails were brittle, and they had curly hair at birth. This study clearly showed that the c.561_562delCT mutation had not only enamel defects, but also other clinical phenotypes resembling those of TDO syndrome.

  15. Mutation spectrum of phenylketonuria in Syrian population: genotype-phenotype correlation.

    PubMed

    Murad, Hossam; Dabboul, Amir; Moassas, Faten; Alasmar, Diana; Al-Achkar, Walid

    2013-10-10

    Characterization of the molecular basis of phenylketonuria (PKU) in Syria has been accomplished through the analysis of 78 unrelated chromosomes from 39 Syrian patients with PKU. Phenylalanine hydroxylase (PAH) gene mutations have been analyzed by using molecular detection methods based on the restriction fragment length polymorphism (RFLP), artificial constructed restriction sites (ACRS) PCR and direct DNA sequencing. 56.4% of the patients had cPKU. A mutation detection rate of 79.49% was achieved and sixteen different mutations were found: missense 56.25%, splice site 37.5%, and frameshift 6.25%. The predominant mutation in this population sample was p.R261Q G>A, p.F55>Lfs and p.R243Q G>A. No mutation in six PKU patients was observed. In 57.9% of patient genotypes, the metabolic phenotype could be predicted. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, implementation of optimal dietary therapy, and determination of prognosis in the patients and genetic counseling for the patient's relatives.

  16. Normosmic Congenital Hypogonadotropic Hypogonadism Due to TAC3/TACR3 Mutations: Characterization of Neuroendocrine Phenotypes and Novel Mutations

    PubMed Central

    Voican, Adela; Amazit, Larbi; Trabado, Séverine; Fagart, Jérôme; Meduri, Geri; Brailly-Tabard, Sylvie; Chanson, Philippe; Lecomte, Pierre; Guiochon-Mantel, Anne; Young, Jacques

    2011-01-01

    Context TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. Objective To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations. Results From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%). We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants) found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn) probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001) higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio. Conclusion The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations. PMID:22031817

  17. Phenotypic Suppression of Streptomycin Resistance by Mutations in Multiple Components of the Translation Apparatus

    PubMed Central

    Carr, Jennifer F.; Lee, Hannah J.; Jaspers, Joshua B.; Dahlberg, Albert E.; Jogl, Gerwald

    2015-01-01

    ABSTRACT The bacterial ribosome and its associated translation factors are frequent targets of antibiotics, and antibiotic resistance mutations have been found in a number of these components. Such mutations can potentially interact with one another in unpredictable ways, including the phenotypic suppression of one mutation by another. These phenotypic interactions can provide evidence of long-range functional interactions throughout the ribosome and its functional complexes and potentially give insights into antibiotic resistance mechanisms. In this study, we used genetics and experimental evolution of the thermophilic bacterium Thermus thermophilus to examine the ability of mutations in various components of the protein synthesis apparatus to suppress the streptomycin resistance phenotypes of mutations in ribosomal protein S12, specifically those located distant from the streptomycin binding site. With genetic selections and strain constructions, we identified suppressor mutations in EF-Tu or in ribosomal protein L11. Using experimental evolution, we identified amino acid substitutions in EF-Tu or in ribosomal proteins S4, S5, L14, or L19, some of which were found to also relieve streptomycin resistance. The wide dispersal of these mutations is consistent with long-range functional interactions among components of the translational machinery and indicates that streptomycin resistance can result from the modulation of long-range conformational signals. IMPORTANCE The thermophilic bacterium Thermus thermophilus has become a model system for high-resolution structural studies of macromolecular complexes, such as the ribosome, while its natural competence for transformation facilitates genetic approaches. Genetic studies of T. thermophilus ribosomes can take advantage of existing high-resolution crystallographic information to allow a structural interpretation of phenotypic interactions among mutations. Using a combination of genetic selections, strain constructions

  18. The hemoglobin O mutation in Indonesia: distribution and phenotypic expression.

    PubMed

    Daud, D; Harahap, A; Setianingsih, I; Nainggolan, I; Tranggana, S; Pakasi, R; Marzuki, S

    2001-01-01

    We have investigated hemoglobin O Indonesia (HbOIna) in related ethnic populations of the Indonesian archipelago: 1725 individuals of the five ethnic populations of South Sulawesi (Bugis, Toraja, Makassar, Mandar, and Kajang) and 959 individuals of the neighboring islands, who were divided into five phylogenetic groups: (a) Batak; (b) Malay from Padang, Pakanbaru, and Palembang in the island of Sumatra; (c) Javanese-related populations (Java, Tengger, and Bali) from the islands of Java and Bali; (d) populations of the Lesser Sunda Islands of Lombok, Sumba, and Sumbawa; and (e) the Papuan-languagespeaking population of Alor Island. Nineteen individuals heterozygous for HbO(Ina) were identified from the Bugis, Toraja, Makassar, and Kajang ethnic populations, but none from the other populations. In all cases, the underlying mutation was found to be in codon 116 (GAG to AAG) of the alpha1-globin gene, resulting in the Glull6Lys amino acid change. The level of HbO in the 17 individuals plus 12 additional family members carrying the mutation was found to be 11.6 +/- 1.0%, significantly lower than the expected 17%-22%, indicating the instability of HbO.

  19. Inactivating Mutations in ESCO2 Cause SC Phocomelia and Roberts Syndrome: No Phenotype-Genotype Correlation

    PubMed Central

    Schüle, Birgitt; Oviedo, Angelica; Johnston, Kathreen; Pai, Shashidhar; Francke, Uta

    2005-01-01

    The rare, autosomal recessive Roberts syndrome (RBS) is characterized by tetraphocomelia, profound growth deficiency of prenatal onset, craniofacial anomalies, microcephaly, and mental deficiency. SC phocomelia (SC) has a milder phenotype, with a lesser degree of limb reduction and with survival to adulthood. Since heterochromatin repulsion (HR) is characteristic for both disorders and is not complemented in somatic-cell hybrids, it has been hypothesized that the disorders are allelic. Recently, mutations in ESCO2 (establishment of cohesion 1 homolog 2) on 8p21.1 have been reported in RBS. To determine whether ESCO2 mutations are also responsible for SC, we studied three families with SC and two families in which variable degrees of limb and craniofacial abnormalities, detected by fetal ultrasound, led to pregnancy terminations. All cases were positive for HR. We identified seven novel mutations in exons 3–8 of ESCO2. In two families, affected individuals were homozygous—for a 5-nucleotide deletion in one family and a splice-site mutation in the other. In three nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice-site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, we conclude that genotype does not predict phenotype. Having established that RBS and SC are caused by mutations in the same gene, we delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations and differentiated it from other types of phocomelia that are negative for HR. PMID:16380922

  20. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects.

    PubMed

    Lim, Chiao Xin; Ricos, Michael G; Dibbens, Leanne M; Heron, Sarah E

    2016-04-01

    Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.

  1. Complex Inheritance of ABCA4 Disease: Four Mutations in a Family with Multiple Macular Phenotypes

    PubMed Central

    Lee, Winston; Xie, Yajing (Angela); Zernant, Jana; Yuan, Bo; Bearelly, Srilaxmi; Tsang, Stephen H.; Lupski, James R.; Allikmets, Rando

    2015-01-01

    Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants (SNV) and copy number variants (CNV) that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes. PMID:26527198

  2. A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain.

    PubMed

    Sabater-Molina, María; Saura, Daniel; García-Molina Sáez, Esperanza; González-Carrillo, Josefa; Polo, Luis; Pérez-Sánchez, Inmaculada; Olmo, María Del Carmen; Oliva-Sandoval, María José; Barriales-Villa, Roberto; Carbonell, Pablo; Pascual-Figal, Domigo; Gimeno, Juan R

    2017-02-01

    Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A). We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed. A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308+1 G>A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308+1G>A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis. The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  3. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy

    SciTech Connect

    Ionasescu, V.; Ionasescu, R.; Searby, C.

    1996-06-14

    We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size. 25 refs., 1 fig., 1 tab.

  4. A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations.

    PubMed

    Wallace, Stephanie E; Conta, Jessie H; Winder, Thomas L; Willer, Tobias; Eskuri, Jamie M; Haas, Richard; Patterson, Kathleen; Campbell, Kevin P; Moore, Steven A; Gospe, Sidney M

    2014-04-01

    Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort.

    PubMed

    Lindquist, S G; Schwartz, M; Batbayli, M; Waldemar, G; Nielsen, J E

    2009-08-01

    Autosomal dominantly transmitted Alzheimer's disease (AD) and frontotemporal dementia (FTD) are genetically heterogeneous disorders. To date, three genes have been identified in which mutations cause early-onset autosomal dominant inherited AD: APP, PSEN1, and PSEN2. Mutations in two genes on chromosome 17, the MAPT and the PGRN genes, are associated with autosomal dominant inherited FTD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in families with inherited dementia. The identification of novel mutations and/or atypical genotype-phenotype correlations contributes to further characterizing the disorders. DNA-samples from the 90 index cases from a Danish referral-based cohort representing families with presumed autosomal dominant inherited AD or FTD were screened for mutations in the known genes with sequencing, denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) techniques. Seven presumed pathogenic mutations (two PSEN1, one PSEN2, one APP, one MAPT, and two PGRN) were identified, including a novel PSEN2 mutation (V393M). No dosage aberrations were identified.

  6. Oncogenic mutations produce similar phenotypes in Drosophila tissues of diverse origins

    PubMed Central

    Stickel, Stefanie; Su, Tin Tin

    2014-01-01

    ABSTRACT An emerging interest in oncology is to tailor treatment to particular cancer genotypes, i.e. oncogenic mutations present in the tumor, and not the tissue of cancer incidence. Integral to such a practice is the idea that the same oncogenic mutation(s) produces similar outcomes in different tissues. To test this idea experimentally, we studied tumors driven by a combination of RasV12 and scrib1 mutations in Drosophila larvae. We found that tumors induced in tissues of neural ectodermal and mesodermal origins behaved similarly in every manner examined: cell cycle checkpoints, apoptosis, cellular morphology, increased aneuploidy and response to Taxol. We conclude that oncogenic effects override tissue-specific differences, at least for the mutations, tissues, and phenotypes studied herein. PMID:24570398

  7. Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters

    PubMed Central

    Bröer, Stefan; Bailey, Charles G.; Kowalczuk, Sonja; Ng, Cynthia; Vanslambrouck, Jessica M.; Rodgers, Helen; Auray-Blais, Christiane; Cavanaugh, Juleen A.; Bröer, Angelika; Rasko, John E.J.

    2008-01-01

    Iminoglycinuria (IG) is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families, and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B0AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular explanations depending on a major gene and accompanying modifier genes. PMID:19033659

  8. Mutations in RIT1 cause Noonan syndrome – additional functional evidence and expanding the clinical phenotype

    PubMed Central

    Koenighofer, Martin; Hung, Christina Y.; McCauley, Jacob L.; Dallman, Julia; Back, Emma J.; Mihalek, Ivana; Gripp, Karen W.; Sol-Church, Katia; Rusconi, Paolo; Zhang, Zhaiyi; Shi, Geng-Xian; Andres, Douglas A.; Bodamer, Olaf A.

    2015-01-01

    RASopathies are a clinically heterogeneous group of conditions caused by mutations in one of sixteen proteins in the RAS-MAPK pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and, p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins, however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma. PMID:25959749

  9. Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes.

    PubMed Central

    Braun, A; Ambach, H; Kammerer, S; Rolinski, B; Stöckler, S; Rabl, W; Gärtner, J; Zierz, S; Roscher, A A

    1995-01-01

    Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expression of X-ALD and in their female relatives; these clinical expressions were cerebral childhood ALD, adrenomyeloneuropathy (AMN), and "Addison disease only" (ADO) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5' portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7717396

  10. Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

    SciTech Connect

    Braun, A.; Ambach, H.; Kammerer, S.; Rolinski, B.; Roscher, A.; Rabl, W.; Stoeckler, S.; Gaertner, J.; Zierz, S.

    1995-04-01

    Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.

  11. A Computational Protein Phenotype Prediction Approach to Analyze the Deleterious Mutations of Human MED12 Gene.

    PubMed

    Banaganapalli, Babajan; Mohammed, Kaleemuddin; Khan, Imran Ali; Al-Aama, Jumana Y; Elango, Ramu; Shaik, Noor Ahmad

    2016-09-01

    Genetic mutations in MED12, a subunit of Mediator complex are seen in a broad spectrum of human diseases. However, the underlying basis of how these pathogenic mutations elicit protein phenotype changes in terms of 3D structure, stability and protein binding sites remains unknown. Therefore, we aimed to investigate the structural and functional impacts of MED12 mutations, using computational methods as an alternate to traditional in vivo and in vitro approaches. The MED12 gene mutations details and their corresponding clinical associations were collected from different databases and by text-mining. Initially, diverse computational approaches were applied to categorize the different classes of mutations based on their deleterious impact to MED12. Then, protein structures for wild and mutant types built by integrative modeling were analyzed for structural divergence, solvent accessibility, stability, and functional interaction deformities. Finally, this study was able to identify that genetic mutations mapped to exon-2 region, highly conserved LCEWAV and Catenin domains induce biochemically severe amino acid changes which alters the protein phenotype as well as the stability of MED12-CYCC interactions. To better understand the deleterious nature of FS-IDs and Indels, this study asserts the utility of computational screening based on their propensity towards non-sense mediated decay. Current study findings may help to narrow down the number of MED12 mutations to be screened for mediator complex dysfunction associated genetic diseases. This study supports computational methods as a primary filter to verify the plausible impact of pathogenic mutations based on the perspective of evolution, expression and phenotype of proteins. J. Cell. Biochem. 117: 2023-2035, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Insights into genotype-phenotype correlation in pachyonychia congenita from the human intermediate filament mutation database.

    PubMed

    McLean, W H Irwin; Smith, Frances J D; Cassidy, Andrew J

    2005-10-01

    Keratins are the intermediate filament proteins specifically expressed by epithelial cells. The Human Genome Project has uncovered a total of 54 functional keratin genes that are differentially expressed in specific epithelial structures of the body, many of which involve the epidermis and its appendages. Pachyonychia congenita (PC) is a group of autosomal dominant genodermatoses affecting the nails, thick skin and other ectodermal structures, according to specific sub-type. The major clinical variants of the disorder (PC-1 and PC-2) are known to be caused by dominant-negative mutations in one of four differentiation-specific keratins: K6a, K6b, K16, and K17. A total of 20 human keratin genes are currently linked to single-gene disorders or are predisposing factors in complex traits. In addition, a further six intermediate filament genes have been linked to other non-epithelial genetic disorders. We have established a comprehensive mutation database that catalogs all published independent occurrences of intermediate filament mutations (http://www.interfil.org), with details of phenotypes, published papers, patient support groups and other information. Here, we review the genotype-phenotype trends emerging from the spectrum of mutations in these genes and apply these correlations to make predictions about PC phenotypes based on the site of mutation and keratin pair involved.

  13. Mutation spectrum and genotype-phenotype correlation of hearing loss patients caused by SLC26A4 mutations in the Japanese: a large cohort study.

    PubMed

    Miyagawa, Maiko; Nishio, Shin-Ya; Usami, Shin-Ichi

    2014-05-01

    Mutations in SLC26A4 cause a broad phenotypic spectrum, from typical Pendred syndrome to nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Identification of these mutations is important for accurate diagnosis, proper medical management and appropriate genetic counseling and requires updated information regarding spectrum, clinical characteristics and genotype-phenotype correlations, based on a large cohort. In 100 patients with bilateral enlarged vestibular aqueduct among 1511 Japanese hearing loss probands registered in our gene bank, goiter data were available for 79, of whom 15 had Pendred syndrome and 64 had nonsyndromic hearing loss. We clarified the mutation spectrum for the SLC26A4 mutations and also summarized hearing levels, progression, fluctuation and existence of genotype-phenotype correlation. SLC26A4 mutations were identified in 82 of the 100 patients (82.0%). Of the Pendred syndrome patients, 93% (14/15) were carriers, as were 77% (49/64) of the nonsyndromic hearing loss patients. Clinical characteristics of patients with SLC26A4 mutations were congenital, fluctuating and progressive hearing loss usually associated with vertigo and/or goiter. We found no genotype-phenotype correlations, indicating that, unlike in the case of GJB2 mutations, the phenotype cannot be predicted from the genotype. Our mutation analysis confirmed the importance of mutations in the SLC26A4 gene among hearing loss patients with enlarged vestibular aqueduct and revealed the mutation spectrum, essential information when performing genetic testing.

  14. Variability in dentofacial phenotypes in four families with WNT10A mutations

    PubMed Central

    Vink, Christian P; Ockeloen, Charlotte W; ten Kate, Sietske; Koolen, David A; Ploos van Amstel, Johannes Kristian; Kuijpers-Jagtman, Anne-Marie; van Heumen, Celeste C; Kleefstra, Tjitske; Carels, Carine E L

    2014-01-01

    This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schöpf–Schulz–Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology. PMID:24398796

  15. Exploring the Phenotypic Space and the Evolutionary History of a Natural Mutation in Drosophila melanogaster.

    PubMed

    Ullastres, Anna; Petit, Natalia; González, Josefa

    2015-07-01

    A major challenge of modern Biology is elucidating the functional consequences of natural mutations. Although we have a good understanding of the effects of laboratory-induced mutations on the molecular- and organismal-level phenotypes, the study of natural mutations has lagged behind. In this work, we explore the phenotypic space and the evolutionary history of a previously identified adaptive transposable element insertion. We first combined several tests that capture different signatures of selection to show that there is evidence of positive selection in the regions flanking FBti0019386 insertion. We then explored several phenotypes related to known phenotypic effects of nearby genes, and having plausible connections to fitness variation in nature. We found that flies with FBti0019386 insertion had a shorter developmental time and were more sensitive to stress, which are likely to be the adaptive effect and the cost of selection of this mutation, respectively. Interestingly, these phenotypic effects are not consistent with a role of FBti0019386 in temperate adaptation as has been previously suggested. Indeed, a global analysis of the population frequency of FBti0019386 showed that climatic variables explain well the FBti0019386 frequency patterns only in Australia. Finally, although FBti0019386 insertion could be inducing the formation of heterochromatin by recruiting HP1a (Heterochromatin Protein 1a) protein, the insertion is associated with upregulation of sra in adult females. Overall, our integrative approach allowed us to shed light on the evolutionary history, the relevant fitness effects, and the likely molecular mechanisms of an adaptive mutation and highlights the complexity of natural genetic variants.

  16. Identification and genotype/phenotype correlation of mutations in a large German cohort with hearing loss.

    PubMed

    Beck, Christopher; Pérez-Álvarez, Jose Carmelo; Sigruener, Alexander; Haubner, Frank; Seidler, Till; Aslanidis, Charalampos; Strutz, Jürgen; Schmitz, Gerd

    2015-10-01

    The prevalence of hearing impairment is estimated as approximately 1 on 1,000 newborn children. To assess a higher mutation detection rate in individuals with hearing loss a three-step mutation screening program consisting of GJB2 in first line, then GJB1, GJB3 and GJB6 (second step) and if tested negative or heterozygote, testing of GJA1, GJB4, SLC26A4 and PJVK (third) was performed. Audiograms were derived from all patients to characterize audiological features of GJB2 mutations especially. In 59 patients (31.3%) of the 188 probands, the hearing impairment was due to GJB2 mutations, 45 (23.9%) of these being homozygous for 35delG mutation and 14 (7.4%) compound heterozygous for GJB2 mutations in the coding region of exon 2 whereas no significant sequence variation was found in exon 1. In 22 (11.7%) additional patients a single recessive mutation in GJB2, GJB3, GJB6 and SLC26A4 without a second mutation on the other allele was identified, making genetic counseling difficult. Our study showed significant difference in hearing loss degree in the patients with GJB2-mutations. Forty-five (45.5%) GJB2-cases were identified in 99 individuals diagnosed with severe to profound hearing loss, 14 (17.7%) GJB2-cases were identified in 79 individuals with moderate deafness whereas no clear GJB2 mutation was found in 10 patients with mild hearing loss (p < 0.001). Revealing a high variability of hearing levels in identical genotypes (even intrafamilial), a significant genotype-phenotype correlation could not be established. Based on the identified mutations spectrum and frequencies, speaking mostly of GJB2, a step by step screening for mutations can be devised and in addition may lead to a better stratification of patients for specific therapeutical approaches.

  17. Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations.

    PubMed

    Hoshi, Malcolm; Du, Xi X; Shinlapawittayatorn, Krekwit; Liu, Haiyan; Chai, Sam; Wan, Xiaoping; Ficker, Eckhard; Deschênes, Isabelle

    2014-04-01

    Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A, the gene encoding for the pore-forming α-subunit of the cardiac sodium channel. Typically, BrS mutations in SCN5A result in a reduction of sodium current with some mutations even exhibiting a dominant-negative effect on wild-type (WT) channels, thus leading to an even more prominent decrease in current amplitudes. However, there is also a category of apparently benign (atypical) BrS SCN5A mutations that in vitro demonstrates only minor biophysical defects. It is therefore not clear how these mutations produce a BrS phenotype. We hypothesized that similar to dominant-negative mutations, atypical mutations could lead to a reduction in sodium currents when coexpressed with WT to mimic the heterozygous patient genotype. WT and atypical BrS mutations were coexpressed in Human Embryonic Kidney-293 cells, showing a reduction in sodium current densities similar to typical BrS mutations. Importantly, this reduction in sodium current was also seen when the atypical mutations were expressed in rat or human cardiomyocytes. This decrease in current density was the result of reduced surface expression of both mutant and WT channels. Taken together, we have shown how apparently benign SCN5A BrS mutations can lead to the ECG abnormalities seen in patients with BrS through an induced defect that is only present when the mutations are coexpressed with WT channels. Our work has implications for risk management and stratification for some SCN5A-implicated BrS patients.

  18. Mutational spectrum and geno-phenotype correlation in Chinese families with hereditary angioedema.

    PubMed

    Xu, Y-Y; Zhi, Y-X; Yin, J; Wang, L-L; Wen, L-P; Gu, J-Q; Guan, K; Craig, T; Zhang, H-Y

    2012-11-01

    Hereditary angioedema is a rare autosomal dominant disease, and its correlation between genotype and phenotype seems not to exist. So far, there are very few studies on Chinese population. We aimed to establish a Chinese genetic database of hereditary angioedema and investigated the potential correlation between genotype and phenotype. All the eight exons and intron-exon boundaries of C1 inhibitor gene were detected in 48 unrelated families with HAE. The correlations between genotype and clinical parameters were evaluated by R statistical software. Thirty-five different mutations (25 of them were novel) and 7 SNPs (3 of them were novel) were identified. Significant difference was found in the level of C1 inhibitor antigen (P = 0.01793) between different groups of mutational types. The correlation between different groups of mutational types and the level of C1 inhibitor antigen (0.5047, P = 0.00027) was significant. The different groups of mutational types showed neither difference nor correlations of clinical parameters (severity score and the level of C1 inhibitor function). It appears that nonsense, frameshift, and mutations on Arg466 can cause lower level of C1 inhibitor antigen than missense and in-frame mutations; however, it does not affect severity of symptoms. © 2012 John Wiley & Sons A/S.

  19. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia.

    PubMed

    Wooderchak-Donahue, Whitney L; McDonald, Jamie; O'Fallon, Brendan; Upton, Paul D; Li, Wei; Roman, Beth L; Young, Sarah; Plant, Parker; Fülöp, Gyula T; Langa, Carmen; Morrell, Nicholas W; Botella, Luisa M; Bernabeu, Carmelo; Stevenson, David A; Runo, James R; Bayrak-Toydemir, Pinar

    2013-09-05

    Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  20. Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor.

    PubMed

    Moore, Jeffrey R; Leinwand, Leslie; Warshaw, David M

    2012-07-20

    Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are inherited diseases with a high incidence of death due to electric abnormalities or outflow tract obstruction. In many of the families afflicted with either disease, causative mutations have been identified in various sarcomeric proteins. In this review, we focus on mutations in the cardiac muscle molecular motor, myosin, and its associated light chains. Despite the >300 identified mutations, there is still no clear understanding of how these mutations within the same myosin molecule can lead to the dramatically different clinical phenotypes associated with HCM and DCM. Localizing mutations within myosin's molecular structure provides insight into the potential consequence of these perturbations to key functional domains of the motor. Review of biochemical and biophysical data that characterize the functional capacities of these mutant myosins suggests that mutant myosins with enhanced contractility lead to HCM, whereas those displaying reduced contractility lead to DCM. With gain and loss of function potentially being the primary consequence of a specific mutation, how these functional changes trigger the hypertrophic response and lead to the distinct HCM and DCM phenotypes will be the future investigative challenge.

  1. Darier disease in Slovenia: spectrum of ATP2A2 mutations and relation to patients' phenotypes.

    PubMed

    Godic, Aleksandar; Strazisar, Mojca; Zupan, Andrej; Korosec, Branka; Kansky, Aleksej; Glavac, Damjan

    2010-01-01

    ATP2A2 encodes the sarco/endoplasmic reticulum Ca2+- ATPase (SERCA2) and has been identified as a defective gene in Darier disease (DD). It is an autosomal dominant genodermatosis, which is characterized by loss of adhesion between suprabasal epidermal keratinocytes (acantholysis) and abnormal keratinization (dyskeratosis). We examined 28 Slovenian patients with DD (the cohort of patients represents over 50% of all DD patients in Slovenia) and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 544+1del6, and 1762-6del18. We also found two previously described polymorphisms 2741+54 G>A in intron XVIII and 2172 G>A (A724A) in exon 15, with allele frequencies of 64.2% and 11.3%, respectively. The mutations are scattered throughout the gene and affect the actuator, phosphorylation, stalk and transmembrane domains of SERCA2. A P160L mutation in a Slovene patient with severe DD and a history of deafness is another consistent genotype-phenotype correlation. It seems that mutations of the ATP2A2 gene may also play a role in the pathogenesis of deafness, which seems to be a new phenotypic characteristic of DD patients.

  2. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.

    PubMed Central

    Park, W J; Theda, C; Maestri, N E; Meyers, G A; Fryburg, J S; Dufresne, C; Cohen, M M; Jabs, E W

    1995-01-01

    A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26%, for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences. Images Figure 2 Figure 3 Figure 4 PMID:7668257

  3. A "dose" effect of mutations in the GBA gene on Parkinson's disease phenotype.

    PubMed

    Thaler, Avner; Gurevich, Tanya; Bar Shira, Anat; Gana Weisz, Mali; Ash, Elissa; Shiner, Tamara; Orr-Urtreger, Avi; Giladi, Nir; Mirelman, Anat

    2017-03-01

    Mutations in the GBA gene are associated with Parkinson's disease (PD). A definite description of the clinical characteristics of PD patients who are compound heterozygotes or homozygotes for mutations in the GBA gene (GD-PD) requires further elucidation. We assessed motor, cognitive, olfactory and autonomic functions as well as demographic data and medical history in a cohort of Ashkenazi Jewish PD patients who were screened for seven common mutations in the GBA gene. We then compared three groups of patients (matched for age and disease duration) who were distinguished by their GBA mutation status, idiopathic PD (iPD), GBA heterozygote PD (GBA-PD) and GD-PD. Out of a total of 1050 AJ PD patients screened, 12 were found to be either homozygotes or compound heterozygotes for mutations in the GBA gene. These patients had an earlier age of onset, more severe motor impairment, poorer cognition and lower olfactory scores. They also had a higher prevalence of REM sleep behavior disorder and higher frequencies of hallucinations compared to both GBA-PD and iPD. The severity of PD phenotype is related to the burden of GBA mutations with GD-PD patients manifesting a more severe phenotype. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.

    PubMed

    Valence, S; Garel, C; Barth, M; Toutain, A; Paris, C; Amsallem, D; Barthez, M-A; Mayer, M; Rodriguez, D; Burglen, L

    2016-12-01

    Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome

    SciTech Connect

    Park, Woo-Jin; Theda, C.; Maestri, N.E.

    1995-08-01

    A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26% for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences. 34 refs., 4 figs., 1 tab.

  6. Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis

    PubMed Central

    Li, Jia-Kai; Fei, Ping; Li, Yian; Huang, Qiu-Jing; Zhang, Qi; Zhang, Xiang; Rao, Yu-Qing; Li, Jing; Zhao, Peiquan

    2016-01-01

    KIF11 gene mutations cause a rare autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR). Recently, such mutations were also found to be associated with familial exudative vitreoretinopathy (FEVR). Here, we report 7 novel KIF11 mutations identified by targeted gene capture in a cohort of 142 probands with FEVR who were diagnosed in our clinic between March 2015 and November 2015. These mutations were: p.L171V, c.790-2A>C, p.Q525*, p.Q842*, p.S936*, p.L983fs and p.R1025G. Phenotypic analysis revealed that all of the affected probands had advanced FEVR (stage 4 or above). Three had microcephaly, and one had chorioretinopathy, which indicated a phenotypic overlap with MCLMR. Two mutations were also found in the families of the affected probands. One parent with a p.R1025G mutation had an avascular peripheral retina and abnormal looping vessels. However, one parent with p.L983fs had normal retina, which indicated incomplete penetration of the genotype. Our results further confirmed that KIF11 is causative of FEVR in an autosomal dominant manner. We also suggest the examination of MCLMR-like features, such as microcephaly, chorioretinopathy, for patients with FEVR and wide-field fundus photography for patients with MCLMR in future practice. PMID:27212378

  7. Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies

    PubMed Central

    2012-01-01

    Background Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal condition that is a ciliopathy. MKS has marked phenotypic variability and genetic heterogeneity, with mutations in nine genes identified as causative to date. Methods Families diagnosed with Meckel-Gruber syndrome were recruited for research studies following informed consent. DNA samples were analyzed by microsatellite genotyping and direct Sanger sequencing. Results We now report the genetic analyses of 87 individuals from 49 consanguineous and 19 non-consanguineous families in an unselected cohort with reported MKS, or an associated severe ciliopathy in a kindred. Linkage and/or direct sequencing were prioritized for seven MKS genes (MKS1, TMEM216, TMEM67/MKS3, RPGRIP1L, CC2D2A, CEP290 and TMEM237) selected on the basis of reported frequency of mutations or ease of analysis. We have identified biallelic mutations in 39 individuals, of which 13 mutations are novel and previously unreported. We also confirm general genotype-phenotype correlations. Conclusions TMEM67 was the most frequently mutated gene in this cohort, and we confirm two founder splice-site mutations (c.1546 + 1 G > A and c.870-2A > G) in families of Pakistani ethnic origin. In these families, we have also identified two separate founder mutations for RPGRIP1L (c. 1945 C > T p.R649X) and CC2D2A (c. 3540delA p.R1180SfsX6). Two missense mutations in TMEM67 (c. 755 T > C p.M252T, and c. 1392 C > T p.R441C) are also probable founder mutations. These findings will contribute to improved genetic diagnosis and carrier testing for affected families, and imply the existence of further genetic heterogeneity in this syndrome. PMID:23351400

  8. Founder mutations and genotype-phenotype correlations in Meckel-Gruber syndrome and associated ciliopathies.

    PubMed

    Szymanska, Katarzyna; Berry, Ian; Logan, Clare V; Cousins, Simon Rr; Lindsay, Helen; Jafri, Hussain; Raashid, Yasmin; Malik-Sharif, Saghira; Castle, Bruce; Ahmed, Mushtag; Bennett, Chris; Carlton, Ruth; Johnson, Colin A

    2012-10-01

    Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal condition that is a ciliopathy. MKS has marked phenotypic variability and genetic heterogeneity, with mutations in nine genes identified as causative to date. Families diagnosed with Meckel-Gruber syndrome were recruited for research studies following informed consent. DNA samples were analyzed by microsatellite genotyping and direct Sanger sequencing. We now report the genetic analyses of 87 individuals from 49 consanguineous and 19 non-consanguineous families in an unselected cohort with reported MKS, or an associated severe ciliopathy in a kindred. Linkage and/or direct sequencing were prioritized for seven MKS genes (MKS1, TMEM216, TMEM67/MKS3, RPGRIP1L, CC2D2A, CEP290 and TMEM237) selected on the basis of reported frequency of mutations or ease of analysis. We have identified biallelic mutations in 39 individuals, of which 13 mutations are novel and previously unreported. We also confirm general genotype-phenotype correlations. TMEM67 was the most frequently mutated gene in this cohort, and we confirm two founder splice-site mutations (c.1546 + 1 G > A and c.870-2A > G) in families of Pakistani ethnic origin. In these families, we have also identified two separate founder mutations for RPGRIP1L (c. 1945 C > T p.R649X) and CC2D2A (c. 3540delA p.R1180SfsX6). Two missense mutations in TMEM67 (c. 755 T > C p.M252T, and c. 1392 C > T p.R441C) are also probable founder mutations. These findings will contribute to improved genetic diagnosis and carrier testing for affected families, and imply the existence of further genetic heterogeneity in this syndrome.

  9. Phenotypic consequences of somatic mutations in the ataxia-telangiectasia mutated gene in non-small cell lung cancer

    PubMed Central

    Weber, Anika Maria; Drobnitzky, Neele; Devery, Aoife Maire; Bokobza, Sivan Mili; Adams, Richard A.; Maughan, Timothy S.; Ryan, Anderson Joseph

    2016-01-01

    Mutations in the Ataxia-telangiectasia mutated (ATM) gene are frequently found in human cancers, including non-small cell lung cancer (NSCLC). Loss of ATM function confers sensitivity to ionising radiation (IR) and topoisomerase inhibitors and may thus define a subset of cancer patients that could get increased benefit from these therapies. In this study, we evaluated the phenotypic consequences of ATM missense changes reported in seven NSCLC cell lines with regard to radiosensitivity and functionality of ATM signalling. Our data demonstrate that only 2/7 NSCLC cell lines (H1395 and H23) harbouring ATM missense mutations show a functional impairment of ATM signalling following IR-exposure. In these two cell lines, the missense mutations caused a significant reduction in ATM protein levels, impairment of ATM signalling and marked radiosensitivity. Of note, only cell lines with homozygous mutations in the ATM gene showed significant impairment of ATM function. Based on these observations, we developed an immunohistochemistry-based assay to identify patients with loss or reduction of ATM protein expression in a clinical setting. In a set of 137 NSCLC and 154 colorectal cancer specimens we identified tumoral loss of ATM protein expression in 9.5% and 3.9% of cases, respectively, demonstrating the potential utility of this method. PMID:27602502

  10. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.

    PubMed

    Hackett, Anna; Tarpey, Patrick S; Licata, Andrea; Cox, James; Whibley, Annabel; Boyle, Jackie; Rogers, Carolyn; Grigg, John; Partington, Michael; Stevenson, Roger E; Tolmie, John; Yates, John Rw; Turner, Gillian; Wilson, Meredith; Futreal, Andrew P; Corbett, Mark; Shaw, Marie; Gecz, Jozef; Raymond, F Lucy; Stratton, Michael R; Schwartz, Charles E; Abidi, Fatima E

    2010-05-01

    Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.

  11. Interplay between DMD Point Mutations and Splicing Signals in Dystrophinopathy Phenotypes

    PubMed Central

    Juan-Mateu, Jonàs; González-Quereda, Lidia; Rodríguez, Maria José; Verdura, Edgard; Lázaro, Kira; Jou, Cristina; Nascimento, Andrés; Jiménez-Mallebrera, Cecilia; Colomer, Jaume; Monges, Soledad; Lubieniecki, Fabiana; Foncuberta, Maria Eugenia; Pascual-Pascual, Samuel Ignacio; Molano, Jesús; Baiget, Montserrat; Gallano, Pia

    2013-01-01

    DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements. PMID:23536893

  12. KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.

    PubMed

    Figueroa, Karla P; Minassian, Natali A; Stevanin, Giovanni; Waters, Michael; Garibyan, Vartan; Forlani, Sylvie; Strzelczyk, Adam; Bürk, Katrin; Brice, Alexis; Dürr, Alexandra; Papazian, Diane M; Pulst, Stefan M

    2010-02-01

    We recently identified KCNC3, encoding the Kv3.3 voltage-gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late-onset ataxia resulting in a nonfunctional channel subunit with dominant-negative properties. A French early-onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channel's open conformation. Coding exons were amplified and sequenced in 260 autosomal-dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late-onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early-onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant-negative properties. The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late-onset progressive ataxia. In two families the p.Arg423His mutation was associated with early-onset slow-progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early-onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant-negative effect.

  13. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.

    PubMed

    Lerner-Ellis, Jordan P; Anastasio, Natascia; Liu, Junhui; Coelho, David; Suormala, Terttu; Stucki, Martin; Loewy, Amanda D; Gurd, Scott; Grundberg, Elin; Morel, Chantal F; Watkins, David; Baumgartner, Matthias R; Pastinen, Tomi; Rosenblatt, David S; Fowler, Brian

    2009-07-01

    Methylmalonic aciduria and homocystinuria, cblC type, is a rare disorder of intracellular vitamin B(12) (cobalamin [Cbl]) metabolism caused by mutations in the MMACHC gene. MMACHC was sequenced from the gDNA of 118 cblC individuals. Eleven novel mutations were identified, as well as 23 mutations that were observed previously. Six sequence variants capture haplotype diversity in individuals across the MMACHC interval. Genotype-phenotype correlations of common mutations were apparent; individuals with c.394C>T tend to present with late-onset disease whereas patients with c.331C>T and c.271dupA tend to present in infancy. Other missense variants were also associated with late- or early-onset disease. Allelic expression analysis was carried out on human cblC fibroblasts compound heterozygous for different combinations of mutations including c.271dupA, c.331C>T, c.394C>T, and c.482G>A. The early-onset c.271dupA mutation was consistently underexpressed when compared to control alleles and the late-onset c.394C>T and c.482G>A mutations. The early-onset c.331C>T mutation was also underexpressed when compared to control alleles and the c.394C>T mutation. Levels of MMACHC mRNA transcript in cell lines homozygous for c.271dupA, c.331C>T, and c.394C>T were assessed using quantitative real-time RT-PCR. Cell lines homozygous for the late onset c.394C>T mutation had significantly higher levels of transcript when compared to cell lines homozygous for the early-onset mutations. Differential or preferential MMACHC transcript levels may provide a clue as to why individuals carrying c.394C>T generally present later in life. (c) 2009 Wiley-Liss, Inc.

  14. Next-generation Sequencing Extends the Phenotypic Spectrum for LCA5 Mutations: Novel LCA5 Mutations in Cone Dystrophy.

    PubMed

    Chen, Xue; Sheng, Xunlun; Sun, Xiantao; Zhang, Yuxin; Jiang, Chao; Li, Huiping; Ding, Sijia; Liu, Yani; Liu, Wenzhou; Li, Zili; Zhao, Chen

    2016-04-12

    We aim to characterize the clinical features and genetic causes for two affected siblings from a Chinese family with cone dystrophy (CD). Two patients and four unaffected family members were recruited and received complete ophthalmic examinations. Genomic DNA was isolated from the peripheral blood samples from all patients. Targeted next-generation sequencing (NGS) approach followed by intrafamilal cosegregation and in silico analyses were employed to determine the genetic defects. Ophthalmic evaluations finalized the clinical diagnosis of CD for the two patients in this family, both of whom presented macular atrophy with no remarkable changes in the peripheral retina. Comprehensive genetic screening approach revealed biallelic missense mutations in the Leber congenital amaurosis 5 (LCA5) gene, p.[Ala212Pro];[Tyr441Cys], as disease causative for this family. Both mutations were novel. The first substitution was predicted to eliminate a hydrogen bond and alter the tertiary structure of lebercilin, protein encoded by LCA5. We for the first time report novel biallelic LCA5 mutations in causing CD. Our study extends the phenotypic and genotypic spectrums for LCA5-associated retinopathies and better illustrates its genotype-phenotype correlations, which would help with better genetic diagnosis, prognosis, and personalized treatment for CD patients.

  15. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2

    PubMed Central

    Jayadev, Suman; Leverenz, James B.; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En

    2010-01-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer’s disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world’s literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years ± 7.8 (range 39–75) and mean age at death of 64.2 years ± 9.8 (range 43–88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer’s disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging

  16. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2.

    PubMed

    Jayadev, Suman; Leverenz, James B; Steinbart, Ellen; Stahl, Justin; Klunk, William; Yu, Cheng-En; Bird, Thomas D

    2010-04-01

    Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel

  17. Multiple phenotypes resulting from a mutagenesis screen for pharynx muscle mutations in Caenorhabditis elegans.

    PubMed

    Ferrier, Andrew; Charron, Alexandra; Sadozai, Yama; Switaj, Lynn; Szutenbach, Anneliese; Smith, Pliny A

    2011-01-01

    We describe a novel screen to isolate pharyngeal cell morphology mutants in Caenorhabditis elegans using myo-2::GFP to rapidly identify abnormally shaped pharynxes in EMS (Ethyl Methanesulfonate) mutagenized worms. We observed over 83 C. elegans lines with distinctive pharyngeal phenotypes in worms surviving to the L1 larval stage, with phenotypes ranging from short pharynx, unattached pharynx, missing cells, asymmetric morphology, and non-adherent pharynx cells. Thirteen of these mutations have been chromosomally mapped using Single Nucleotide Polymorphisms (SNPs) and deficiency strain complementation. Our studies have focused on genetically mapping and functionally testing two phenotypes, the short pharynx and the loss of muscle cohesion phenotypes. We have also identified new alleles of sma-1, and our screen suggests many genes directing pharynx assembly and structure may be either pharynx specific or less critical in other tissues.

  18. Multiple Phenotypes Resulting from a Mutagenesis Screen for Pharynx Muscle Mutations in Caenorhabditis elegans

    PubMed Central

    Ferrier, Andrew; Charron, Alexandra; Sadozai, Yama; Switaj, Lynn; Szutenbach, Anneliese; Smith, Pliny A.

    2011-01-01

    We describe a novel screen to isolate pharyngeal cell morphology mutants in Caenorhabditis elegans using myo-2::GFP to rapidly identify abnormally shaped pharynxes in EMS (Ethyl Methanesulfonate) mutagenized worms. We observed over 83 C. elegans lines with distinctive pharyngeal phenotypes in worms surviving to the L1 larval stage, with phenotypes ranging from short pharynx, unattached pharynx, missing cells, asymmetric morphology, and non-adherent pharynx cells. Thirteen of these mutations have been chromosomally mapped using Single Nucleotide Polymorphisms (SNPs) and deficiency strain complementation. Our studies have focused on genetically mapping and functionally testing two phenotypes, the short pharynx and the loss of muscle cohesion phenotypes. We have also identified new alleles of sma-1, and our screen suggests many genes directing pharynx assembly and structure may be either pharynx specific or less critical in other tissues. PMID:22073173

  19. Blepharophimosis, short humeri, developmental delay and hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.

    PubMed

    Isidor, Bertrand; Lefebvre, Tiphaine; Le Vaillant, Claudine; Caillaud, Gaëlle; Faivre, Laurence; Jossic, Frédéric; Joubert, Madeleine; Winer, Norbert; Le Caignec, Cédric; Borck, Guntram; Pelet, Anna; Amiel, Jeanne; Toutain, Annick; Ronce, Nathalie; Raynaud, Martine; Verloes, Alain; David, Albert

    2014-07-01

    We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg-Shprintzen syndrome and the Say-Barber-Biesecker-Young-Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz-Kaveggia syndrome, Lujan-Fryns syndrome and X-linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations. © 2014 Wiley Periodicals, Inc.

  20. Mutations of the Wiskott-Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes.

    PubMed

    Ochs, Hans D

    2009-01-01

    Mutations of the Wiskott-Aldrich Syndrome Protein (WASP) are responsible for classic Wiskott-Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and in rare instances congenital X-linked neutropenia (XLN). WASP is a regulator of actin polymerization in hematopoietic cells with well-defined functional domains that are involved in cell signaling and cell locomotion, immune synapse formation, and apoptosis. Mutations of WASP are located throughout the gene and either inhibit or disregulate normal WASP function. Analysis of a large patient population demonstrates a strong phenotype-genotype correlation. Classic WAS occurs when WASP is absent, XLT when mutated WASP is expressed and XLN when missense mutations occur in the Cdc42-binding site. However, because there are exceptions to this rule it is difficult to predict the long-term prognosis of a given affected boy solely based on the analysis of WASP expression.

  1. FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report.

    PubMed

    Méduri, Géri; Bachelot, Anne; Duflos, Catherine; Bständig, Bettina; Poirot, Catherine; Genestie, Catherine; Veitia, Reiner; De Baere, Elfride; Touraine, Philippe

    2010-01-01

    FOXL2 mutations cause the autosomal dominant Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) that may be associated with premature ovarian failure (POF). However, little is known about the molecular mechanisms of FOXL2 actions in the human ovary. We conducted an extensive clinical, hormonal and ovarian histological study in two patients carrying a FOXL2 mutation associated with the typical eyelid malformations and infertility. This observational study was conducted at referral centres for POF. Histological and immunohistological studies were conducted on ovarian biopsies from two women with POF carrying a FOXL2 mutation resulting in putative polyalanine expansions of the protein. Abnormalities similar to those observed in mice with FOXL2 gene inactivation were present in the first patient's ovary, although the ovarian histology of the second patient was apparently normal. Different ovarian phenotypes, follicular defects and distribution of FOXL2 protein were observed in two patients carrying a FOXL2 mutation.

  2. Experimental approaches to evaluate the contributions of candidate protein-coding mutations to phenotypic evolution.

    PubMed

    Storz, Jay F; Zera, Anthony J

    2011-01-01

    Identifying mechanisms of molecular adaptation can provide important insights into the process of phenotypic evolution, but it can be exceedingly difficult to quantify the phenotypic effects of specific mutational changes. To verify the adaptive significance of genetically based changes in protein function, it is necessary to document functional differences between the products of derived and wild-type alleles and to demonstrate that such differences impinge on higher-level physiological processes (and ultimately, fitness). In the case of metabolic enzymes, this requires documenting in vivo differences in reaction rate that give rise to differences in flux through the pathway in which the enzymes function. These measured differences in pathway flux should then give rise to differences in cellular or systemic physiology that affect fitness-related variation in whole-organism performance. Efforts to establish these causal connections between genotype, phenotype, and fitness require experiments that carefully control for environmental variation and background genetic variation. Here, we discuss experimental approaches to evaluate the contributions of amino-acid mutations to adaptive phenotypic change. We discuss conceptual and methodological issues associated with in vitro and in vivo studies of protein function, and the evolutionary insights that can be gleaned from such studies. We also discuss the importance of isolating the effects of individual mutations to distinguish between positively selected substitutions that directly contribute to improvements in protein function versus positively selected, compensatory substitutions that mitigate negative pleiotropic effects of antecedent changes.

  3. Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms.

    PubMed

    Aggarwal, Annu; Schneider, Susanne A; Houlden, Henry; Silverdale, Monty; Paudel, Reema; Paisan-Ruiz, Coro; Desai, Shrinivas; Munshi, Mihir; Sanghvi, Darshana; Hardy, John; Bhatia, Kailash P; Bhatt, Mohit

    2010-07-30

    Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype-genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation.

  4. Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes*

    PubMed Central

    Larimore, Jennifer; Zlatic, Stephanie A.; Gokhale, Avanti; Tornieri, Karine; Singleton, Kaela S.; Mullin, Ariana P.; Tang, Junxia; Talbot, Konrad; Faundez, Victor

    2014-01-01

    Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5mu/mu) and dysbindin (Bloc1s8sdy/sdy). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5mu/mu and Bloc1s8sdy/sdy mice. Unlike Bloc1s8sdy/sdy, elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders. PMID:24713699

  5. Complexity of the Class B Phenotype in Autosomal Dominant Retinitis Pigmentosa Due to Rhodopsin Mutations

    PubMed Central

    Jacobson, Samuel G.; McGuigan, David B.; Sumaroka, Alexander; Roman, Alejandro J.; Gruzensky, Michaela L.; Sheplock, Rebecca; Palma, Judy; Schwartz, Sharon B.; Aleman, Tomas S.; Cideciyan, Artur V.

    2016-01-01

    Purpose Previously, patients with RHO mutations and a class A phenotype were found to have severe early-onset loss of rod function, whereas patients with a class B phenotype retained rod function at least in certain retinal regions. Here class B patients were studied at different disease stages to understand the topographic details of the phenotype in preparation for therapies of this regionalized retinopathy. Methods A cohort of patients with RHO mutations and class B phenotype (n = 28; ages 10–80 years) were studied with rod and cone perimetry and optical coherence tomography (OCT). Results At least three components of the phenotype were identified in these cross-sectional studies. Patients could have hemifield dysfunction, pericentral loss of function, or a diffuse rod sensitivity loss across the visual field. Combinations of these different patterns were also found. Colocalized photoreceptor layer thicknesses were in agreement with the psychophysical results. Conclusions These disorders with regional retinal variation of severity require pre-evaluations before enrollment into clinical trials to seek answers to questions about where in the retina would be appropriate to deliver focal treatments, and, for retina-wide treatment strategies, where in the retina should be monitored for therapeutic efficacy (or safety). PMID:27654411

  6. Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

    PubMed

    Parenti, Ilaria; Teresa-Rodrigo, María E; Pozojevic, Jelena; Ruiz Gil, Sara; Bader, Ingrid; Braunholz, Diana; Bramswig, Nuria C; Gervasini, Cristina; Larizza, Lidia; Pfeiffer, Lutz; Ozkinay, Ferda; Ramos, Feliciano; Reiz, Benedikt; Rittinger, Olaf; Strom, Tim M; Watrin, Erwan; Wendt, Kerstin; Wieczorek, Dagmar; Wollnik, Bernd; Baquero-Montoya, Carolina; Pié, Juan; Deardorff, Matthew A; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J

    2017-03-01

    The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin-Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.

  7. Mutation in collagen II alpha 1 isoforms delineates Stickler and Wagner syndrome phenotypes

    PubMed Central

    Tran-Viet, Khanh-Nhat; Soler, Vincent; Quiette, Valencia; Powell, Caldwell; Yanovitch, Tammy; Metlapally, Ravikanth; Luo, Xiaoyan; Katsanis, Nicholas; Nading, Erica

    2013-01-01

    Purpose Stickler syndrome is an arthro-ophthalmopathy with phenotypic overlap with Wagner syndrome. The common Stickler syndrome type I is inherited as an autosomal dominant trait, with causal mutations in collagen type II alpha 1 (COL2A1). Wagner syndrome is associated with mutations in versican (VCAN), which encodes for a chondroitin sulfate proteoglycan. A three-generation Caucasian family variably diagnosed with either syndrome was screened for sequence variants in the COL2A1 and VCAN genes. Methods Genomic DNA samples derived from saliva were collected from all family members (six affected and four unaffected individuals). Complete sequencing of COL2A1 and VCAN was performed on two affected individuals. Direct sequencing of remaining family members was conducted if the discovered variants followed segregation. Results A base-pair substitution (c.258C>A) in exon 2 of COL2A1 cosegregated with familial disease status. This known mutation occurs in a highly conserved site that causes a premature stop codon (p.C86X). The mutation was not seen in 1,142 ethnically matched control DNA samples. Conclusions Premature stop codons in COL2A1 exon 2 lead to a Stickler syndrome type I ocular-only phenotype with few or no systemic manifestations. Mutation screening of COL2A1 exon 2 in families with autosomal dominant vitreoretinopathy is important for accurate clinical diagnosis. PMID:23592912

  8. Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation.

    PubMed

    Spivak, Jerry L

    2010-03-02

    The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.

  9. Marfan syndrome: ocular findings and novel mutations-in pursuit of genotype-phenotype associations.

    PubMed

    Latasiewicz, Marta; Fontecilla, Christian; Millá, Elena; Sánchez, Aurora

    2016-04-01

    To analyze ocular involvement in patients diagnosed with Marfan syndrome (MFS), study their clinical findings and prognosis based on the type of FBN1 mutation, and evaluate possible genotype-phenotype correlations. Observational single-centre case series. Eleven patients diagnosed with MFS were included. All subjects met the Ghent criteria of MFS, the diagnosis was confirmed by genetic testing. All subjects underwent a complete ophthalmologic examination. We evaluated clinical data, the incidence of ectopia lentis (EL), and other eye disorders. The association of ocular signs with the type of mutation was analyzed. Four of the 11 patients had EL, of which 3 developed secondary glaucoma, and 62.5% of the phakic patients had myopia. Other ocular abnormalities included strabismus, retinal tears, retinal detachment, and amblyopia. The encountered types of mutations were premature termination codon (PTC) in 7 patients, missense in 2 cases, 1 aberration of splicing, and 1 indel mutation. Two novel mutations were found. Of the patients with EL, 2 had a missense, 1 an indel, and 1 a nonsense mutation. Myopia was the most frequent ocular involvement. Patients with a PTC mutation revealed to have a smaller risk of EL; however, more studies are required to indicate the mechanism of the correlation. Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

  10. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation.

    PubMed

    Fishbein, Ianai; Kuo, Yien-Ming; Giasson, Benoit I; Nussbaum, Robert L

    2014-12-01

    The involvement of the protein α-synuclein (SNCA) in the pathogenesis of Parkinson's disease is strongly supported by the facts that (i) missense and copy number mutations in the SNCA gene can cause inherited Parkinson's disease; and (ii) Lewy bodies in sporadic Parkinson's disease are largely composed of aggregated SNCA. Unaffected heterozygous carriers of Gaucher disease mutations have an increased risk for Parkinson's disease. As mutations in the GBA gene encoding glucocerebrosidase (GBA) are known to interfere with lysosomal protein degradation, GBA heterozygotes may demonstrate reduced lysosomal SNCA degradation, leading to increased steady-state SNCA levels and promoting its aggregation. We have created mouse models to investigate the interaction between GBA mutations and synucleinopathies. We investigated the rate of SNCA degradation in cultured primary cortical neurons from mice expressing wild-type mouse SNCA, wild-type human SNCA, or mutant A53T SNCA, in a background of either wild-type Gba or heterozygosity for the L444P GBA mutation associated with Gaucher disease. We also tested the effect of this Gaucher mutation on motor and enteric nervous system function in these transgenic animals. We found that human SNCA is stable, with a half-life of 61 h, and that the A53T mutation did not significantly affect its half-life. Heterozygosity for a naturally occurring Gaucher mutation, L444P, reduced GBA activity by 40%, reduced SNCA degradation and triggered accumulation of the protein in culture. This mutation also resulted in the exacerbation of motor and gastrointestinal deficits found in the A53T mouse model of Parkinson's disease. This study demonstrates that heterozygosity for a Gaucher disease-associated mutation in Gba interferes with SNCA degradation and contributes to its accumulation, and exacerbates the phenotype in a mouse model of Parkinson's disease.

  11. A novel mutation in ABCD1 unveils different clinical phenotypes in a family with adrenoleukodystrophy.

    PubMed

    Margoni, M; Soli, F; Sangalli, A; Bellizzi, M; Cecchini, E; Buganza, M

    2017-09-01

    X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is the consequence of mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids. We describe a family with six members carrying a novel heterozygous mutation IVS4+2T>A (c.1393+2T>A) of the ABCD1 gene, highlighting the wide range of phenotypic manifestations of ALD and the importance of genetic screening before any pregnancy in asymptomatic women whose carrier status is unknown. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype

    PubMed Central

    Simunovic, Matthew P.; Jolly, Jasleen K.; Xue, Kanmin; Edwards, Thomas L.; Groppe, Markus; Downes, Susan M.; MacLaren, Robert E.

    2016-01-01

    Purpose We report the underlying genotype and explore possible genotypic-phenotypic correlations in a large cohort of choroideremia patients. Methods We studied prospectively a cohort of 79 patients diagnosed within a tertiary referral service for patients with retinal dystrophies. Phenotypic evaluation consisted of clinical examination, including visual acuity and residual retinal area by fundus autofluorescence (FAF). Genotype was established by sequencing. We also investigated whether particular genotypes were associated with more severe phenotypes by performing analysis of covariance (ANCOVA), with visual acuity and FAF as the dependent variables and age as the covariant. Results A total of 74 (94%) of patients in our cohort had causative mutations by sequencing, the majority of which were anticipated to be null. Of these, 35 (47%) had insertions and deletions, 13 (18%) had mutations predicted to affect splicing, and 26 (35%) had single point mutations. In the latter case, 13 of 21 (62%) pedigrees with single point mutations were C to T transitions at C-phosphate-G (CpG) dinucleotides. These mutations were spread across 5 of only 24 CpG dinucleotides in the entire CHM cDNA. Furthermore, these 5 locations are the only sites at which C to T transitions result in a stop codon. No clear evidence was found for genotype–phenotype correlation except in the instance of a patient with a large deletion involving neighbouring sequences. Conclusions In patients with a diagnosis of choroideremia made by a specialty service, there is a high likelihood of establishing a genetic diagnosis. The majority of causative mutations appear to be null and, therefore, may benefit from gene replacement therapy. A disproportionate number of single point mutations observed were C to T transitions, consistent with the evolutionary decay of CpG dinucleotides through methylation and subsequent deamination. Hence, the development of choroideremia in such patients may represent the unwanted

  13. Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype.

    PubMed

    Santos-Silva, Rita; Passas, Armanda; Rocha, Carla; Figueiredo, Rita; Mendes-Ribeiro, Jose; Fernandes, Susana; Biskup, Saskia; Leão, Miguel

    2015-04-01

    Loss of function of GPR56 causes a specific brain malformation called the bilateral frontoparietal polymicrogyria (BFPP), which has typical clinical and neuroradiological findings. So far, 35 families and 26 independent mutations have been described.We present a Portuguese 5-year-old boy, born from nonconsanguineous parents, with BFPP. This patient has a novel GPR56 mutation (R271X) and an unusual phenotype, because he presents hot water epilepsy.To the best of our knowledge, this is the first reported case of BFPP evolving hot water epilepsy.

  14. A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance.

    PubMed

    Khattab, Ahmed; Yuen, Tony; Al-Malki, Sultan; Yau, Mabel; Kazmi, Diya; Sun, Li; Harbison, Madeleine; Haider, Shozeb; Zaidi, Mone; New, Maria I

    2016-01-01

    Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and nonclassical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype-phenotype nonconcordance. We aimed to study the genotype-phenotype nonconcordance in a family with three siblings affected with nonclassical CAH. All had hormonal evidence of nonclassical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three siblings a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with nonclassical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype-phenotype nonconcordance is observed in patients with autosomal recessive monogenic disorders, including CAH.

  15. Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.

    PubMed

    Tanaka, A; Lai-Cheong, J E; Café, M E M; Gontijo, B; Salomão, P R; Pereira, L; McGrath, J A

    2009-03-01

    Inherited mutations in components of desmosomes result in a spectrum of syndromes characterized by variable abnormalities in the skin and its appendages, including blisters and erosions, palmoplantar hyperkeratosis, woolly hair or hypotrichosis and, in some cases, extracutaneous features such as cardiomyopathy. We investigated the molecular basis of two Brazilian patients presenting with clinical features consistent with ectodermal dysplasia-skin fragility syndrome. In patient 1 we identified a homozygous nonsense mutation, p.R672X, in the PKP1 gene (encoding plakophilin 1). This particular mutation has not been reported previously but is similar to the molecular pathology underlying other cases of this syndrome. In patient 2 we found compound heterozygosity for two frameshift mutations, c.2516del4 and c.3971del4, in the DSP gene (encoding desmoplakin). Although there was considerable clinical overlap in the skin and hair abnormalities in these two cases, patient 2 also had early-onset cardiomyopathy. The mutation c.3971del4 occurs in the longer desmoplakin-I isoform (which is the major cardiac transcript) but not in the more ubiquitous desmoplakin-II. In contrast, PKP1 is not expressed in the heart, which accounts for the lack of cardiomyopathy in patient 1. Collectively, these cases represent the first desmosomal genodermatoses to be reported from Brazil and add to genotype-phenotype correlation in this group of inherited disorders. Loss-of-function mutations in the DSP gene can result in a phenotype similar to ectodermal dysplasia-skin fragility syndrome resulting from PKP1 mutations but only DSP pathology is associated with cardiac disease.

  16. Clinical characteristics and genotype-phenotype correlation of hearing loss patients with SLC26A4 mutations.

    PubMed

    Suzuki, Hiroaki; Oshima, Aki; Tsukamoto, Koji; Abe, Satoko; Kumakawa, Kozo; Nagai, Kyoko; Satoh, Hitoshi; Kanda, Yukihiko; Iwasaki, Satoshi; Usami, Shin-ichi

    2007-12-01

    The present study confirmed the clinical characteristics of patients with SLC26A4 mutations: congenital, fluctuating, and progressive hearing loss usually associated with vertigo and/or goiter during long-term follow-up. This clarification should help to facilitate appropriate genetic counseling and proper medical management for patients with these mutations, but there was no particular genotype-phenotype correlation among them, suggesting that other factors may contribute to such variability. Due to the wide range of phenotypes caused by SLC26A4 mutations, there is controversy with regard to genotype-phenotype correlation. The present study was performed: (1) to determine phenotypic range in patients with biallelic SLC26A4 mutations, and (2) to evaluate whether possible genotype-phenotype correlation exists. Phenotypes in 39 hearing loss patients with SLC26A4 mutations were summarized and genotype-phenotype correlation was analyzed. Hearing level varied in the individuals from mild to profound severity. Most of the patients had fluctuating and progressive hearing loss that may have been of prelingual onset. Twenty-four (70.6%) patients had episodes of vertigo, and 10 (27.8%) patients had goiter, which had appeared at age 12 or older. In contrast to such phenotypic variabilities, no apparent correlation was found between these phenotypes and their genotypes.

  17. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients.

    PubMed

    Choi, B-O; Nakhro, K; Park, H J; Hyun, Y S; Lee, J H; Kanwal, S; Jung, S-C; Chung, K W

    2015-06-01

    Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy.

  18. The tRNA-Tyr gene family of Saccharomyces cerevisiae: agents of phenotypic variation and position effects on mutation frequency.

    PubMed Central

    Ito-Harashima, Sayoko; Hartzog, Phillip E; Sinha, Himanshu; McCusker, John H

    2002-01-01

    Extensive phenotypic diversity or variation exists in clonal populations of microorganisms and is thought to play a role in adaptation to novel environments. This phenotypic variation or instability, which occurs by multiple mechanisms, may be a form of cellular differentiation and a stochastic means for modulating gene expression. This work dissects a case of phenotypic variation in a clinically derived Saccharomyces cerevisiae strain involving a cox15 ochre mutation, which acts as a reporter. The ochre mutation reverts to sense at a low frequency while tRNA-Tyr ochre suppressors (SUP-o) arise at a very high frequency to produce this phenotypic variation. The SUP-o mutations are highly pleiotropic. In addition, although all SUP-o mutations within the eight-member tRNA-Tyr gene family suppress the ochre mutation reporter, there are considerable phenotypic differences among the different SUP-o mutants. Finally, and of particular interest, there is a strong position effect on mutation frequency within the eight-member tRNA-Tyr gene family, with one locus, SUP6, mutating at a much higher than average frequency and two other loci, SUP2 and SUP8, mutating at much lower than average frequencies. Mechanisms for the position effect on mutation frequency are evaluated. PMID:12196388

  19. Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation.

    PubMed

    McCue, M E; Valberg, S J; Jackson, M; Borgia, L; Lucio, M; Mickelson, J R

    2009-01-01

    In this study we examined a family of Quarter Horses with Polysaccharide Storage Myopathy (PSSM) with a dominant mutation in the skeletal muscle glycogen synthase (GYS1) gene. A subset of horses within this family had a more severe and occasionally fatal PSSM phenotype. The purpose of this study was to identify a modifying gene(s) for the severe clinical phenotype. A genetic association analysis was used to identify RYR1 as a candidate modifying gene. A rare, known equine RYR1 mutation, associated with malignant hyperthermia (MH), was found to segregate in this GYS1 PSSM family. Retrospective analysis of patient records (n=179) demonstrated that horses with both the GYS1 and RYR1 mutations had a more severe clinical phenotype than horses with the GYS1 mutation alone. A treadmill trial (n=8) showed that serum creatine kinase activity was higher and exercise intolerance greater in horses with both mutations compared to the GYS1 mutation alone.

  20. Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations.

    PubMed

    Arredondo, Juan; Lara, Marian; Gospe, Sídney M; Mazia, Claudio G; Vaccarezza, Maria; Garcia-Erro, Marcela; Bowe, Constance M; Chang, Celia H; Mezei, Michelle M; Maselli, Ricardo A

    2015-09-01

    Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype-phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of phosphorylated ChAT of seven CHAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys, and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal stability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp, and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met, which is located far from both active and substrate-binding sites, produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes.

  1. Choline acetyltransferase mutations causing congenital myasthenic syndrome: molecular findings and genotype-phenotype correlations

    PubMed Central

    Arredondo, Juan; Lara, Marian; Gospe, Sídney M.; Mazia, Claudio G.; Vaccarezza, Maria; Garcia-Erro, Marcela; Bowe, Constance; Chang, Celia; Mezei, Michelle; Maselli, Ricardo A.

    2015-01-01

    Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome (CMS) due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype–phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of seven ChAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal instability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met is located far from both active and substrate-binding sites produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes. PMID:26080897

  2. Cloning of the neurodegeneration gene drop-dead and characterization of additional phenotypes of its mutation.

    PubMed

    Blumenthal, Edward M

    2008-01-01

    Mutations in the Drosophila gene drop-dead (drd) result in early adult lethality and neurodegeneration, but the molecular identity of the drd gene and its mechanism of action are not known. This paper describes the characterization of a new X-linked recessive adult-lethal mutation, originally called lot's wife (lwf(1)) but subsequently identified as an allele of drd (drd(lwf)); drd(lwf) mutants die within two weeks of eclosion. Through mapping and complementation, the drd gene has been identified as CG33968, which encodes a putative integral membrane protein of unknown function. The drd(lwf) allele is associated with a nonsense mutation that eliminates nearly 80% of the CG33968 gene product; mutations in the same gene were also found in two previously described drd alleles. Characterization of drd (lwf) flies revealed additional phenotypes of drd, most notably, defects in food processing by the digestive system and in oogenesis. Mutant flies store significantly more food in their crops and defecate less than wild-type flies, suggesting that normal transfer of ingested food from the crop into the midgut is dependent upon the DRD gene product. The defect in oogenesis results in the sterility of homozygous mutant females and is associated with a reduction in the number of vitellogenic egg chambers. The disruption in vitellogenesis is far more severe than that seen in starved flies and so is unlikely to be a secondary consequence of the digestive phenotype. This study demonstrates that mutation of the drd gene CG33968 results in a complex phenotype affecting multiple physiological systems within the fly.

  3. The Phenotypic Spectrum of DYT24 Due to ANO3 Mutations

    PubMed Central

    Stamelou, Maria; Charlesworth, Gavin; Cordivari, Carla; Schneider, Susanne A; Kägi, Georg; Sheerin, Una-Marie; Rubio-Agusti, Ignacio; Batla, Amit; Houlden, Henry; Wood, Nicholas W; Bhatia, Kailash P

    2014-01-01

    Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations. © 2014 The Authors. Movement Disorders published by International Parkinson and Movement Disorder Society PMID:24442708

  4. Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans.

    PubMed

    Pang, Xiuhong; Chai, Yongchuan; Sun, Lianhua; Chen, Dongye; Chen, Ying; Zhang, Zhihua; Wu, Hao; Yang, Tao

    2014-01-01

    Dominant mutations in GJB2 may lead to various degrees of sensorineural hearing impairment and/or hyperproliferative epidermal disorders. So far studies of dominant GJB2 mutations were mostly limited to case reports of individual patients and families. In this study, we identified 7 families, 11 subjects with dominant GJB2 mutations by sequencing of GJB2 in 2168 Chinese Han probands with sensorineural hearing impairment and characterized the associated spectrum, de novo rate and genotype-phenotype correlation. We identified p.R75Q, p.R75W and p.R184Q as the most frequent dominant GJB2 mutations among Chinese Hans, which had a very high de novo rate (71% of probands). A majority (10/11) of subjects carrying dominant GJB2 mutations exhibited palmoplantar keratoderma in addition to hearing impairment. In two families segregated with additional c.235delC or p.V37I mutations of GJB2, family members with the compound heterozygous mutations exhibited more severe phenotype than those with single dominant GJB2 mutation. Our study suggested that the high de novo mutation rate gives rise to a significant portion of dominant GJB2 mutations. The severity of the hearing and epidermal phenotypes associated with dominant GJB2 mutations may be modified by additional recessive mutations of GJB2.

  5. Novel KRT14 mutation causing epidermolysis bullosa simplex with variable phenotype.

    PubMed

    Jankowski, Marek; Wertheim-Tysarowska, Katarzyna; Jakubowski, Rafal; Sota, Justyna; Nowak, Wieslaw; Czajkowski, Rafal

    2014-09-01

    About 75% of cases of epidermolysis bullosa simplex result from mutations in KRT5 and KRT14 genes. Here, we report a family with a novel heterozygous missense mutation p.Leu418Gln in the KRT14 gene causing EBS of phenotype varying from EBS-loc to EBS-gen intermed. To the best of our knowledge, the family reported by us is the largest one in which two different phenotypes can be distinguished. The molecular dynamics simulations show that p.Leu418Gln mutation results in clear disruption of intermolecular π-stacking between KRT14:Tyr415 and KRT5:Tyr470, which in turn may affect putative phosphorylation site at KRT14:Thr414. This study further supports the importance of the EIATYR/KLLEGE motif in maintaining structural stability of KRT14:KRT5 heterodimer and indicates that physical properties of introduced amino acid can modulate the disease severity. The results obtained indicate further need of genotype-phenotype studies in EBS. In conclusion, genotype-based prognosis should be given to patients with caution. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?

    PubMed

    Elsaid, M F; Chalhoub, N; Kamel, H; Ehlayel, M; Ibrahim, N; Elsaid, A; Kumar, P; Khalak, H; Ilyin, V A; Suhre, K; Abdel Aleem, A

    2016-02-01

    We present a Qatari family with two children who displayed a characteristic phenotype of congenital marked pain insensitivity with hypohidrosis and progressive aseptic destruction of joints and vertebrae resembling that of hereditary sensory and autonomic neuropathies (HSANs). The patients, aged 10 and 14, remained of uncertain genetic diagnosis until whole genome sequencing was pursued. Genome sequencing identified a novel homozygous C65S mutation in the LIFR gene that is predicted to markedly destabilize and alter the structure of a particular domain and consequently to affect the functionality of the whole multi-domain LIFR protein. The C65S mutant LIFR showed altered glycosylation and an elevated expression level that might be attributed to a slow turnover of the mutant form. LIFR mutations have been reported in Stüve-Wiedemann syndrome (SWS), a severe autosomal recessive skeletal dysplasia often resulting in early death. Our patients share some clinical features of rare cases of SWS long-term survivors; however, they also phenocopy HSAN due to the marked pain insensitivity phenotype and progressive bone destruction. Screening for LIFR mutations might be warranted in genetically unresolved HSAN phenotypes.

  7. Phenotypic Variability of Osteogenesis Imperfecta Type V Caused by an IFITM5 Mutation

    PubMed Central

    Shapiro, Jay R; Lietman, Caressa; Grover, Monica; Lu, James T; Nagamani, Sandesh CS; Dawson, Brian C; Baldridge, Dustin M; Bainbridge, Matthew N; Cohn, Dan H; Blazo, Maria; Roberts, Timothy T; Brennen, Feng-Shu; Wu, Yimei; Gibbs, Richard A; Melvin, Pamela; Campeau, Philippe M; Lee, Brendan H

    2013-01-01

    In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation. PMID:23408678

  8. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

    PubMed Central

    Travaglini, Lorena; Brancati, Francesco; Silhavy, Jennifer; Iannicelli, Miriam; Nickerson, Elizabeth; Elkhartoufi, Nadia; Scott, Eric; Spencer, Emily; Gabriel, Stacey; Thomas, Sophie; Ben-Zeev, Bruria; Bertini, Enrico; Boltshauser, Eugen; Chaouch, Malika; Roberta Cilio, Maria; de Jong, Mirjam M; Kayserili, Hulya; Ogur, Gonul; Poretti, Andrea; Signorini, Sabrina; Uziel, Graziella; Zaki, Maha S; Johnson, Colin; Attié-Bitach, Tania; Gleeson, Joseph G; Valente, Enza Maria

    2013-01-01

    Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus. PMID:23386033

  9. ADAMTSL4-associated isolated ectopia lentis: Further patients, novel mutations and a detailed phenotype description.

    PubMed

    Neuhann, Teresa M; Stegerer, Annette; Riess, Angelika; Blair, Edward; Martin, Thomas; Wieser, Stefanie; Kläs, Rüdiger; Bouman, Arjan; Kuechler, Alma; Rittinger, Olaf

    2015-10-01

    ADAMTSL4 mutations seem to be the most common cause of isolated ectoplia lentis (EL) and thus are important concerning the differential diagnosis of connective tissue syndromes with EL as main feature. In this study, we describe an additional cohort of patients with apparently isolated EL. All underwent a detailed clinical exam with cardiac evaluation combined with ADAMTSL4 mutation analysis. Mutations were identified in 12/15 patients with EL. Besides the European founder mutation p. (Gln256Profs*38) we identified five further mutations not yet described in the literature: p. (Leu249Tyrfs*21), p. (Ala388Glyfs*8), p. (Arg746His), p. (Gly592Ser), and p. (Arg865His). Clinical evaluation showed common additional ocular features such as high myopia, but no major systemic findings. In particular: no dilatation of the aortic root was reported on. This report increases the total number of patients with ADAMTSL4 mutations reported on today and reviews in detail the clinical findings in all patients reported on to date demonstrate, that these patients have a mainly ocular phenotype. There are no consistent systemic findings. The differentiation between syndromic and isolated EL is crucial for the further surveillance, treatment, and counseling of these patients, especially in young children.

  10. SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype.

    PubMed

    Bugiardini, E; Rivolta, I; Binda, A; Soriano Caminero, A; Cirillo, F; Cinti, A; Giovannoni, R; Botta, A; Cardani, R; Wicklund, M P; Meola, G

    2015-04-01

    In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (CLCN1) mutations. No DM2 cases have been described with sodium channel gene (SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5 mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.

  11. Intra-familiar discordant PKU phenotype explained by mutation analysis in three pedigrees.

    PubMed

    Trunzo, Roberta; Santacroce, Rosa; D'Andrea, Giovanna; Longo, Vittoria; De Girolamo, Giuseppe; Dimatteo, Claudia; Leccese, Angelica; Lillo, Vincenza; Papadia, Francesco; Margaglione, Maurizio

    2014-02-01

    Classical phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are two phenotypes of phenylalanine hydroxylase (PAH) deficiency with different degrees of severity. We have analyzed three families in which classical PKU, MHP and a normal phenotype occurred within each family due to the different combinations of three mutations segregating within the family. Indeed, sequence PAH analysis revealed three different alleles segregating in each family. This report suggests that when discordant phenotypes occur in a family, complete analysis of the PAH gene may be performed in order to support the diagnosis and assist in accurate genetic counseling and patient management. We further support the marked heterogeneity of hyperphenylalaninemia primarily due to allelic heterogeneity at the PAH locus. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  12. WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype.

    PubMed

    Bacino, Carlos A; Dhar, Shweta U; Brunetti-Pierri, Nicola; Lee, Brendan; Bonnen, Penelope E

    2012-11-01

    Sensenbrenner syndrome and unclassified short rib-polydactyly conditions are ciliopathies with overlapping phenotypes and genetic heterogeneity. Mutations in WDR35 were identified recently in a sub-group of patients with Sensenbrenner syndrome and in a single family that presented with an unclassified form of short-rib polydactyly (SRP) syndrome. We report on siblings with an unusual combination of phenotypes: narrow thorax, short stature, minor anomalies, developmental delay, and severe hepatic fibrosis leading to liver failure and early death in two of the children. Both parents were unaffected suggesting autosomal recessive inheritance. The family and their affected children were followed over a decade. Exome sequencing was performed in one affected individual. It showed a homozygous missense mutation in a highly conserved position of the WDR35 gene. This family represents a WDR35-ciliopathy with a complex clinical presentation that includes significant overlap of the phenotypes described in Sensenbrenner syndrome and the unclassified SRPs. The accurate molecular diagnosis of this family exemplifies the power of exome sequencing in the diagnosis of Mendelian disorders and enabled us to broaden and refine our understanding of Sensenbrenner syndrome and SRP. Detailed genotype-phenotype information is provided as well as discussion of previously reported cases. Copyright © 2012 Wiley Periodicals, Inc.

  13. Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation.

    PubMed

    Feben, Candice; Kromberg, Jennifer; Wainwright, Rosalind; Stones, David; Sutton, Chris; Poole, Janet; Haw, Tabitha; Krause, Amanda

    2014-05-01

    Fanconi anemia is a genotypically and phenotypically heterogeneous condition, characterized microscopically by chromosomal instability and breakage. Affected individuals manifest growth restriction and congenital physical abnormalities; most progress to hematological disease including bone marrow aplasia. Black South African Fanconi anemia patients share a common causative founder mutation in the Fanconi G gene in 80% of cases (637_643delTACCGCC). The aim of this study was to investigate the genotype-physical phenotype correlation in a cohort of individuals homozygous for this mutation. Thirty-five black patients were recruited from tertiary level hematology/oncology clinics in South Africa. Participants were subjected to a comprehensive clinical examination, documenting growth, congenital anomalies, and phenotypic variability. Descriptive statistical analysis showed significant growth abnormalities in many patients and a high frequency (97%) of skin pigmentary anomalies. Subtle anomalies of the eyes, ears, and hands occurred frequently (≥70%). Apart from malformations of the kidney (in 37%) and gastrointestinal tract (in 8.5%), congenital anomalies of other systems including the cardiovascular and central nervous systems, genitalia, and vertebrae were infrequent (<5%). The diagnosis of Fanconi anemia in black South African patients before the onset of hematological symptoms remains a clinical challenge, with the physical phenotype unlikely to be recognized by those without dysmorphology expertise.

  14. Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

    PubMed Central

    Faivre, L. ; Collod-Beroud, G. ; Loeys, B. L. ; Child, A. ; Binquet, C. ; Gautier, E. ; Callewaert, B. ; Arbustini, E. ; Mayer, K. ; Arslan-Kirchner, M. ; Kiotsekoglou, A. ; Comeglio, P. ; Marziliano, N. ; Dietz, H. C. ; Halliday, D. ; Beroud, C. ; Bonithon-Kopp, C. ; Claustres, M. ; Muti, C. ; Plauchu, H. ; Robinson, P. N. ; Adès, L. C. ; Biggin, A. ; Benetts, B. ; Brett, M. ; Holman, K. J. ; De Backer, J. ; Coucke, P. ; Francke, U. ; De Paepe, A. ; Jondeau, G. ; Boileau, C. 

    2007-01-01

    Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24–32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGFβ signalling). Exon 24–32 mutations define a high-risk group for cardiac manifestations associated with

  15. PCR assay confirms diagnosis in syndrome with variably expressed phenotype: mutation detection in Stickler syndrome.

    PubMed Central

    Ahmad, N N; McDonald-McGinn, D M; Dixon, P; Zackai, E H; Tasman, W S

    1996-01-01

    Stickler syndrome is an autosomal dominant disease with ocular (severe myopia, vitreal degeneration, and retinal detachment) and other systemic manifestations (hearing loss, cleft palate, epiphyseal dysplasia, and premature osteoarthritis). As with other dominantly inherited conditions, the clinical phenotype of Stickler syndrome varies considerably. To date, all mutations have been located in the type II procollagen (COL2A1) gene. Analysis of a C-->T mutation we had identified previously, in COL2A1 gene in exon 40, in a three generation pedigree showed the loss of a cleavage site for the TaqI restriction enzyme. We designed a rapid PCR based restriction enzyme assay to detect this mutation and used it to establish the diagnosis in a neonate from the same pedigree, presenting with the first occurrence of the Pierre-Robin sequence in the family and minimal ocular findings. These results underline the potential diagnostic value of many as yet undetected DNA mutations in families affected with Stickler syndrome, since the variability of the phenotype can impede accurate diagnosis, appropriate genetic counselling, and effective intervention and prophylactic treatment for affected people. Images PMID:8863161

  16. Phenotypic spectrum of alpha-synuclein mutations: New insights from patients and cellular models.

    PubMed

    Petrucci, Simona; Ginevrino, Monia; Valente, Enza Maria

    2016-01-01

    The identification of the p.A53T mutation in the SNCA gene encoding alpha-synuclein (alpha-syn), as causative of autosomal dominant Parkinson disease (PD) represented a fundamental milestone, which paved the way to the extremely prolific field of PD genetics. Despite being the oldest player in this field and only a rare cause of inherited PD, research on alpha-syn has remained incredibly active over nearly twenty decades, leading to identify alpha-syn aggregation as a key mechanism in PD pathogenesis. The past two years have witnessed new exciting findings, with the discovery of at least three novel pathogenic mutations (p.H50Q, p.G51D and p.A53E) causative of complex parkinsonian phenotypes, and the identification of additional patients carrying "old" SNCA mutations (p.A53T, p.A30P, p.E46K and whole gene multiplications), which has allowed to further expand their phenotypic spectrum. This review aims at providing a clinical and functional update on the most recent findings in alpha-syn genetics, at the same time discussing novel avenues of SNCA research such as those on somatic mutations and epigenetic mechanisms. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

    PubMed Central

    Buonocore, Federica; Kühnen, Peter; Suntharalingham, Jenifer P.; Del Valle, Ignacio; Digweed, Martin; Khajavi, Noushafarin; Didi, Mohammed; Brady, Angela F.; Procter, Annie M.; Dimitri, Paul; Wales, Jerry K.H.; Ghirri, Paolo; Knöbl, Dieter; Strahm, Brigitte; Erlacher, Miriam; Wlodarski, Marcin W.; Chen, Wei; Kokai, George K.; Anderson, Glenn; Morrogh, Deborah; Moulding, Dale A.; McKee, Shane A.; Niemeyer, Charlotte M.; Grüters, Annette; Achermann, John C.

    2017-01-01

    It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized. PMID:28346228

  18. A mouse kidney cell line with a G:C --> C:G transversion mutator phenotype.

    PubMed

    Shin, Chi Y; Ponomareva, Olga N; Connolly, Lanelle; Turker, Mitchell S

    2002-06-19

    We report the identification of a mouse kidney epithelial cell line (K435) in which G:C-->C:G transversion mutations occur at an elevated rate and are the predominant spontaneous events observed at the selectable Aprt locus. Of three genotoxins tested, ultraviolet radiation (UV), ionizing radiation, and hydrogen peroxide, only UV exposure was able to alter the spectrum of small mutational events. To determine if the G:C-->C:G mutator phenotype was due to a deficiency in the mismatch repair pathway, the K435 cells were tested for resistance to 6-thioguanine, cisplatin, and MNNG. Although the K435 cells were as resistant to 6-thioguanine and cisplatin as Pms2 and Mlh1 null kidney cells, they were hypersensitive to MNNG. Moreover, the K435 cells do not exhibit microsatellite instability, a hallmark of mismatch repair deficiency. These results suggest that a novel mechanism, which does not include a classical deficiency in mismatch repair, accounts for the G:C-->C:G mutator phenotype.

  19. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.

    PubMed

    Alder, Jonathan K; Parry, Erin M; Yegnasubramanian, Srinivasan; Wagner, Christa L; Lieblich, Lawrence M; Auerbach, Robert; Auerbach, Arleen D; Wheelan, Sarah J; Armanios, Mary

    2013-11-01

    Dyskeratosis congenita (DC) is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity.

  20. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene

    PubMed Central

    Alder, Jonathan K.; Parry, Erin M.; Yegnasubramanian, Srinivasan; Wagner, Christa L.; Lieblich, Lawrence M.; Auerbach, Robert; Auerbach, Arleen D.; Wheelan, Sarah J.; Armanios, Mary

    2013-01-01

    Dyskeratosis congenita is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of dyskeratosis congenita, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing telomere phenotypes that, at times, may be associated with clinical morbidity. PMID:23946118

  1. CASE REPORT: Phenotypic presentation of the Ser63Del MPZ mutation

    PubMed Central

    Miller, Lindsey J.; Patzko, Agnes; Lewis, Richard A.; Shy, Michael E.

    2013-01-01

    Mutations in MPZ cause CMT1B, the second most frequent cause of CMT1. Elegant studies with Ser63del mice suggest that Ser63del MPZ is retained in the ER where it activates the unfolded protein response (UPR) that contributes to the neuropathy. Clinical information about patients with this mutation is limited. We present clinical and electrophysiological data on a large multigenerational family with CMT1B caused by Ser63del MPZ. The patients have a classical CMT1 phenotype that is much less severe than that of patients with Arg98Cys MPZ that also activates the UPR. These results suggest that clinical presentation along cannot predict which MPZ mutations will be retained in the ER and activate the UPR. PMID:22734905

  2. Single Synonymous Mutations in KRAS Cause Transformed Phenotypes in NIH3T3 Cells

    PubMed Central

    Waters, Andrew M.; Bagni, Rachel; Portugal, Franklin; Hartley, James L.

    2016-01-01

    Synonymous mutations in the KRAS gene are clustered at G12, G13, and G60 in human cancers. We constructed 9 stable NIH3T3 cell lines expressing KRAS, each with one of these synonymous mutations. Compared to the negative control cell line expressing the wild type human KRAS gene, all the synonymous mutant lines expressed more KRAS protein, grew more rapidly and to higher densities, and were more invasive in multiple assays. Three of the cell lines showed dramatic loss of contact inhibition, were more refractile under phase contrast, and their refractility was greatly reduced by treatment with trametinib. Codon usage at these glycines is highly conserved in KRAS compared to HRAS, indicating selective pressure. These transformed phenotypes suggest that synonymous mutations found in driver genes such as KRAS may play a role in human cancers. PMID:27684555

  3. Four novel point mutations in the PMP22 gene with phenotypes of HNPP and Dejerine-Sottas neuropathy.

    PubMed

    Brožková, Dana; Mazanec, Radim; Rychlý, Zdeněk; Haberlová, Jana; Böhm, Jiří; Staněk, Jan; Plevová, Pavlína; Lisoňová, Jana; Sabová, Jana; Sakmaryová, Iva; Seeman, Pavel

    2011-11-01

    We report four novel point mutations in the PMP22 gene with two different phenotypes: mutation p.Ser79Thr arose de novo in a patient with the Dejerine-Sottas neuropathy (DSN) phenotype; and mutations c.78+5 G>A, c.320-1 G>C, and p.Trp140Stop segregated with HNPP in 5 families.Our findings show that point mutations in PMP22 may be more likely in HNPP patients than in CMT1 patients after exclusion of CMT1A/HNPP.

  4. Genome-wide annotation of mutations in a phenotyped mutant library provides an efficient platform for discovery of casual gene mutations

    USDA-ARS?s Scientific Manuscript database

    Ethyl methanesulfonate (EMS) efficiently generates high-density mutations in genomes. Conventionally, these mutations are identified by techniques that can detect single-nucleotide mismatches in heteroduplexes of individual PCR amplicons. We applied whole-genome sequencing to 256-phenotyped mutant l...

  5. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome

    PubMed Central

    Brown, Kyla; Selfridge, Jim; Lagger, Sabine; Connelly, John; De Sousa, Dina; Kerr, Alastair; Webb, Shaun; Guy, Jacky; Merusi, Cara; Koerner, Martha V.; Bird, Adrian

    2016-01-01

    Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions. PMID:26647311

  6. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.

    PubMed

    Brown, Kyla; Selfridge, Jim; Lagger, Sabine; Connelly, John; De Sousa, Dina; Kerr, Alastair; Webb, Shaun; Guy, Jacky; Merusi, Cara; Koerner, Martha V; Bird, Adrian

    2016-02-01

    Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions.

  7. Modeling tumor predisposing FH mutations in yeast: effects on fumarase activity, growth phenotype and gene expression profile.

    PubMed

    Kokko, Antti; Ylisaukko-Oja, Sanna S K; Kiuru, Maija; Takatalo, Maarit S; Salmikangas, Paula; Tuimala, Jarno; Arango, Diego; Karhu, Auli; Aaltonen, Lauri A; Jäntti, Jussi

    2006-03-15

    Heterozygous mutations in the fumarase (FH) gene cause the tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (MIM 605839). While most families segregate a benign phenotype of multiple leiomyomas, others display a phenotype with early-onset renal cancer and leiomyosarcoma. Modifier genes may play a role in this, but an alternative explanation is simple genotype-phenotype association. FH mutations predisposing to cancer appear to be truncating or in fully conserved amino acids, suggesting that mutations severely affecting FH activity might predispose to malignancy. In the present study, we analyzed 2 conserved fumarase mutations in yeast. H153R has been described in 3 cancer predisposition families; whereas all 3 reported K187R families have displayed the benign phenotype. Examining H153R and K187R should clarify whether cancer-related FH mutations differ from their benign phenotype-associated counterparts. Yeast strains containing the 2 mutations, and knockout and wild type (WT) references, were created and the growth phenotypes studied on selected carbon sources to assess mitochondrial function. Additionally, Fum1 protein production and activity were measured, and the strains were subjected to transcriptional profiling. On nonfermentable lactate medium, the fumarase knockout strains did not grow, whereas the mutants showed no differences, as compared to WT yeast. Although both mutant strains produced fumarase, a considerable decrease in enzyme activity was seen in mutants with respect to WT. Transcription of the majority of Krebs cycle enzymes was downregulated in response to mutations in fumarase. In conclusion, both mutants displayed some, albeit greatly reduced, fumarase activity. This activity was sufficient to support normal growth on nonfermentable carbon source, unlike the deletion phenotype, demonstrating the significance of the residual activity. The findings support the hypothesis that modifier gene(s), rather than phenotype

  8. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

    PubMed Central

    Munot, Pinki; Saunders, Dawn E.; Milewicz, Dianna M.; Regalado, Ellen S.; Ostergaard, John R.; Braun, Kees P.; Kerr, Timothy; Lichtenbelt, Klaske D.; Philip, Sunny; Rittey, Christopher; Jacques, Thomas S.; Cox, Timothy C.

    2012-01-01

    Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal ‘moyamoya’ collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal ‘moyamoya’ collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of ‘moyamoya’ should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life-threatening aortic dissection

  9. Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL).

    PubMed

    Ueda, Ikuyo; Ishii, Eiichi; Morimoto, Akira; Ohga, Shouichi; Sako, Masahiro; Imashuku, Shinsaku

    2006-04-01

    Classification of familial hemophagocytic lymphohistiocytosis (FHL) into FHL2, FHL3, and other subtypes based on genetic abnormalities has recently become possible. We studied the phenotypic differences among these subtypes in Japan. Forty patients clinically diagnosed with FHL were analyzed. Perforin abnormality was screened by flow cytometric analysis and/or DNA sequencing in these patients, and those without perforin abnormalities were further examined for the presence of mutations in the Munc13-4 gene by DNA sequencing. The correlation between clinical features and genetic subtypes was investigated. Of the 40 HLH patients, 11 showed perforin gene mutations (classified as FHL2) and ten had Munc13-4 gene mutations (FHL3), but neither mutation was noted in 19 patients (non-FHL2/3). Although the majority of the patients developed the disease before the age of 1 year, the onset in three FHL2 patients with missense mutations was late (7, 11, and 12 years). Incidence of deficient natural killer cell activity was higher in FHL2 patients (9/9 FHL2, 4/9 FHL3, and 6/17 non-FHL2/3; P = 0.005). The serum levels of ferritin and soluble interleukin-2 receptor were significantly higher in FHL2 patients with nonsense perforin mutations compared to other subgroups (P < or = 0.05). Epstein-Barr virus infection was involved in 8 of the 40 HLH patients: one FHL2, one FHL3, and six non-FHL2/3. Although clinical features of FHL3 appear to be homogeneous, the heterogeneous clinical features of FHL2 depend upon the nature of perforin gene mutations. Characterization of the non-FHL2/3 group with regard to FHL1 or other novel gene mutations remains to be conducted.

  10. Pancreatic phenotype in infants with cystic fibrosis identified by mutation screening

    PubMed Central

    Cipolli, Marco; Castellani, Carlo; Wilcken, Bridget; Massie, John; McKay, Karen; Gruca, Margie; Tamanini, Anna; Assael, Maurice Baroukh; Gaskin, Kevin

    2007-01-01

    Objective To determine the pancreatic phenotype of infants with cystic fibrosis (CF) diagnosed in the first week of life by a combined immunoreactive trypsin/mutation screening program. Design A prospective evaluation of pancreatic function in infants with CF at the time of neonatal diagnosis and up to the age of 12. Setting Two different centres (Verona, Italy and Westmead, Australia) to enable comparison of results between two regions where <60% or ⩾90% of patients, respectively, have at least one single ΔF508 a mutation. Patients 315 children with CF including 149 at Verona and 166 at Westmead. Interventions Fat balance studies over 3–5 days and pancreatic stimulation tests with main outcome measures being faecal fat or pancreatic colipase secretion. Patients with malabsorption are pancreatic insufficient (PI) or with normal absorption and pancreatic sufficient (PS). Results 34 infants (23%) at Verona and 46 (28%) at Westmead were PS at diagnosis. 15% of those with two class I, II or III “severe” mutations and 26/28 (93%) of those with class IV or V mutations were PS at this early age. Of the 80 infants with PS, 20 became PI before the age of 12. All 20 had two severe mutations. Conclusion Neonatal mutational screening programs for CF are less likely to detect PS patients with non‐ΔF508 mutations. Of PS patients who are detected, those with two severe class I, II or III mutations are at particularly high risk of becoming PI during early childhood. PMID:17449517

  11. Mutations in PSMB8 Cause CANDLE Syndrome with Evidence of Genetic and Phenotypic Heterogeneity

    PubMed Central

    Liu, Yin; Ramot, Yuval; Torrelo, Antonio; Paller, Amy S.; Si, Nuo; Babay, Sofia; Kim, Peter W.; Sheikh, Afzal; Lee, Chyi-Chia Richard; Chen, Yongqing; Vera, Angel; Zhang, Xue; Goldbach-Mansky, Raphaela; Zlotogorski, Abraham

    2011-01-01

    Objective Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is an autoinflammatory syndrome recently described in children. We investigated the clinical phenotype, genetic cause and the immune dysregulation in nine CANDLE patients. Methods Genomic DNA from all patients was screened for PSMB8 (Proteasome subunit beta type-8) mutations. Serum cytokine levels were measured from four patients. Skin biopsies were evaluated immunohistochemically and blood microarray profile (n=4) and stat-1 phosphorylation (n=3) were assessed. Results One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A) suggesting a protein truncation, four patients were homozygous and two were heterozygous for a previously reported missense mutation (c.224C>T), and one patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the four patients with the same mutation, only two share the same haplotype indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high IP-10 (Interferon gamma-induced protein 10) levels. Levels of MCP-1, IL-6, and IL-1Ra were moderately elevated. Microarray profiles and monocyte stat-1 activation suggested a unique interferon (IFN) signaling signature, unlike in other autoinflammatory disorders. Conclusion CANDLE is caused by mutations in PSMB8, a gene recently reported to cause JMP syndrome (joint contractures, muscle atrophy and panniculitis induced lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target. PMID:21953331

  12. Longitudinal imaging in C9orf72 mutation carriers: Relationship to phenotype.

    PubMed

    Floeter, Mary Kay; Bageac, Devin; Danielian, Laura E; Braun, Laura E; Traynor, Bryan J; Kwan, Justin Y

    2016-01-01

    Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations

  13. 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.

  14. Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2.

    PubMed

    Bornholdt, Dorothea; Atkinson, T Prescott; Bouadjar, Bakar; Catteau, Benoit; Cox, Helen; De Silva, Deepthi; Fischer, Judith; Gunasekera, Chalukya N; Hadj-Rabia, Smaïl; Happle, Rudolf; Holder-Espinasse, Muriel; Kaminski, Elke; König, Arne; Mégarbané, André; Mégarbané, Hala; Neidel, Ulrike; Oeffner, Frank; Oji, Vinzenz; Theos, Amy; Traupe, Heiko; Vahlquist, Anders; van Bon, Bregje W; Virtanen, Marie; Grzeschik, Karl-Heinz

    2013-04-01

    Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.

  15. Rare familial TSC2 gene mutation associated with atypical phenotype presentation of Tuberous Sclerosis Complex.

    PubMed

    Fox, Jonah; Ben-Shachar, Shay; Uliel, Shimrit; Svirsky, Ran; Saitsu, Hirotomo; Matsumoto, Naomichi; Fattal-Valevski, Aviva

    2017-03-01

    Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. We describe an 18-month-old boy who presented with seizures and a single hypopigmented macule. He did not meet consensus criteria for the clinical diagnosis of TSC. Exome sequencing revealed a heterozygous TSC2 mutation (c.5138G>A (p.Arg1713His)) in the patient. This heterozygous alteration was detected in his mother as well as several other maternal family members. The mother and other family members with the mutation were asymptomatic except for the presence of hypopigmented macules. The phenotypic characteristics of the individuals in this family were not suggestive of a TSC2 mutation as none satisfied the clinical criteria for even a diagnosis of possible TSC. This case provides evidence for a unique TSC2 mutation that resulted in an atypical clinical presentation and indicates potential shortcomings of the current diagnostic criteria for TSC. These findings may have implications for genetic counseling and screening. © 2017 Wiley Periodicals, Inc.

  16. Mutations in MC1R gene determine black coat color phenotype in Chinese sheep.

    PubMed

    Yang, Guang-Li; Fu, Dong-Li; Lang, Xia; Wang, Yu-Tao; Cheng, Shu-Ru; Fang, Su-Li; Luo, Yu-Zhu

    2013-01-01

    The melanocortin receptor 1 (MC1R) plays a central role in regulation of animal coat color formation. In this study, we sequenced the complete coding region and parts of the 5'- and 3'-untranslated regions of the MC1R gene in Chinese sheep with completely white (Large-tailed Han sheep), black (Minxian Black-fur sheep), and brown coat colors (Kazakh Fat-Rumped sheep). The results showed five single nucleotide polymorphisms (SNPs): two non-synonymous mutations previously associated with coat color (c.218 T>A, p.73 Met>Lys. c.361 G>A, p.121 Asp>Asn) and three synonymous mutations (c.429 C>T, p.143 Tyr>Tyr; c.600 T>G, p.200 Leu>Leu. c.735 C>T, p.245 Ile>Ile). Meanwhile, all mutations were detected in Minxian Black-fur sheep. However, the two nonsynonymous mutation sites were not in all studied breeds (Large-tailed Han, Small-tailed Han, Gansu Alpine Merino, and China Merino breeds), all of which are in white coat. A single haplotype AATGT (haplotype3) was uniquely associated with black coat color in Minxian Black-fur breed (P = 9.72E - 72, chi-square test). The first and second A alleles in this haplotype 3 represent location at 218 and 361 positions, respectively. Our results suggest that the mutations of MC1R gene are associated with black coat color phenotype in Chinese sheep.

  17. Genotype-phenotype relationship in 12 patients carrying cystic fibrosis mutation R334W.

    PubMed Central

    Antiñolo, G; Borrego, S; Gili, M; Dapena, J; Alfageme, I; Reina, F

    1997-01-01

    We present a phenotype-genotype correlation analysis in 12 patients with cystic fibrosis (CF) carrying the mutation R334W in the CFTR gene. The clinical data obtained for this group were compared with the clinical data of deltaF508/deltaF508 patients. Current age and age at diagnosis were significantly higher in the R334W mutation group (p=0.028 and p=0.0001). We found a lower rate of Pseudomonas aeruginosa colonisation in patients carrying the R334W mutation, although the difference was not found to be statistically significant. However, we found a statistically significant higher age of onset of Pseudomonas aeruginosa colonisation (p=0.0036) in the group of patients with the R334W mutation. Thirty three percent of R334W patients were pancreatic insufficient, significantly lower than the deltaF508/deltaF508 patients (p=0.004). We also found that the weight expressed as a percentage of ideal weight for height was significantly higher in patients with the R334W mutation (p=0.0028). PMID:9039981

  18. Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype.

    PubMed

    Kuehn, Hye Sun; Niemela, Julie E; Sreedhara, Karthik; Stoddard, Jennifer L; Grossman, Jennifer; Wysocki, Christian A; de la Morena, M Teresa; Garofalo, Mary; Inlora, Jingga; Snyder, Michael P; Lewis, David B; Stratakis, Constantine A; Fleisher, Thomas A; Rosenzweig, Sergio D

    2017-09-28

    NF-κB signaling through its NFKB1-dependent canonical and NFKB2-dependent noncanonical pathways plays distinctive roles in a diverse range of immune processes. Recently, mutations in these 2 genes have been associated with common variable immunodeficiency (CVID). While studying patients with genetically uncharacterized primary immunodeficiencies, we detected 2 novel nonsense gain-of-function (GOF) NFKB2 mutations (E418X and R635X) in 3 patients from 2 families, and a novel missense change (S866R) in another patient. Their immunophenotype was assessed by flow cytometry and protein expression; activation of canonical and noncanonical pathways was examined in peripheral blood mononuclear cells and transfected HEK293T cells through immunoblotting, immunohistochemistry, luciferase activity, real-time polymerase chain reaction, and multiplex assays. The S866R change disrupted a C-terminal NF-κΒ2 critical site affecting protein phosphorylation and nuclear translocation, resulting in CVID with adrenocorticotropic hormone deficiency, growth hormone deficiency, and mild ectodermal dysplasia as previously described. In contrast, the nonsense mutations E418X and R635X observed in 3 patients led to constitutive nuclear localization and activation of both canonical and noncanonical NF-κΒ pathways, resulting in a combined immunodeficiency (CID) without endocrine or ectodermal manifestations. These changes were also found in 2 asymptomatic relatives. Thus, these novel NFKB2 GOF mutations produce a nonfully penetrant CID phenotype through a different pathophysiologic mechanism than previously described for mutations in NFKB2.

  19. 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.

  20. A novel mutation in retinitis pigmentosa GTPase regulator gene with a distinctive retinitis pigmentosa phenotype in a Chinese family.

    PubMed

    Sheng, Xunlun; Li, Zili; Zhang, Xinfang; Wang, Jing; Ren, Hongwang; Sun, Yanbo; Meng, Ruihua; Rong, Weining; Zhuang, Wenjuan

    2010-08-15

    To screen the mutation in the retinitis pigmentosa GTPase regulator (RPGR) ORF15 in a large Chinese family with X-linked recessive retinitis pigmentosa and describe the phenotype in affected male and female carriers. Ophthalmic examination was performed on 77 family members to identify affected individuals and to characterize the disease phenotype. PCR and direct sequencing were used for screening mutations in the RPGR gene. Mutation screening demonstrated a novel mutation ORF15+577_578 delAG, which caused an open reading frameshift and resulted in premature truncation of the RPGR protein. The mutation was detected in eight affected male individuals and 14 obligate female carriers of the family and was found to segregate with the phenotype in this family. The mutation led to a severe retinitis pigmentosa (RP) phenotype in male-affected individuals, with some variability in the age of onset of night blindness and visual acuity, but was recessive in female carriers without an RP phenotype. However, the state associated with the carrier was moderate to high myopia with the refractive error ranging from -5.00 D to 22.00 D in 14 female carriers. This novel mutation in RPGR ORF15 causes a serious RP phenotype in males and no RP phenotype in female carriers. Moderate to high myopia was a particular feature for female carriers in this pedigree. Our finding expands the spectrum of RPGR mutations causing X-linked RP and expands phenotypic spectrum of the disease in a Chinese family. This finding will be useful for further genetic consultations and genetic diagnosis.

  1. A novel mutation in retinitis pigmentosa GTPase regulator gene with a distinctive retinitis pigmentosa phenotype in a Chinese family

    PubMed Central

    Zhang, Xinfang; Wang, Jing; Ren, Hongwang; Sun, Yanbo; Meng, Ruihua; Rong, Weining

    2010-01-01

    Purpose To screen the mutation in the retinitis pigmentosa GTPase regulator (RPGR) ORF15 in a large Chinese family with X-linked recessive retinitis pigmentosa and describe the phenotype in affected male and female carriers. Methods Ophthalmic examination was performed on 77 family members to identify affected individuals and to characterize the disease phenotype. PCR and direct sequencing were used for screening mutations in the RPGR gene. Results Mutation screening demonstrated a novel mutation ORF15+577_578 delAG, which caused an open reading frameshift and resulted in premature truncation of the RPGR protein. The mutation was detected in eight affected male individuals and 14 obligate female carriers of the family and was found to segregate with the phenotype in this family. The mutation led to a severe retinitis pigmentosa (RP) phenotype in male-affected individuals, with some variability in the age of onset of night blindness and visual acuity, but was recessive in female carriers without an RP phenotype. However, the state associated with the carrier was moderate to high myopia with the refractive error ranging from −5.00 D to 22.00 D in 14 female carriers. Conclusions This novel mutation in RPGR ORF15 causes a serious RP phenotype in males and no RP phenotype in female carriers. Moderate to high myopia was a particular feature for female carriers in this pedigree. Our finding expands the spectrum of RPGR mutations causing X-linked RP and expands phenotypic spectrum of the disease in a Chinese family. This finding will be useful for further genetic consultations and genetic diagnosis. PMID:20806050

  2. A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1.

    PubMed

    Garza, Rene; Hudson, Robert A; McMahan, C Alex; Walter, Christi A; Vogel, Kristine S

    2007-02-03

    Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF=4.70) when compared to normal peripheral nerve and brain (MF=2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

  3. Novel Mutations of RPGR in Chinese Retinitis Pigmentosa Patients and the Genotype-Phenotype Correlation

    PubMed Central

    You, Debo; Wu, Lemeng; Chen, Ningning; Li, Aijun; Li, Genlin; Ma, Zhizhong

    2014-01-01

    X-linked Retinitis Pigmentosa (XLRP) accounts for 10–20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70–75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function. PMID:24454928

  4. Novel mutations of RPGR in Chinese retinitis pigmentosa patients and the genotype-phenotype correlation.

    PubMed

    Yang, Liping; Yin, Xiaobei; Feng, Lina; You, Debo; Wu, Lemeng; Chen, Ningning; Li, Aijun; Li, Genlin; Ma, Zhizhong

    2014-01-01

    X-linked Retinitis Pigmentosa (XLRP) accounts for 10-20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70-75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function.

  5. SUBCLINICAL ECHOCARDIOGRAPHIC ABNORMALITIES IN PHENOTYPE-NEGATIVE CARRIERS OF MYBPC3 GENE MUTATION FOR HYERTROPHIC CARDIOMYOPATHY

    PubMed Central

    De, Sabe; Borowski, Allen G.; Wang, Heng; Nye, Leah; Xin, Baozhong; Thomas, James D.; Tang, W.H. Wilson

    2011-01-01

    Background Early diastolic myocardial tissue Doppler (TD) velocities have reported to be reduced in mutation-positive patients with HCM in some studies even in the absence of left ventricular hypertrophy (LVH). Strain is a sensitive tool in detecting early systolic abnormalities in patients with hypertrophic cardiomyopathy (HCM). Our goal is to examine novel echocardiographic characteristics of phenotype-negative carriers for a known sarcomeric gene mutation for HCM. Methods We evaluated 41 consecutive subjects with a known myosin binding protein C3 (MYBPC3) mutation (c.3330+2T>G). Subjects who were mutation-positive without LVH (G+/LVH−, n=35) were compared to healthy controls (n=30) regarding tissue Doppler and segmental longitudinal strain measures. Results The G+/LVH− group was similar to the normal controls with respect to chamber size, LV mass index, and most diastolic filling parameters, including tissue Doppler derived Ea. Global longitudinal strain was similar for both groups (20.3 ± 2.1 vs. 19.8 ± 1.8; p=0.36) although regional segment analysis showed a notable reduction in the basal septum (16.8 ± 3.1 vs. 19.0 ± 4.0%, p=0.02) and increase in the basal posterior (22.5 ± 5.2 vs. 17.9 ± 5.2, p=0.001) as well as mid posterior (21.8 ± 4.7 vs. 18.2 ± 3.0, p=0.001) walls. Conclusions In our cohort of phenotype-negative carriers of a specific MYBPC3 mutation, there were minimal differences in conventional 2-dimensional, Doppler, and speckle-tracking derived parameters of systolic and diastolic function compared to that of normal subjects. The presence of regional alterations in strain indicative of the presence of underlying subclinical disease requires further validation. PMID:21835286

  6. Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype

    PubMed Central

    Bouchelion, Ashleigh; Zhang, Zhongjian; Li, Yichao; Qian, Haohua; Mukherjee, Anil B

    2014-01-01

    Objective Nonsense mutations account for 5–70% of all genetic disorders. In the United States, nonsense mutations in the CLN1/PPT1 gene underlie >40% of the patients with infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of INCL carrying the most common Ppt1 nonsense mutation (c.451C>T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo. Methods We knocked-in c.451C>T nonsense mutation in the Ppt1 gene in C57 embryonic stem (ES) cells using a targeting vector in which LoxP flanked the Neo cassette, which was removed from targeted ES cells by electroporating Cre. Two independently targeted ES clones were injected into blastocysts to generate syngenic C57 knock-in mice, obviating the necessity for extensive backcrossing. Results Generation of Ppt1-KI mice was confirmed by DNA sequencing, which showed the presence of c.451C>T mutation in the Ppt1 gene. These mice are viable and fertile, although they developed spasticity (a “clasping” phenotype) at a median age of 6 months. Autofluorescent storage materials accumulated throughout the brain regions and in visceral organs. Electron microscopic analysis of the brain and the spleen showed granular osmiophilic deposits. Increased neuronal apoptosis was particularly evident in cerebral cortex and abnormal histopathological and electroretinographic (ERG) analyses attested striking retinal degeneration. Progressive deterioration of motor coordination and behavioral parameters continued until eventual death. Interpretation Our findings show that Ppt1-KI mice reliably recapitulate INCL phenotype providing a platform for testing the efficacy of existing and novel nonsense suppressors in vivo. PMID:25574475

  7. Mutations in hepatocyte nuclear factor‐1β and their related phenotypes

    PubMed Central

    Edghill, E L; Bingham, C; Ellard, S; Hattersley, A T

    2006-01-01

    Background Hepatocyte nuclear factor‐1 beta (HNF‐1β) is a widely distributed transcription factor which plays a critical role in embryonic development of the kidney, pancreas, liver, and Mullerian duct. Thirty HNF‐1β mutations have been reported in patients with renal cysts and other renal developmental disorders, young‐onset diabetes, pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities. Methods We sequenced the HNF‐1β gene in 160 unrelated subjects with renal disease, 40% of whom had a personal/family history of diabetes. Results Twenty three different heterozygous HNF‐1β mutations were identified in 23/160 subjects (14%), including 10 novel mutations (V61G, V110G, S148L, K156E, Q176X, R276Q, S281fsinsC, R295P, H324fsdelCA, Q470X). Seven (30%) cases were proven to be due to de novo mutations. Renal cysts were found in 19/23 (83%) patients (four with glomerulocystic kidney disease, GCKD) and diabetes in 11/23 (48%, while three other families had a family history of diabetes. Only 26% of families met diagnostic criteria for maturity‐onset diabetes of the young (MODY) but 39% had renal cysts and diabetes (RCAD). We found no clear genotype/phenotype relationships. Conclusion We report the largest series to date of HNF‐1β mutations and confirm HNF‐1β mutations as an important cause of renal disease. Despite the original description of HNF‐1β as a MODY gene, a personal/family history of diabetes is often absent and the most common clinical manifestation is renal cysts. Molecular genetic testing for HNF‐1β mutations should be considered in patients with unexplained renal cysts (including GCKD), especially when associated with diabetes, early‐onset gout, or uterine abnormalities. PMID:15930087

  8. The Relationship between the p.V37I Mutation in GJB2 and Hearing Phenotypes in Chinese Individuals.

    PubMed

    Huang, Shasha; Huang, Bangqing; Wang, Guojian; Yuan, Yongyi; Dai, Pu

    2015-01-01

    The most common cause of nonsyndromic autosomal recessive hearing loss is mutations in GJB2. The mutation spectrum and prevalence of mutations vary significantly among ethnic groups, and the relationship between p.V37I mutation in GJB2 and the hearing phenotype is controversial. Among the 3,864 patients in this study, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other GJB2 pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). The hearing loss phenotype ranged from mild to profound in all patients with the homozygous p.V37I variation or compound p.V37I plus other GJB2 pathogenic mutation. There was no difference in the distribution of the hearing level in the group with the homozygous p.V37I variation and the group with the compound p.V37I variation plus pathogenic mutation. Most patients (66.04%) with the V37I-homozygous variation or p.V37I plus other pathogenic mutation had a mild or moderate hearing level. This study found a definite relationship between p.V37I and deafness, and most patients who carried the pathogenic combination with p.V37I mutation had mild or moderate hearing loss. Therefore, otolaryngologists should consider that the milder phenotype might be caused by the GJB2 p.V37I mutation.

  9. Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10

    PubMed Central

    Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie

    2014-01-01

    Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. PMID:24845202

  10. Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations.

    PubMed

    Réblová, Kamila; Hrubá, Zuzana; Procházková, Dagmar; Pazdírková, Renata; Pouchlá, Slávka; Zeman, Jiří; Fajkusová, Lenka

    2013-04-18

    Hyperphenylalaninemia (HPA) is one of the most common inherited metabolic disorders caused by deficiency of the enzyme phenylalanine hydroxylase (PAH). HPA is associated with mutations in the PAH gene, which leads to reduced protein stability and/or impaired catalytic function. Currently, almost 700 different disease-causing mutations have been described. The impact of mutations on enzyme activity varies ranging from classical PKU, mild PKU, to non-PKU HPA phenotype. We provide results of molecular genetic diagnostics of 665 Czech unrelated HPA patients, structural analysis of missense mutations associated with classical PKU and non-PKU HPA phenotype, and prediction of effects of 6 newly discovered HPA missense mutations using bioinformatic approaches and Molecular Dynamics simulations. Ninety-eight different types of mutations were indentified. Thirteen of these were novel (6 missense, 2 nonsense, 1 splicing, and 4 small gene rearrangements). Structural analysis revealed that classical PKU mutations are more non-conservative compared to non-PKU HPA mutations and that specific sequence and structural characteristics of a mutation might be critical when distinguishing between non-PKU HPA and classical PKU mutations. The greatest impact was predicted for the p.(Phe263Ser) mutation while other novel mutations p.(Asn167Tyr), p.(Thr200Asn), p.(Asp229Gly), p.(Leu358Phe), and p.(Ile406Met) were found to be less deleterious. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies.

    PubMed

    Ponti, Giovanni; Martorana, Davide; Pellacani, Giovanni; Ruini, Cristel; Loschi, Pietro; Baccarani, Alessio; De Santis, Giorgio; Pollio, Annamaria; Neri, Tauro Maria; Mandel, Victor Desmond; Maiorana, Antonio; Maccio, Livia; Maccaferri, Monia; Tomasi, Aldo

    2014-06-01

    Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  12. Mosaicism for dominant collagen VI mutations as a cause for intra-familial phenotypic variability

    PubMed Central

    Donkervoort, Sandra; Hu, Ying; Stojkovic, Tanya; Voermans, Nicol; Foley, A. Reghan; Leach, Meganne E; Dastgir, Jahannaz; Bolduc, Veronique; Cullup, Thomas; de Becdelièvre, Alix; Yang, Lin; Su, Hai; Meilleur, Katherine; Schindler, Alice B.; Kamsteeg, Erik-Jan; Richard, Pascale; Butterfield, Russell; Winder, Thomas L.; Crawford, Thomas; Weiss, Robert B.; Muntoni, Francesco; Allamand, Valérie; Bönnemann, Carsten G.

    2015-01-01

    Collagen VI-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy (UCMD), intermediate phenotypes, to the milder Bethlem myopathy (BM). Both inter- and intra-familial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked inter-generational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional 5th simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2 and COL6A3) in genomic DNA (gDNA) from various tissues; including blood, saliva, and dermal fibroblasts. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared to the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intra-familial/inter-generational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected. PMID:25204870

  13. Disintegrating the fly: A mutational perspective on phenotypic integration and covariation.

    PubMed

    Haber, Annat; Dworkin, Ian

    2017-01-01

    The structure of environmentally induced phenotypic covariation can influence the effective strength and magnitude of natural selection. Yet our understanding of the factors that contribute to and influence the evolutionary lability of such covariation is poor. Most studies have either examined environmental variation without accounting for covariation, or examined phenotypic and genetic covariation without distinguishing the environmental component. In this study, we examined the effect of mutational perturbations on different properties of environmental covariation, as well as mean shape. We use strains of Drosophila melanogaster bearing well-characterized mutations known to influence wing shape, as well as naturally derived strains, all reared under carefully controlled conditions and with the same genetic background. We find that mean shape changes more freely than the covariance structure, and that different properties of the covariance matrix change independently from each other. The perturbations affect matrix orientation more than they affect matrix eccentricity or total variance. Yet, mutational effects on matrix orientation do not cluster according to the developmental pathway that they target. These results suggest that it might be useful to consider a more general concept of "decanalization," involving all aspects of variation and covariation.

  14. Three Routes to Suppression of the Neurodegenerative Phenotypes Caused by Kinesin Heavy Chain Mutations

    PubMed Central

    Djagaeva, Inna; Rose, Debra J.; Lim, Angeline; Venter, Chris E.; Brendza, Katherine M.; Moua, Pangkong; Saxton, William M.

    2012-01-01

    Kinesin-1 is a motor protein that moves stepwise along microtubules by employing dimerized kinesin heavy chain (Khc) subunits that alternate cycles of microtubule binding, conformational change, and ATP hydrolysis. Mutations in the Drosophila Khc gene are known to cause distal paralysis and lethality preceded by the occurrence of dystrophic axon terminals, reduced axonal transport, organelle-filled axonal swellings, and impaired action potential propagation. Mutations in the equivalent human gene, Kif5A, result in similar problems that cause hereditary spastic paraplegia (HSP) and Charcot–Marie–Tooth type 2 (CMT2) distal neuropathies. By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5A HSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin-1. Our results reveal the value of large-scale complementation analysis for gaining insight into protein structure–function relationships in vivo and point to possible paths for suppressing symptoms of HSP and related distal neuropathies. PMID:22714410

  15. Neurobehavioral phenotype observed in KBG syndrome caused by ANKRD11 mutations.

    PubMed

    Lo-Castro, Adriana; Brancati, Francesco; Digilio, Maria Cristina; Garaci, Francesco Giuseppe; Bollero, Patrizio; Alfieri, Paolo; Curatolo, Paolo

    2013-01-01

    KBG syndrome is a rare disease characterized by typical facial dysmorphism, macrodontia of upper central incisors, skeletal abnormalities, and developmental delay. Recently, mutations in ANKRD11 gene have been identified in a subset of patients with KBG syndrome, while a contiguous gene deletion syndrome involving 16q24.3 region (including ANKRD11) was delineated in patients with facial dysmorphism, autism, intellectual disability, and brain abnormalities. Although numerous evidences point to a central causative role of ANKRD11 in the neurologic features of these patients, their neurocognitive and behavior phenotypes are still poorly characterized. Herein, we report the complete neurological and psychiatric features observed in two patients with KBG syndrome due to ANKRD11 mutations. Both patients show intellectual disabilities, severe impairment in communication skills, deficits in several aspects of executive functions and working memory and anxious traits. Their features are compared with those of previously reported patients with KBG syndrome aiding in the delineation of neurocognitive phenotype associated to ANKRD11 mutations.

  16. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

    PubMed

    Flex, Elisabetta; Jaiswal, Mamta; Pantaleoni, Francesca; Martinelli, Simone; Strullu, Marion; Fansa, Eyad K; Caye, Aurélie; De Luca, Alessandro; Lepri, Francesca; Dvorsky, Radovan; Pannone, Luca; Paolacci, Stefano; Zhang, Si-Cai; Fodale, Valentina; Bocchinfuso, Gianfranco; Rossi, Cesare; Burkitt-Wright, Emma M M; Farrotti, Andrea; Stellacci, Emilia; Cecchetti, Serena; Ferese, Rosangela; Bottero, Lisabianca; Castro, Silvana; Fenneteau, Odile; Brethon, Benoît; Sanchez, Massimo; Roberts, Amy E; Yntema, Helger G; Van Der Burgt, Ineke; Cianci, Paola; Bondeson, Marie-Louise; Cristina Digilio, Maria; Zampino, Giuseppe; Kerr, Bronwyn; Aoki, Yoko; Loh, Mignon L; Palleschi, Antonio; Di Schiavi, Elia; Carè, Alessandra; Selicorni, Angelo; Dallapiccola, Bruno; Cirstea, Ion C; Stella, Lorenzo; Zenker, Martin; Gelb, Bruce D; Cavé, Hélène; Ahmadian, Mohammad R; Tartaglia, Marco

    2014-08-15

    RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.

  17. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis

    PubMed Central

    Flex, Elisabetta; Jaiswal, Mamta; Pantaleoni, Francesca; Martinelli, Simone; Strullu, Marion; Fansa, Eyad K.; Caye, Aurélie; De Luca, Alessandro; Lepri, Francesca; Dvorsky, Radovan; Pannone, Luca; Paolacci, Stefano; Zhang, Si-Cai; Fodale, Valentina; Bocchinfuso, Gianfranco; Rossi, Cesare; Burkitt-Wright, Emma M.M.; Farrotti, Andrea; Stellacci, Emilia; Cecchetti, Serena; Ferese, Rosangela; Bottero, Lisabianca; Castro, Silvana; Fenneteau, Odile; Brethon, Benoît; Sanchez, Massimo; Roberts, Amy E.; Yntema, Helger G.; Van Der Burgt, Ineke; Cianci, Paola; Bondeson, Marie-Louise; Cristina Digilio, Maria; Zampino, Giuseppe; Kerr, Bronwyn; Aoki, Yoko; Loh, Mignon L.; Palleschi, Antonio; Di Schiavi, Elia; Carè, Alessandra; Selicorni, Angelo; Dallapiccola, Bruno; Cirstea, Ion C.; Stella, Lorenzo; Zenker, Martin; Gelb, Bruce D.; Cavé, Hélène; Ahmadian, Mohammad R.; Tartaglia, Marco

    2014-01-01

    RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease. PMID:24705357

  18. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2.

    PubMed

    Rossor, Alexander M; Oates, Emily C; Salter, Hannah K; Liu, Yang; Murphy, Sinead M; Schule, Rebecca; Gonzalez, Michael A; Scoto, Mariacristina; Phadke, Rahul; Sewry, Caroline A; Houlden, Henry; Jordanova, Albena; Tournev, Iyailo; Chamova, Teodora; Litvinenko, Ivan; Zuchner, Stephan; Herrmann, David N; Blake, Julian; Sowden, Janet E; Acsadi, Gyuda; Rodriguez, Michael L; Menezes, Manoj P; Clarke, Nigel F; Auer Grumbach, Michaela; Bullock, Simon L; Muntoni, Francesco; Reilly, Mary M; North, Kathryn N

    2015-02-01

    Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu

  19. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2

    PubMed Central

    Rossor, Alexander M.; Oates, Emily C.; Salter, Hannah K.; Liu, Yang; Murphy, Sinead M.; Schule, Rebecca; Gonzalez, Michael A.; Scoto, Mariacristina; Phadke, Rahul; Sewry, Caroline A.; Houlden, Henry; Jordanova, Albena; Tournev, Iyailo; Chamova, Teodora; Litvinenko, Ivan; Zuchner, Stephan; Herrmann, David N.; Blake, Julian; Sowden, Janet E.; Acsadi, Gyuda; Rodriguez, Michael L.; Menezes, Manoj P.; Clarke, Nigel F.; Auer Grumbach, Michaela; Bullock, Simon L.; Muntoni, Francesco; North, Kathryn N.

    2015-01-01

    Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible ‘hot spot’ mutation, p.Ser107

  20. Novel mutations, including a novel G659A missense mutation, of the FUT1 gene are responsible for the para-Bombay phenotype.

    PubMed

    Sun, C F; Lo, M D; Lee, C H; Chu, D C

    2000-10-01

    Para-Bombay phenotype, with an estimated incidence of 1 in 8000 in Taiwanese residents based on serological analysis, is caused by aberrant alpha(1,2)-fucosyltransferase function and hence diminished H-antigen synthesis. In an individual with para-Bombay phenotype, DNA sequencing revealed two missense mutations previously reported C658T mutation and a novel G659A mutation. Haplotype analysis with restriction enzyme digestion showed that the two mutations are located on opposing alleles of the H (FUT1) gene and lead to compound heterozygosity. Since no other known genetic changes were evident, it appears that the new missense mutation, G659A, is deleterious to the alpha(1,2)-fucosyltransferase function encoded by the H (FUT1) gene.

  1. MEFV gene mutations and cardiac phenotype in children with familial Mediterranean fever: a cohort study

    PubMed Central

    2014-01-01

    Background Familial Mediterranean fever (FMF) is the most common autoinflammatory disorder in the world. It is characterized by recurrent febrile inflammatory attacks of serosal and synovial membranes. MEFV gene mutations are responsible for the disease and its protein product, pyrin or marenostrin, plays an essential role in the regulation of the inflammatory reactions. Although the disease may carry a potential for cardiovascular disorders because of sustained inflammation during its course, the spectrum of cardiac involvement in children with FMF has not been well studied. We aimed at defining the frequency and spectrum of cardiac affection in children with FMF. The correlation between these affections and MEFV gene mutations was searched for to establish the relationship between cardiac phenotype and the patient's genotype in FMF. Methods The present work is a cohort study including 55 patients with the clinical diagnosis of FMF based on the Tel-Hashomere criteria, confirmed by genetic analysis showing homozygous or compound heterozygous mutation of MEFV genes. Fifty age- and sex-matched normal children were included as controls. The entire study group underwent detailed cardiac examination, 12-lead ECG and echocardiography. All data was statistically analysed using SPSS version-15. Results Patients had an average age of 8.5+/−4.2 years; with an average disease duration of 2.1+/−2.2 years; 28 were males. All controls showed no MEVF gene mutations. The most frequent gene mutation of the studied cases was E148Q mutation seen in 34% of cases and the most frequent compound mutation was E148Q/V726A seen in 16.6% of cases. Echocardiographic examination revealed pericardial effusion in nine patients. Twelve had aortic regurgitation; nine had mitral regurgitation and six had pulmonary regurgitation. The most common mutation associated with pericardial effusion was E148Q/V726A in 5/9 of cases. Valvular involvement were significantly more common in FMF patients

  2. Hereditary and Sporadic Papillary Renal Carcinomas with c-met Mutations Share a Distinct Morphological Phenotype

    PubMed Central

    Lubensky, Irina A.; Schmidt, Laura; Zhuang, Zhengping; Weirich, Gregor; Pack, Svetlana; Zambrano, Norman; Walther, McClellan M.; Choyke, Peter; Linehan, W. Marston; Zbar, Berton

    1999-01-01

    Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1–2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic

  3. Mutation Update and Genotype–Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

    PubMed Central

    Marttila, Minttu; Lehtokari, Vilma-Lotta; Marston, Steven; Nyman, Tuula A.; Barnerias, Christine; Beggs, Alan H.; Bertini, Enrico; Ceyhan-Birsoy, OÖzge; Cintas, Pascal; Gerard, Marion; Gilbert-Dussardier, Brigitte; Hogue, Jacob S.; Longman, Cheryl; Eymard, Bruno; Frydman, Moshe; Kang, Peter B.; Klinge, Lars; Kolski, Hanna; Lochmüller, Hans; Magy, Laurent; Manel, Véronique; Mayer, Michèle; Mercuri, Eugenio; North, Kathryn N.; Peudenier-Robert, Sylviane; Pihko, Helena; Probst, Frank J.; Reisin, Ricardo; Stewart, Willie; Taratuto, Ana Lia; de Visser, Marianne; Wilichowski, Ekkehard; Winer, John; Nowak, Kristen; Laing, Nigel G.; Winder, Tom L.; Monnier, Nicole; Clarke, Nigel F.; Pelin, Katarina; Grönholm, Mikaela; Wallgren-Pettersson, Carina

    2014-01-01

    Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head-to-tail binding. PMID:24692096

  4. Rapid Emergence of Resistance to Linezolid and Mutator Phenotypes in Staphylococcus aureus Isolates from an Adult Cystic Fibrosis Patient

    PubMed Central

    Tazi, Asmaa; Chapron, Jeanne; Touak, Gerald; Longo, Magalie; Hubert, Dominique; Collobert, Gislène; Dusser, Daniel; Poyart, Claire

    2013-01-01

    Linezolid has emerged as an important therapeutic option for the treatment of Staphylococcus aureus in patients with cystic fibrosis. We report the rapid emergence, upon treatment with linezolid, of linezolid-resistant S. aureus clinical isolates through the accumulation of resistance-associated 23S rRNA mutations, together with acquisition of an altered mutator phenotype. PMID:23917314

  5. Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.

    PubMed Central

    Jeanpierre, C; Denamur, E; Henry, I; Cabanis, M O; Luce, S; Cécille, A; Elion, J; Peuchmaur, M; Loirat, C; Niaudet, P; Gubler, M C; Junien, C

    1998-01-01

    Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germ-line mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46, XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions. PMID:9529364

  6. Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations.

    PubMed Central

    Delaney, S J; Alton, E W; Smith, S N; Lunn, D P; Farley, R; Lovelock, P K; Thomson, S A; Hume, D A; Lamb, D; Porteous, D J; Dorin, J R; Wainwright, B J

    1996-01-01

    We have generated a mouse carrying the human G551D mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR) by a one-step gene targeting procedure. These mutant mice show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice show greatly reduced CFTR-related chloride transport, displaying activity intermediate between that of cftr(mlUNC) replacement ('null') and cftr(mlHGU) insertional (residual activity) mutants and equivalent to approximately 4% of wild-type CFTR activity. The long-term survival of these animals should provide an excellent model with which to study cystic fibrosis, and they illustrate the value of mouse models carrying relevant mutations for examining genotype-phenotype correlations. Images PMID:8605891

  7. Mutations Conferring a Noncytotoxic Phenotype on Chikungunya Virus Replicons Compromise Enzymatic Properties of Nonstructural Protein 2

    PubMed Central

    Utt, Age; Das, Pratyush Kumar; Varjak, Margus; Lulla, Valeria; Lulla, Aleksei

    2014-01-01

    ABSTRACT Chikungunya virus (CHIKV) (genus Alphavirus) has a positive-sense RNA genome. CHIKV nonstructural protein 2 (nsP2) proteolytically processes the viral nonstructural polyprotein, possesses nucleoside triphosphatase (NTPase), RNA triphosphatase, and RNA helicase activities, and induces cytopathic effects in vertebrate cells. Although alphaviral nsP2 mutations can result in a noncytotoxic phenotype, the effects of such mutations on nsP2 enzymatic activities are not well understood. In this study, we introduced a P718G (PG) mutation and selected for additional mutations in CHIKV nsP2 that resulted in a CHIKV replicon with a noncytotoxic phenotype in BHK-21 cells. Combinations of PG and either an E116K (EK) substitution or a GEEGS sequence insertion after residue T648 (5A) markedly reduced RNA synthesis; however, neither PG nor 5A prevented nsP2 nuclear translocation. Introducing PG into recombinant nsP2 inhibited proteolytic cleavage of nsP1/nsP2 and nsP3/nsP4 sites, reduced GTPase and RNA helicase activities, and abolished RNA stimulation of GTPase activity. 5A and EK modulated the effects of PG. However, only the RNA helicase activity of nsP2 was reduced by both of these mutations, suggesting that defects in this activity may be linked to a noncytotoxic phenotype. These results increase our understanding of the molecular basis for the cytotoxicity that accompanies alphaviral replication. Furthermore, adaptation of the CHIKV replicon containing both 5A and PG allowed the selection of a CHIKV replicon with adaptive mutations in nsP1 and nsP3 that enable persistence in human cell line. Such cell lines represent valuable experimental systems for discovering host factors and for screening inhibitors of CHIKV replication at lower biosafety levels. IMPORTANCE CHIKV is a medically important pathogen that causes febrile illness and can cause chronic arthritis. No approved vaccines or antivirals are available for CHIKV. The attenuation of CHIKV is critical to the

  8. Phenotype Characterization and DSPP Mutational Analysis of Three Brazilian Dentinogenesis Imperfecta Type II Families

    PubMed Central

    Acevedo, A.C.; Santos, L.J.S.; Paula, L.M.; Dong, J.; MacDougall, M.

    2008-01-01

    The aim of this study was to perform phenotype analysis and dentin sialophosphoprotein (DSPP) mutational analysis on 3 Brazilian families diagnosed with dentinogenesis imperfecta type II (DGI-II) attending the Dental Anomalies Clinic in Brasilia, Brazil. Physical and oral examinations, as well as radiographic and histopathological analyses, were performed on 28 affected and unaffected individuals. Clinical, radiographic and histopathological analyses confirmed the diagnosis of DGI-II in 19 individuals. Pulp stones were observed in ground sections of several teeth in 2 families, suggesting that obliteration of pulp chambers and root canals results from the growth of these nodular structures. Mutational DSPP gene analysis of representative affected family members revealed 7 various non-disease-causing alterations in exons 1–4 within the dentin sialoprotein domain. Further longitudinal studies are necessary to elucidate the progression of pulpal obliteration in the DGI-II patients studied as well as the molecular basis of their disease. PMID:18797159

  9. Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4.

    PubMed

    Abdul-Rahman, Omar A; La, Trang H; Kwan, Andrea; Schlaubitz, Silke; Barsh, Greg S; Enns, Gregory M; Hudgins, Louanne

    2006-07-15

    Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.

  10. Expansion of the TARP syndrome phenotype associated with de novo mutations and mosaicism.

    PubMed

    Johnston, Jennifer J; Sapp, Julie C; Curry, Cynthia; Horton, Margaret; Leon, Eyby; Cusmano-Ozog, Kristina; Dobyns, William B; Hudgins, Louanne; Zackai, Elaine; Biesecker, Leslie G

    2014-01-01

    The TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) is an X-linked disorder that was determined to be caused by mutations in RBM10 in two families, and confirmed in a subsequent case report. The first two original families were quite similar in phenotype, with uniform early lethality although a confirmatory case report showed survival into childhood. Here we report on five affecteds from three newly recognized families, including patients with atypical manifestations. None of the five patients had talipes and others also lacked cardinal TARP features of Robin sequence and atrial septal defect. All three families demonstrated de novo mutations, and one of the families had two recurrences, with demonstrable maternal mosaicism.

  11. Neuroimaging features in C9orf72 and TARDBP double mutation with FTD phenotype.

    PubMed

    Origone, Paola; Accardo, Jennifer; Verdiani, Simonetta; Lamp, Merit; Arnaldi, Dario; Bellone, Emilia; Picco, Agnese; Morbelli, Silvia; Mandich, Paola; Nobili, Flavio

    2015-01-01

    Increasing evidence has shown that morphological and functional neuroimaging may help to understand the pathophysiological mechanisms leading to behavioral disturbances in patients with genetic or sporadic frontotemporal dementia (FTD). The C9orf72 expansion was found in association with the N267S TARDBP mutation in two siblings with behavioral-variant FTD (bvFTD). In one of them with very mild dementia, MRI showed symmetric atrophy of temporal, inferolateral and orbital frontal cortex, while [18F]FDG-PET disclosed more extended hypometabolism in dorsolateral and inferolateral frontal cortex, anterior cingulate, and caudate nucleus. Hypometabolism in right lateral and orbital frontal cortex was confirmed also in comparison with a group of sporadic bvFTD patients. These findings appear as the neuroimaging hallmark of double C9orf72 and TARDBP gene mutation with a bvFTD phenotype.

  12. Phenotypic spectrum of the Tubulin-related Disorders and Functional Implications of Disease-causing Mutations

    PubMed Central

    Tischfield, Max A.; Cederquist, Gustav Y.; Gupta, Mohan L.; Engle, Elizabeth C.

    2011-01-01

    A spectrum of neurological disorders characterized by abnormal neuronal migration, differentiation, and axon guidance and maintenance have recently been attributed to missense mutations in the genes that encode α– and β-tubulin isotypes TUBA1A, TUBA8, TUBB2B, and TUBB3, all of which putatively co-assemble into neuronal microtubules. The resulting nervous system malformations can include different types of cortical malformations, defects in commissural fiber tracts, and degeneration of motor and sensory axons. Many clinical phenotypes and brain malformations are shared among the various mutations regardless of structural location and/or isotype, while others segregate with distinct amino acids or functional domains within tubulin. Collectively, these disorders provide novel paradigms for understanding the biological functions of microtubules and their core components in normal health and disease. PMID:21292473

  13. Colorectal Carcinomas With CpG Island Methylator Phenotype 1 Frequently Contain Mutations in Chromatin Regulators

    PubMed Central

    Tahara, Tomomitsu; Yamamoto, Eiichiro; Madireddi, Priyanka; Suzuki, Hiromu; Maruyama, Reo; Chung, Woonbok; Garriga, Judith; Jelinek, Jaroslav; Yamano, Hiro-o; Sugai, Tamotsu; Kondo, Yutaka; Toyota, Minoru; Issa, Jean-Pierre J.; Estécio, Marcos R. H.

    2014-01-01

    BACKGROUND & AIMS Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients’ prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. METHODS We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. RESULTS We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate—dependent chromatin remodeling family. Somaticmutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P < .01) or CIMP-negative tumors (2 of 34 [6%]; P < .001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. CONCLUSIONS Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status. PMID

  14. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype.

    PubMed

    Romaniello, Romina; Saettini, Francesco; Panzeri, Elena; Arrigoni, Filippo; Bassi, Maria T; Borgatti, Renato

    2015-03-25

    This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin-binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors' density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy.

  15. Prediction of phenotypes of missense mutations in human proteins from biological assemblies.

    PubMed

    Wei, Qiong; Xu, Qifang; Dunbrack, Roland L

    2013-02-01

    Single nucleotide polymorphisms (SNPs) are the most frequent variation in the human genome. Nonsynonymous SNPs that lead to missense mutations can be neutral or deleterious, and several computational methods have been presented that predict the phenotype of human missense mutations. These methods use sequence-based and structure-based features in various combinations, relying on different statistical distributions of these features for deleterious and neutral mutations. One structure-based feature that has not been studied significantly is the accessible surface area within biologically relevant oligomeric assemblies. These assemblies are different from the crystallographic asymmetric unit for more than half of X-ray crystal structures. We find that mutations in the core of proteins or in the interfaces in biological assemblies are significantly more likely to be disease-associated than those on the surface of the biological assemblies. For structures with more than one protein in the biological assembly (whether the same sequence or different), we find the accessible surface area from biological assemblies provides a statistically significant improvement in prediction over the accessible surface area of monomers from protein crystal structures (P = 6e-5). When adding this information to sequence-based features such as the difference between wildtype and mutant position-specific profile scores, the improvement from biological assemblies is statistically significant but much smaller (P = 0.018). Combining this information with sequence-based features in a support vector machine leads to 82% accuracy on a balanced dataset of 50% disease-associated mutations from SwissVar and 50% neutral mutations from human/primate sequence differences in orthologous proteins.

  16. Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form.

    PubMed

    Tanaka, Akemi; Hoang, Lan Thi Ngcok; Nishi, Yasuaki; Maniwa, Satoshi; Oka, Makio; Yamano, Tsunekazu

    2003-01-01

    Eight mutations of the alpha subunit of beta-hexosaminidase A gene ( HEXA) were identified in eight patients with GM2 gangliosidosis variant B. They were five missense mutations, two splice-site mutations, and one two-base deletion. Five of them, R252L (CGT-->CTT), N295S (AAT-->AAC), W420C (TGG-->TGT), IVS 13, +2A-->C, and del 265-266AC (exon 2), were novel mutations responsible for infantile acute form of GM2 gangliosidosis. Two missense mutations, R499H and R499C, were found in one allele of two patients with attenuated phenotypes. The patient with R499C showed a late infantile form, and the other patient with R499H showed a juvenile form. These two mutations have been reported previously in the patients of other ethnic groups, and they have been known to cause attenuated phenotypes. The milder phenotypes of GM2 gangliosidosis variant B, different from the infantile acute form, have not been reported so far in Japan, and this is the first report of Japanese patients with attenuated phenotypes and their molecular analysis.

  17. Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes.

    PubMed

    Towns, Katherine V; Kipioti, Athina; Long, Vernon; McKibbin, Martin; Maubaret, Cecilia; Vaclavik, Veronika; Ehsani, Parastoo; Springell, Kelly; Kamal, Mohammed; Ramesar, Raj S; Mackey, David A; Moore, Anthony T; Mukhopadhyay, Rajarshi; Webster, Andrew R; Black, Graeme C M; O'Sullivan, James; Bhattacharya, Shomi S; Pierce, Eric A; Beggs, Jean D; Inglehearn, Chris F

    2010-05-01

    PRPF8-retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8-RP. Clinical data for 75 PRPF8-RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8-RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit. (c) 2010 Wiley-Liss, Inc.

  18. Chi Mutation in a Transposon and the Orientation-Dependence of Chi Phenotype

    PubMed Central

    Yagil, Ezra; Dower, Nancy A.; Chattoraj, Dhruba; Stahl, Mary; Pierson, Carey; Stahl, Franklin W.

    1980-01-01

    Chi, an element that stimulates recombination via the E. coli RecBC pathway, can arise by spontaneous mutation in the transposon Tn5. When in phage λ in one orientation, the mutant transposon confers Chi+ phenotype (large plaque and a high rate of exchange near the transposon). In the other orientation, however, the transposon does not confer Chi+ phenotype. The mobility of the transposon allows us to show that the Chi+ orientation of the mutant Tn5 is the same at different locations in λ. These include a site near gene J, one in gam at 69, one to the right of gam at 73 and several to the right of R between 95.7 and 99.5. To the right of R, the mutant transposon could be found in only one orientation, that which confers Chi+ phenotype. We speculate that the other orientation of Tn5 in that locale is lethal to λ. The orientation-dependence of Chi+ phenotype also revealed that Tn5 flip-flops in λ. PMID:6259016

  19. Two recessive mutations in FGF5 are associated with the long-hair phenotype in donkeys.

    PubMed

    Legrand, Romain; Tiret, Laurent; Abitbol, Marie

    2014-09-25

    Seven donkey breeds are recognized by the French studbook. Individuals from the Pyrenean, Provence, Berry Black, Normand, Cotentin and Bourbonnais breeds are characterized by a short coat, while those from the Poitou breed (Baudet du Poitou) are characterized by a long-hair phenotype. We hypothesized that loss-of-function mutations in the FGF5 (fibroblast growth factor 5) gene, which are associated with a long-hair phenotype in several mammalian species, may account for the special coat feature of Poitou donkeys. To the best of our knowledge, mutations in FGF5 have never been described in Equidae. We sequenced the FGF5 gene from 35 long-haired Poitou donkeys, as well as from a panel of 67 short-haired donkeys from the six other French breeds and 131 short-haired ponies and horses. We identified a recessive c.433_434delAT frameshift deletion in FGF5, present in Poitou and three other donkey breeds and a recessive nonsense c.245G > A substitution, present in Poitou and four other donkey breeds. The frameshift deletion was associated with the long-hair phenotype in Poitou donkeys when present in two copies (n = 31) or combined with the nonsense mutation (n = 4). The frameshift deletion led to a stop codon at position 159 whereas the nonsense mutation led to a stop codon at position 82 in the FGF5 protein. In silico, the two truncated FGF5 proteins were predicted to lack the critical β strands involved in the interaction between FGF5 and its receptor, a mandatory step to inhibit hair growth. Our results highlight the allelic heterogeneity of the long-hair phenotype in donkeys and enlarge the panel of recessive FGF5 loss-of-function alleles described in mammals. Thanks to the DNA test developed in this study, breeders of non-Poitou breeds will have the opportunity to identify long-hair carriers in their breeding stocks.

  20. XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

    SciTech Connect

    Tainer, John; Fan, Li; Fuss, Jill O.; Cheng, Quen J.; Arvai, Andrew S.; Hammel, Michal; Roberts, Victoria A.; Cooper, Priscilla K.; Tainer, John A.

    2008-06-02

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  1. XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

    SciTech Connect

    Fan, L.; Fuss, J.O.; Cheng, Q.J.; Arvai, A.S.; Hammel, M.; Roberts, V.A.; Cooper, P.K.; Tainer, J.A.

    2009-05-18

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicase activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.

  2. Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

    PubMed Central

    Caldovic, Ljubica; Abdikarim, Iman; Narain, Sahas; Tuchman, Mendel; Morizono, Hiroki

    2015-01-01

    Ornithine transcarbamylase (OTC) deficiency is an X-linked trait that accounts for nearly half of all inherited disorders of the urea cycle. OTC is one of the enzymes common to both the urea cycle and the bacterial arginine biosynthesis pathway; however, the role of OTC has changed over evolution. For animals with a urea cycle, defects in OTC can trigger hyperammonemic episodes that can lead to brain damage and death. This is the fifth mutation update for human OTC with previous updates reported in 1993, 1995, 2002, and 2006. In the 2006 update, 341 mutations were reported. This current update contains 417 disease-causing mutations, and also is the first report of this series to incorporate information about natural variation of the OTC gene in the general population through examination of publically available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study and the first to evaluate the suitability of systematic computational approaches to predict severity of disease associated with different types of OTC mutations. PMID:26059767

  3. Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome.

    PubMed

    Vaziri-Sani, F; Holmberg, L; Sjöholm, A G; Kristoffersson, A-C; Manea, M; Frémeaux-Bacchi, V; Fehrman-Ekholm, I; Raafat, R; Karpman, D

    2006-03-01

    We investigated the phenotypic expression of factor H mutations in two patients with atypical hemolytic uremic syndrome (HUS). Factor H in serum was assayed by rocket immunoelectrophoresis, immunoblotting, and double immunodiffusion and in tissue by immunohistochemistry. Functional activity was analyzed by hemolysis of sheep erythrocytes and binding to endothelial cells. A homozygous mutation in complement control protein (CCP) domain 10 of factor H was identified in an adult man who first developed membranoproliferative glomerulonephritis and later HUS. C3 levels were very low. The patient had undetectable factor H levels in serum and a weak factor H 150 kDa band. Double immunodiffusion showed partial antigenic identity with factor H in normal serum owing to the presence of factor H-like protein 1. Strong specific labeling for factor H was detected in glomerular endothelium, mesangium and in glomerular and tubular epithelium as well as in bone marrow cells. A heterozygous mutation in CCP 20 of factor H was found in a girl with HUS. C3 levels were moderately decreased at onset. Factor H levels were normal and a normal 150 kDa band was present. Double immunodiffusion showed antigenic identity with normal factor H. Factor H labeling was minimal in the renal cortex. Factor H dysfunction was demonstrated by increased sheep erythrocyte hemolysis and decreased binding to endothelial cells. In summary, two different factor H mutations associated with HUS were examined: in one, factor H accumulated in cells, and in the other, membrane binding was reduced.

  4. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update.

    PubMed

    Caldovic, Ljubica; Abdikarim, Iman; Narain, Sahas; Tuchman, Mendel; Morizono, Hiroki

    2015-05-20

    Ornithine transcarbamylase (OTC) deficiency is an X-linked trait that accounts for nearly half of all inherited disorders of the urea cycle. OTC is one of the enzymes common to both the urea cycle and the bacterial arginine biosynthesis pathway; however, the role of OTC has changed over evolution. For animals with a urea cycle, defects in OTC can trigger hyperammonemic episodes that can lead to brain damage and death. This is the fifth mutation update for human OTC with previous updates reported in 1993, 1995, 2002, and 2006. In the 2006 update, 341 mutations were reported. This current update contains 417 disease-causing mutations, and also is the first report of this series to incorporate information about natural variation of the OTC gene in the general population through examination of publicly available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study and the first to evaluate the suitability of systematic computational approaches to predict severity of disease associated with different types of OTC mutations.

  5. Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.

    PubMed

    Gripp, K W; Stolle, C A; McDonald-McGinn, D M; Markowitz, R I; Bartlett, S P; Katowitz, J A; Muenke, M; Zackai, E H

    1998-07-24

    We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay. His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs. Our patient most closely resembles the case described by Kerr et al. [1996: Am J Med Genet 66:138-143] as Pfeiffer syndrome type III with normal thumbs. Mutations in the genes for fibroblast growth factor receptors (FGFR) 1 and 2 have previously been seen in patients with Pfeiffer syndrome type I. The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III. An identical mutation was described once previously by Pulleyn et al., in a patient whose brief clinical description included cloverleaf skull, significant developmental delay, and normal hands and feet [Eur. J. Hum. Genet. 4: 283-291, 1996]. In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis.

  6. Further defining the phenotypic spectrum of B4GALT7 mutations.

    PubMed

    Salter, Claire G; Davies, Justin H; Moon, Rebecca J; Fairhurst, Joanna; Bunyan, David; Foulds, Nicola

    2016-06-01

    Proteoglycans are components of the extracellular matrix with diverse biological functions. Defects in proteoglycan synthesis have been linked to several human diseases with common features of short stature, hypermobility, joint dislocations, and skeletal dysplasia. B4GALT7 encodes galactosyltransferase-I that catalyzes the addition of a galactose moiety to a xylosyl group in the tetrasaccharide linker of proteoglycans. Mutations in this gene have been associated with the rare progeroid form of Ehlers Danlos syndrome and in addition more recently found to underlie Larsen of Reunion Island syndrome. Nine individuals have been reported with a diagnosis of the progeroid form of Ehlers Danlos syndrome, four of whom have had molecular characterization showing homozygous or compound heterozygous mutations in B4GALT7. We report two newly described patients with compound heterozygous mutations in B4GALT7, and show that the six individuals with confirmed mutations do not have the progeroid features described in the original five patients with a clinical diagnosis of the progeroid form of Ehlers Danlos syndrome. We suggest that galactosyltransferase-I deficiency does not cause the progeroid form of Ehlers Danlos syndrome, but instead results in a clinically recognizable syndrome comprising short stature, joint hypermobility, radioulnar synostosis, and severe hypermetropia. This group of syndromic patients are on a phenotypic spectrum with individuals who have Larsen of Reunion Island syndrome, although the key features of osteopenia, fractures and hypermetropia have not been reported in patients from Reunion Island. © 2016 Wiley Periodicals, Inc.

  7. Different phenotypes in vivo are associated with ATPase motif mutations in Schizosaccharomyces pombe minichromosome maintenance proteins.

    PubMed Central

    Gómez, Eliana B; Catlett, Michael G; Forsburg, Susan L

    2002-01-01

    The six conserved MCM proteins are essential for normal DNA replication. They share a central core of homology that contains sequences related to DNA-dependent and AAA(+) ATPases. It has been suggested that the MCMs form a replicative helicase because a hexameric subcomplex formed by MCM4, -6, and -7 proteins has in vitro DNA helicase activity. To test whether ATPase and helicase activities are required for MCM protein function in vivo, we mutated conserved residues in the Walker A and Walker B motifs of MCM4, -6, and -7 and determined that equivalent mutations in these three proteins have different in vivo effects in fission yeast. Some mutations reported to abolish the in vitro helicase activity of the mouse MCM4/6/7 subcomplex do not affect the in vivo function of fission yeast MCM complex. Mutations of consensus CDK sites in Mcm4p and Mcm7p also have no phenotypic consequences. Co-immunoprecipitation analyses and in situ chromatin-binding experiments were used to study the ability of the mutant Mcm4ps to associate with the other MCMs, localize to the nucleus, and bind to chromatin. We conclude that the role of ATP binding and hydrolysis is different for different MCM subunits. PMID:11973289

  8. Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation

    PubMed Central

    Doi, Hiroshi; Ushiyama, Masao; Baba, Takashi; Tani, Katsuko; Shiina, Masaaki; Ogata, Kazuhiro; Miyatake, Satoko; Fukuda-Yuzawa, Yoko; Tsuji, Shoji; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Saitsu, Hirotomo; Ikeda, Shu-ichi; Tanaka, Fumiaki; Matsumoto, Naomichi; Yoshida, Kunihiro

    2014-01-01

    Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias (ARHSPs) are clinically and genetically heterogeneous neurological disorders. Herein we describe Japanese siblings with a midlife-onset, slowly progressive type of cerebellar ataxia and spastic paraplegia, without intellectual disability. Using whole exome sequencing, we identified a homozygous missense mutation in DDHD2, whose mutations were recently identified as the cause of early-onset ARHSP with intellectual disability. Brain MRI of the patient showed a thin corpus callosum. Cerebral proton magnetic resonance spectroscopy revealed an abnormal lipid peak in the basal ganglia, which has been reported as the hallmark of DDHD2-related ARHSP (SPG 54). The mutation caused a marked reduction of phospholipase A1 activity, supporting that this mutation is the cause of SPG54. Our cases indicate that the possibility of SPG54 should also be considered when patients show a combination of adult-onset spastic ataxia and a thin corpus callosum. Magnetic resonance spectroscopy may be helpful in the differential diagnosis of patients with spastic ataxia phenotype. PMID:25417924

  9. Autosomal dominant spinal muscular atrophy with lower extremity predominance: A recognizable phenotype of BICD2 mutations.

    PubMed

    Rudnik-Schöneborn, Sabine; Deden, Florian; Eggermann, Katja; Eggermann, Thomas; Wieczorek, Dagmar; Sellhaus, Bernd; Yamoah, Alfred; Goswami, Anand; Claeys, Kristl G; Weis, Joachim; Zerres, Klaus

    2016-09-01

    Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED). We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy. We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype. The patients had congenital foot contractures, muscle atrophy of the legs, and slowly progressive weakness of the shoulder girdle. There was no apparent sensory or brain dysfunction. One patient died of unrelated reasons at age 52 years. Autopsy revealed no upper motor neuron and only moderate lower motor neuron loss, but there was distal corticospinal tract degeneration and marked neurogenic muscular atrophy. These findings give further insight into the clinical and pathoanatomical consequences of BICD2 mutations. Muscle Nerve 54: 496-500, 2016. © 2016 Wiley Periodicals, Inc.

  10. Pleiotropic effect of a novel mutation in GCNT2 causing congenital cataract and a rare adult i blood group phenotype

    PubMed Central

    Cheong, Sek-Shir; Hull, Sarah; Jones, Benjamin; Chana, Ravinder; Thornton, Nicole; Plagnol, Vincent; Moore, Anthony T; Hardcastle, Alison J

    2017-01-01

    Mutations in GCNT2 have been associated with the rare adult i blood group phenotype with or without congenital cataract. We report a novel homozygous frameshift mutation c.1163_1166delATCA, p.(Asn388Argfs*20) as the cause of congenital cataract in two affected siblings. Blood group typing confirmed that both affected males have the rare adult i phenotype, supporting the hypothesis that the partial association of I/i phenotype and congenital cataract is due to the differential expression of GCNT2 isoforms. PMID:28224043

  11. Simultaneous Expression of ABCA4 and GPR143 Mutations: A Complex Phenotypic Manifestation

    PubMed Central

    Lee, Winston; Schuerch, Kaspar; Xie, Yajing; Zernant, Jana; Tsang, Stephen H.; Sparrow, Janet R.; Allikmets, Rando

    2016-01-01

    Purpose To describe the complex, overlapping phenotype expressed in a two generation family harboring pathogenic mutations in the ABCA4 and GPR143 genes. Methods Clinical evaluation of a two generation family included quantitative autofluorescence imaging (qAF, 488-nm excitation) using a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for varying laser power detector sensitivity, spectral-domain optical coherence tomography, and full-field ERG testing. Complete sequencing of the ABCA4 and GPR143 genes was carried out in each individual. Results Affected individuals presented with bull's eye lesions and qAF levels above the 95% confidence interval for healthy eyes; full-field ERG revealed no generalized rod dysfunction but mild implicit time delays in cone responses. Complete sequencing of the ABCA4 gene revealed two disease-causing mutations, p.L541P and p.G1961E; and mutational phase was confirmed in each unaffected parent. Further examination in the affected patients revealed a peripheral “mud-splattered” pattern of hypopigmented RPE after which sequencing of GPR143 revealed a novel missense variant, p.Y157C. The GPR143 variant segregated from the father who did not exhibit any indications of retinal disease with the exception of an abnormal near-infrared autofluorescence (NIR-AF) signal distribution in the macula. Conclusions An individual carrying both ABCA4 and GPR143 disease-causing mutations can express a complex, overlapping phenotype associated with both Stargardt disease and X-linked ocular albinism (OA1). The absence of OA1-related disease changes (with the exception of NIR-AF changes associated with melanin distribution) in the father may be indicative of mild expressivity or variable gene penetrance. PMID:27367509

  12. Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene

    PubMed Central

    D'Adamo, Maria C.; Gallenmüller, Constanze; Servettini, Ilenio; Hartl, Elisabeth; Tucker, Stephen J.; Arning, Larissa; Biskup, Saskia; Grottesi, Alessandro; Guglielmi, Luca; Imbrici, Paola; Bernasconi, Pia; Di Giovanni, Giuseppe; Franciolini, Fabio; Catacuzzeno, Luigi; Pessia, Mauro; Klopstock, Thomas

    2015-01-01

    Episodic ataxia type 1 (EA1) is an autosomal dominant K+ channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K+ channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K+ channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1. PMID:25642194

  13. MUTATIONS IN TTC37 CAUSE TRICHOHEPATOENTERIC SYNDROME (PHENOTYPIC DIARRHOEA OF INFANCY)

    PubMed Central

    Hartley, Jane Louise; Zachos, Nicholas C.; Dawood, Ban; Donowitz, Mark; Forman, Julia; Pollitt, Rodney J; Morgan, Neil V; Tee, Louise; Gissen, Paul; Kahr, Walter H.A.; Knisely, A.S.; Watson, Steve; Chitayat, David; Booth, IW; Protheroe, Sue; Murphy, Stephen; de Vries, Esther; Kelly, Deirdre A; Maher, Eamonn R

    2010-01-01

    Background Trichohepatoenteric syndrome (THES) is an autosomal recessive disorder characterised by life-threatening diarrhoea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation and cardiac defects. We attempted to characterise the phenotype and elucidate the molecular basis of THES. Methods Twelve patients with classical THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250k single nucleotide polymorphism (SNP) arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analysed. The effect of mutations on protein production and/or localisation in hepatocytes and intestinal epithelial cells from affected patients was characterised by immunohistochemistry. Results Previously unrecognised platelet abnormalities (reduced platelet α-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3 – 5q21.2. Sequencing of candidate genes demonstrated mutations in TTC37, which encodes the uncharacterised tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (NHE2, NHE3, Aquaporin 7, Na/I symporter and H / K ATPase) showed reduced expression or mislocalisation in all THES patients with different profiles for each. In contrast the basolateral localisation of Na/K ATPase was not altered. Conclusion THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect which may be due to abnormal stability and / or intracellular localisation of TTC37 target proteins. PMID:20176027

  14. Ophthalmological phenotype associated with homozygous null mutation in the NEUROD1 gene

    PubMed Central

    Orosz, Orsolya; Czeglédi, Miklós; Kántor, Irén; Balogh, István; Vajas, Attila; Takács, Lili; Berta, András

    2015-01-01

    Purpose NEUROD1 is a tissue-specific basic helix loop helix (bHLH) protein involved in the development and maintenance of the endocrine pancreas and neuronal elements. Loss of NEUROD1 causes ataxia, cerebellar hypoplasia, sensorineural deafness, and severe retinal dystrophy in mice. Heterozygous loss-of-function mutations in NEUROD1 have previously been described as a cause of maturity-onset diabetes of the young (MODY) and late-onset diabetes. To date, homozygous loss-of-function NEUROD1 mutations have only been detected in two patients. Both mutations caused permanent neonatal diabetes and severe neurologic defects, including visual impairment. However, a detailed ophthalmological phenotype of this novel syndrome has not yet been reported. Our aim was to characterize the ophthalmological phenotype associated with the previously reported homozygous c.427_428CT mutation in the NEUROD1 gene. Methods The female patient was investigated on multiple occasions between 2009 (age 14) and 2014 (age 19), including visual acuity testing, automated perimetry, funduscopy, anterior-segment imaging, optical coherence tomography of the posterior pole, standard full-field electroretinography, and fundus-autofluorescence imaging. Results The patient had nyctalopia, blurry vision, and visual field constriction from early childhood. Her best corrected visual acuity ranged between 20/25 and 15/25 during the investigation period. Perimetry showed concentric constriction of the visual field, sparing only the central 30 degrees in both eyes. The anterior segment did not show any morphological changes. Optical coherence tomography revealed total absence of the photoreceptor layer of the retina outside the fovea, where a discoid remnant of cone photoreceptors could be detected. Neither setting of the standard full-field electroretinography could detect any electrical response from the retina. Color fundus photos presented peripheral chorioretinal atrophy and central RPE mottling. A

  15. Diverse Phenotypic Expression of Cardiomyopathies in a Family with TNNI3 p.Arg145Trp Mutation

    PubMed Central

    Hwang, Ji-won; Jang, Mi-Ae; Jang, Shin Yi; Seo, Soo Hyun; Seong, Moon-Woo; Park, Sung Sup; Ki, Chang-Seok

    2017-01-01

    Genetic diagnosis of cardiomyopathies is challenging, due to the marked genetic and allelic heterogeneity and the lack of knowledge of the mutations that lead to clinical phenotypes. Here, we present the case of a large family, in which a single TNNI3 mutation caused variable phenotypic expression, ranging from restrictive cardiomyopathy (RCMP) to hypertrophic cardiomyopathy (HCMP) to near-normal phenotype. The proband was a 57-year-old female with HCMP. Examining the family history revealed that her elder sister had expired due to severe RCMP. Using a next-generation sequencing-based gene panel to analyze the proband, we identified a known TNNI3 gene mutation, c.433C>T, which is predicted to cause an amino acid substitution (p.Arg145Trp) in the highly conserved inhibitory region of the cardiac troponin I protein. Sanger sequencing confirmed that six relatives with RCMP or near-normal phenotypes also carried this mutation. To our knowledge, this is the first genetically confirmed family with diverse phenotypic expression of cardiomyopathies in Korea. Our findings demonstrate familial implications, where a single mutation in a sarcomere protein can cause diverse phenotypic expression of cardiomyopathies. PMID:28382084

  16. Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis

    PubMed Central

    Yönal, İpek; Dağlar-Aday, Aynur; Akadam-Teker, Başak; Yılmaz, Ceylan; Nalçacı, Meliha; Yavuz, Akif Selim; Sargın, Fatma Deniz

    2016-01-01

    Objective: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. Materials and Methods: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. Results: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb) and hematocrit (Hct) levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. Conclusion: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype. PMID:25913509

  17. Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3.

    PubMed

    Shalev, Stavit Allon; Khayat, Morad; Etty, Daniel-Spiegl; Elpeleg, Orly

    2015-03-01

    Mutations in genes encoding the origin recognition complex subunits cause Meier-Gorlin syndrome. The disease manifests a triad of short stature, small ears, and small and/or absent patellae with variable expressivity. We report on the identification of a homozygous deleterious mutation in the ORC6 gene in previously described fetuses at the severe end of the Meier-Gorlin spectrum. The phenotype included severe intrauterine growth retardation, dislocation of knees, gracile bones, clubfeet, and small mandible and chest. To date, the clinical presentation of ORC6-associated Meier-Gorlin syndrome has been mild compared to other the phenotype associated with other loci. The present report expands the clinical phenotype associated with ORC6 mutations to include severely abnormal embryological development suggesting a possible genotype-phenotype correlation.

  18. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

    PubMed

    Gil-Rodríguez, María Concepción; Deardorff, Matthew A; Ansari, Morad; Tan, Christopher A; Parenti, Ilaria; Baquero-Montoya, Carolina; Ousager, Lilian B; Puisac, Beatriz; Hernández-Marcos, María; Teresa-Rodrigo, María Esperanza; Marcos-Alcalde, Iñigo; Wesselink, Jan-Jaap; Lusa-Bernal, Silvia; Bijlsma, Emilia K; Braunholz, Diana; Bueno-Martinez, Inés; Clark, Dinah; Cooper, Nicola S; Curry, Cynthia J; Fisher, Richard; Fryer, Alan; Ganesh, Jaya; Gervasini, Cristina; Gillessen-Kaesbach, Gabriele; Guo, Yiran; Hakonarson, Hakon; Hopkin, Robert J; Kaur, Maninder; Keating, Brendan J; Kibaek, María; Kinning, Esther; Kleefstra, Tjitske; Kline, Antonie D; Kuchinskaya, Ekaterina; Larizza, Lidia; Li, Yun R; Liu, Xuanzhu; Mariani, Milena; Picker, Jonathan D; Pié, Ángeles; Pozojevic, Jelena; Queralt, Ethel; Richer, Julie; Roeder, Elizabeth; Sinha, Anubha; Scott, Richard H; So, Joyce; Wusik, Katherine A; Wilson, Louise; Zhang, Jianguo; Gómez-Puertas, Paulino; Casale, César H; Ström, Lena; Selicorni, Angelo; Ramos, Feliciano J; Jackson, Laird G; Krantz, Ian D; Das, Soma; Hennekam, Raoul C M; Kaiser, Frank J; FitzPatrick, David R; Pié, Juan

    2015-04-01

    Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼ 1%-2% of CdLS-like phenotypes. © 2015 WILEY PERIODICALS, INC.

  19. Asymmetric phenotype of Axenfeld-Rieger anomaly and aniridia associated with a novel PITX2 mutation

    PubMed Central

    Sami, Maha; Piri, Natik; Coleman, Anne L.; Caprioli, Joseph

    2011-01-01

    Purpose To evaluate the asymmetry of the anterior segment phenotype between the two eyes of a patient with Axenfeld-Rieger syndrome (ARS). Methods The entire database of a tertiary glaucoma practice was screened for patients with ARS. The medical records of patients with ARS were reviewed. The clinical characteristics of ocular examination of the two eyes of each patient were recorded and compared. Dental and medical information were also reviewed where available. The anterior segment phenotype was tabulated to assess asymmetry. Asymmetric anterior segment characteristics of patients with ARS were compared with reported cases in the literature. Results Eight patients with ARS were identified from screening of more than 5,000 patients of a tertiary glaucoma practice. All patients had Axenfeld-Rieger anomaly in both eyes except one patient presented with an asymmetric phenotype of the anterior segment with features of Axenfeld-Rieger anomaly in one eye, but aniridia in the other eye. This patient had non-ocular findings including flat midface, hypodontia with lack of an upper incisor, and redundant periumbilical skin, typical for ARS. A heterozygous C>T nucleotide substitution was identified in exon 4 of the pituitary homeobox 2 (PITX2) gene, resulting in the replacement of a glutamine codon (CAG) with a stop codon (TAG) at amino acid position 67. This mutation is denoted c.199C>T at the cDNA level or p.Gln67Stop (or Q67X) at the protein level. Only three cases with asymmetric anterior segment phenotype between the two eyes of a patient with AGS have been reported in the literature. Conclusions Variability in phenotype may occur between the two eyes of an individual affected by ARS. The current case undermines the advantage of genetic testing to correctly diagnose a rare disease. PMID:21617748

  20. UV fingerprints predominate in the PTCH mutation spectra of basal cell carcinomas independent of clinical phenotype.

    PubMed

    Heitzer, Ellen; Lassacher, Anita; Quehenberger, Franz; Kerl, Helmut; Wolf, Peter

    2007-12-01

    Basal cell carcinoma (BCC) shows a wide interpatient variation in lesion accrual. To determine whether certain tumorigenic fingerprints and potentially predisposing patched (PTCH) tumor suppressor single-nucleotide polymorphisms (SNPs) are distributed differently among sporadic BCC patients, we compared the PTCH mutation spectra in early-onset BCC (first lesion at age < 35 years), regular BCC (first lesion at age > or = 35 years and < 10 lesions), and multiple BCC (> or = 10 lesions). The PTCH gene was mutated in 29 of 60 cases (48%). Most of the PTCH mutations bore the UV fingerprint (i.e., C --> T or tandem CC --> TT transitions at dipyrimidine sites). However, neither the proportion nor the spectra of exonic PTCH mutations differed significantly among the three groups. A large number of SNPs (IVS10+99C/T, IVS11-51G/C, 1665T/C, 1686C/T, IVS15+9G/C, IVS16-80G/C, IVS17+21G/A, and 3944C/T or its combinations) were also detected, but again their incidence did not differ significantly among the groups. Interestingly, expression of the IVS16-80G/C and the IVS17+21G/A genotype did not achieve the Hardy-Weinberg equilibrium in patients with regular and/or early-onset BCC. These data suggest that a (UV-) mutated PTCH gene is important for sporadic BCC formation independent of clinical phenotype and that the IVS16-80G/C and/or IVS17+21G/A SNP site might be important for tumorigenesis in certain BCC patients.

  1. Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.

    PubMed

    Kaustio, Meri; Haapaniemi, Emma; Göös, Helka; Hautala, Timo; Park, Giljun; Syrjänen, Jaana; Einarsdottir, Elisabet; Sahu, Biswajyoti; Kilpinen, Sanna; Rounioja, Samuli; Fogarty, Christopher L; Glumoff, Virpi; Kulmala, Petri; Katayama, Shintaro; Tamene, Fitsum; Trotta, Luca; Morgunova, Ekaterina; Krjutškov, Kaarel; Nurmi, Katariina; Eklund, Kari; Lagerstedt, Anssi; Helminen, Merja; Martelius, Timi; Mustjoki, Satu; Taipale, Jussi; Saarela, Janna; Kere, Juha; Varjosalo, Markku; Seppänen, Mikko

    2017-09-01

    The nuclear factor κ light-chain enhancer of activated B cells (NF-κB) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency. We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation. We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles. In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behçet disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions. Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behçet disease, can be caused by rare monogenic variants in genes of the NF-κB pathway. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All

  2. Correlation between gene expression and mutator phenotype predicts homologous recombination deficiency and outcome in ovarian cancer.

    PubMed

    Lu, Jianping; Wu, Di; Li, Chuanxing; Zhou, Meng; Hao, Dapeng

    2014-11-01

    New strategies are needed to predict response to platinum-based chemotherapy and outcome of ovarian cancers. We hypothesized that the mutator phenotype in the cancer genome represents the overuse of alternative DNA repair mechanisms, which might be a sign of homologous recombination (HR) deficiency and can be captured by gene expression. Multidimensional data of ovarian cancer patients and breast cancer patients from The Cancer Genome Atlas (TCGA) database were used for the development and validation of a potential clinical information-independent score that correlates with HR deficiency and predicts outcome. Correlation of the score with platinum response, outcome, and BRCA mutations was assessed. The score correlated with increased genomic mutation rate in both ovarian cancer and breast cancer cases that harbored a substantial subset of HR-deficient samples. Significantly improved outcomes were observed in the high-scoring group versus the low-scoring group in the TCGA dataset and in three large gene expression microarray datasets. A strong correlation was found between the score and the likelihood of achieving complete response to chemotherapy. The score was also found to be highly robust to noises in genomic mutations. Sixty-four patients harboring BRCA mutations were successfully divided into two groups based on scores, with the high-scoring group showing significantly improved outcomes compared with wild-type cases and the low-scoring group showing no significance in all the same analyses. The score was significantly correlated with the response to platinum therapy and outcome. Evaluation of the score as a prognostic tool in ovarian cancer patients is warranted. We develop a diagnostic signature for the HR-deficiency based on a novel hypothesis. HR-deficiency score is significantly correlated to platinum therapy and outcomes. HRDS was validated by its association with OS, PFS, DFS and CR in validation datasets. Evaluation of the score as a prognostic tool in

  3. Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype.

    PubMed

    Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Jiao, Kangwei; Buena-Atienza, Elena; Sahaboglu, Ayse; Trifunović, Dragana; Balendran, Sukirthini; Koepfli, Tanja; Mühlfriedel, Regine; Schön, Christian; Biel, Martin; Heckmann, Angelique; Beck, Susanne C; Michalakis, Stylianos; Wissinger, Bernd; Seeliger, Mathias W; Paquet-Durand, François

    2015-10-01

    Mutations in the PDE6A gene can cause rod photoreceptors degeneration and the blinding disease retinitis pigmentosa (RP). While a number of pathogenic PDE6A mutations have been described, little is known about their impact on compound heterozygous situations and potential interactions of different disease-causing alleles. Here, we used a novel mouse model for the Pde6a R562W mutation in combination with an existing line carrying the V685M mutation to generate compound heterozygous Pde6a V685M/R562W animals, exactly homologous to a case of human RP. We compared the progression of photoreceptor degeneration in these compound heterozygous mice with the homozygous V685M and R562W mutants, and additionally with the D670G line that is known for a relatively mild phenotype. We investigated PDE6A expression, cyclic guanosine mono-phosphate accumulation, calpain and caspase activity, in vivo retinal function and morphology, as well as photoreceptor cell death and survival. This analysis confirms the severity of different Pde6a mutations and indicates that compound heterozygous mutants behave like intermediates of the respective homozygous situations. Specifically, the severity of the four different Pde6a situations may be categorized by the pace of photoreceptor degeneration: V685M (fastest) > V685M/R562W > R562W > D670G (slowest). While calpain activity was strongly increased in all four mutants, caspase activity was not. This points to the execution of non-apoptotic cell death and may lead to the identification of new targets for therapeutic interventions. For individual RP patients, our study may help to predict time-courses for Pde6a-related retinal degeneration and thereby facilitate the definition of a window-of-opportunity for clinical interventions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita.

    PubMed

    Ekhilevitch, N; Kurolap, A; Oz-Levi, D; Mory, A; Hershkovitz, T; Ast, G; Mandel, H; Baris, H N

    2016-07-01

    Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous nonprogressive multiple joint contractures appearing at birth. We present a consanguineous Israeli-Druze family with several members presenting with AMC. A variable intra-familial phenotype and pected autosomal recessive inheritance prompted molecular diagnosis by whole-exome sequencing. Variant analysis focused on rare homozygous changes, revealed a missense variant in MYBPC1, NM_002465:c.556G>A (p.E286K), affecting the last nucleotide of Exon 8. This novel variant was not observed in the common variant databases and co-segregated as expected within the extended family. MYBPC1 encodes a slow skeletal muscle isoform, essential for muscle contraction. Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4. We present a novel milder MYBPC1 homozygous phenotype. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. A de novo dominant mutation in ACTA1 causing congenital nemaline myopathy associated with a milder phenotype: expanding the spectrum of dominant ACTA1 mutations.

    PubMed

    Levesque, L; Del Bigio, M R; Krawitz, S; Mhanni, A A

    2013-03-01

    We describe the presentation and six-year follow up of a child with nemaline myopathy due to a de novo mutation in the skeletal muscle α-actin gene (ACTA1) characterized by dramatic improvement during the early childhood years. The presentation in this female patient was infantile-onset weakness in the facial, bulbar, respiratory and neck flexor muscles. A six-year follow-up revealed continued progressive improvement in her muscle strength. Based upon the histopathologic and ultrastructural features of nemaline rod disease, ACTA1 was sequenced. This revealed a mutation in exon 4 of ACTA1 (c.557A>G). Our report further expands the phenotypic spectrum associated with ACTA1 mutations. Although it is difficult to infer any genotype-phenotype correlation, this report stimulates the discussion regarding the pathophysiologic mechanism of the clinical improvement seen in some patients with ACTA1 mutations. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Identification of a novel frameshift mutation in the ILDR1 gene in a UAE family, mutations review and phenotype genotype correlation.

    PubMed

    Tlili, Abdelaziz; Fahd Al Mutery, Abdullah; Mahfood, Mona; Kamal Eddine Ahmad Mohamed, Walaa; Bajou, Khalid

    2017-01-01

    Autosomal recessive non-syndromic hearing loss is one of the most common monogenic diseases. It is characterized by high allelic and locus heterogeneities that make a precise diagnosis difficult. In this study, whole-exome sequencing was performed for an affected patient allowing us to identify a new frameshift mutation (c.804delG) in the Immunoglobulin-Like Domain containing Receptor-1 (ILDR1) gene. Direct Sanger sequencing and segregation analysis were performed for the family pedigree. The mutation was homozygous in all affected siblings but heterozygous in the normal consanguineous parents. The present study reports a first ILDR1 gene mutation in the UAE population and confirms that the whole-exome sequencing approach is a robust tool for the diagnosis of monogenic diseases with high levels of allelic and locus heterogeneity. In addition, by reviewing all reported ILDR1 mutations, we attempt to establish a genotype phenotype correlation to explain the phenotypic variability observed at low frequencies.

  7. Phenotypes of Recessive Pediatric Cataract in a Cohort of Children with Identified Homozygous Gene Mutations (An American Ophthalmological Society Thesis).

    PubMed

    Khan, Arif O; Aldahmesh, Mohammed A; Alkuraya, Fowzan S

    2015-01-01

    To assess for phenotype-genotype correlations in families with recessive pediatric cataract and identified gene mutations. Retrospective review (2004 through 2013) of 26 Saudi Arabian apparently nonsyndromic pediatric cataract families referred to one of the authors (A.O.K.) and for which recessive gene mutations were identified. Fifteen different homozygous recessive gene mutations were identified in the 26 consanguineous families; two genes and five families are novel to this study. Ten families had a founder CRYBB1 deletion (all with bilateral central pulverulent cataract), two had the same missense mutation in CRYAB (both with bilateral juvenile cataract with marked variable expressivity), and two had different mutations in FYCO1 (both with bilateral posterior capsular abnormality). The remaining 12 families each had mutations in 12 different genes (CRYAA, CRYBA1, AKR1E2, AGK, BFSP2, CYP27A1, CYP51A1, EPHA2, GCNT2, LONP1, RNLS, WDR87) with unique phenotypes noted for CYP27A1 (bilateral juvenile fleck with anterior and/or posterior capsular cataract and later cerebrotendinous xanthomatosis), EPHA2 (bilateral anterior persistent fetal vasculature), and BFSP2 (bilateral flecklike with cloudy cortex). Potential carrier signs were documented for several families. In this recessive pediatric cataract case series most identified genes are noncrystallin. Recessive pediatric cataract phenotypes are generally nonspecific, but some notable phenotypes are distinct and associated with specific gene mutations. Marked variable expressivity can occur from a recessive missense CRYAB mutation. Genetic analysis of apparently isolated pediatric cataract can sometimes uncover mutations in a syndromic gene. Some gene mutations seem to be associated with apparent heterozygous carrier signs.

  8. Phenotypes of Recessive Pediatric Cataract in a Cohort of Children with Identified Homozygous Gene Mutations (An American Ophthalmological Society Thesis)

    PubMed Central

    Khan, Arif O.; Aldahmesh, Mohammed A.; Alkuraya, Fowzan S.

    2015-01-01

    Purpose: To assess for phenotype-genotype correlations in families with recessive pediatric cataract and identified gene mutations. Methods: Retrospective review (2004 through 2013) of 26 Saudi Arabian apparently nonsyndromic pediatric cataract families referred to one of the authors (A.O.K.) and for which recessive gene mutations were identified. Results: Fifteen different homozygous recessive gene mutations were identified in the 26 consanguineous families; two genes and five families are novel to this study. Ten families had a founder CRYBB1 deletion (all with bilateral central pulverulent cataract), two had the same missense mutation in CRYAB (both with bilateral juvenile cataract with marked variable expressivity), and two had different mutations in FYCO1 (both with bilateral posterior capsular abnormality). The remaining 12 families each had mutations in 12 different genes (CRYAA, CRYBA1, AKR1E2, AGK, BFSP2, CYP27A1, CYP51A1, EPHA2, GCNT2, LONP1, RNLS, WDR87) with unique phenotypes noted for CYP27A1 (bilateral juvenile fleck with anterior and/or posterior capsular cataract and later cerebrotendinous xanthomatosis), EPHA2 (bilateral anterior persistent fetal vasculature), and BFSP2 (bilateral flecklike with cloudy cortex). Potential carrier signs were documented for several families. Conclusions: In this recessive pediatric cataract case series most identified genes are noncrystallin. Recessive pediatric cataract phenotypes are generally nonspecific, but some notable phenotypes are distinct and associated with specific gene mutations. Marked variable expressivity can occur from a recessive missense CRYAB mutation. Genetic analysis of apparently isolated pediatric cataract can sometimes uncover mutations in a syndromic gene. Some gene mutations seem to be associated with apparent heterozygous carrier signs. PMID:26622071

  9. Mutational spectrum of the APC and MUTYH genes and genotype–phenotype correlations in Brazilian FAP, AFAP, and MAP patients

    PubMed Central

    2013-01-01

    Background Patients with multiple colorectal adenomas are currently screened for germline mutations in two genes, APC and MUTYH. APC-mutated patients present classic or attenuated familial adenomatous polyposis (FAP/AFAP), while patients carrying biallelic MUTYH mutations exhibit MUTYH-associated polyposis (MAP). The spectrum of mutations as well as the genotype-phenotype correlations in polyposis syndromes present clinical impact and can be population specific, making important to obtain genetic and clinical data from different populations. Methods DNA sequencing of the complete coding region of the APC and MUTYH genes was performed in 23 unrelated Brazilian polyposis patients. In addition, mutation-negative patients were screened for large genomic rearrangements by multiplex ligation-dependent probe amplification, array-comparative genomic hybridization, and duplex quantitative PCR. Biallelic MUTYH mutations were confirmed by allele-specific PCR. Clinical data of the index cases and their affected relatives were used to assess genotype–phenotype correlations. Results Pathogenic mutations were identified in 20 of the 23 probands (87%): 14 in the APC gene and six in the MUTYH gene; six of them (30%) were described for the first time in this series. Genotype-phenotype correlations revealed divergent results compared with those described in other studies, particularly regarding the extent of polyposis and the occurrence of desmoid tumors in families with mutations before codon 1444 (6/8 families with desmoid). Conclusions This first comprehensive investigation of the APC and MUTYH mutation spectrum in Brazilian polyposis patients showed a high detection rate and identified novel pathogenic mutations. Notably, a significant number of APC-positive families were not consistent with the predicted genotype-phenotype correlations from other populations. PMID:23561487

  10. Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes.

    PubMed Central

    Crawley, A C; Yogalingam, G; Muller, V J; Hopwood, J J

    1998-01-01

    Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulfatase (4S). A feline MPS VI model used to demonstrate efficacy of enzyme replacement therapy is due to the homozygous presence of an L476P mutation in 4-sulfatase. An additional mutation, D520N, inherited independently from L476P and recently identified in the same family of cats, has resulted in three clinical phenotypes. L476P homozygotes exhibit dwarfism and facial dysmorphia due to epiphyseal dysplasia, abnormally low leukocyte 4S/betahexosaminidase ratios, dermatan sulfaturia, lysosomal inclusions in most tissues including chondrocytes, corneal clouding, degenerative joint disease, and abnormal leukocyte inclusions. Similarly, D520N/D520N and L476P/D520N cats have abnormally low leukocyte 4S/betahexosaminidase ratios, mild dermatan sulfaturia, lysosomal inclusions in some chondrocytes, and abnormal leukocyte inclusions. However, both have normal growth and appearance. In addition, L476P/D520N cats have a high incidence of degenerative joint disease. We conclude that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans. The study of L476P/D520N and D520N/ D520N genotypes will improve understanding of genotype to phenotype correlations and the pathogenesis of skeletal dysplasia and joint disease in MPS VI, and will assist in development of therapies to prevent lysosomal storage in chondrocytes. PMID:9421472

  11. ABCD1 translation-initiator mutation demonstrates genotype-phenotype correlation for AMN.

    PubMed

    O'Neill, G N; Aoki, M; Brown, R H

    2001-12-11

    Inherited mutations of the X-linked adrenoleukodystrophy (X-ALD) gene (ABCD1) cause two neuropathologically distinct disorders: cerebral adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). The biochemical hallmark of these disorders is a reduction of very long chain fatty acid (VLCFA) beta-oxidation with accumulation of VLCFA esters in neural white matter. More than 300 mutations of the ABCD1 gene have been described. Genotype-phenotype correlation in X-ALD has not been demonstrated; indeed, the two disorders coexist in individual pedigrees and in homozygotic twin pairs. The authors have identified one large kindred with a highly concordant AMN phenotype resembling an X-linked dominant hereditary spastic paraparesis. All obligate female carriers are clinically affected. The ABCD1 gene was examined by direct sequencing of genomic DNA and full-length cDNA. Mutant gene transcription was analyzed by reverse transcriptase PCR. ALD protein (ALDP) expression was tested by Western blotting and indirect immunofluorescence. VLCFA beta-oxidation was examined by in vitro assay. The authors have identified a novel deletion of the ABCD1 gene ATG translation initiation codon. The authors have demonstrated that an N-terminal truncated ALDP, missing the first 65 amino acids, is expressed by internal initiation of translation and is correctly trafficked to peroxisomes. They have documented complete penetrance of this mutant in all female carriers. They have also shown that VLCFA beta-oxidation is reduced to 20% of normal in association with this mutant ALDP. It appears that initiation of translation at an internal AUG codon generates a truncated ALDP that uniformly leads to an AMN phenotype in this family. Possible models for action of this truncated ALDP and full disease penetrance in heterozygotes are reviewed.

  12. Suppression of pleiotropic phenotypes of a Burkholderia multivorans fur mutant by oxyR mutation.

    PubMed

    Kimura, Akane; Yuhara, Satoshi; Ohtsubo, Yoshiyuki; Nagata, Yuji; Tsuda, Masataka

    2012-05-01

    Fur (ferric uptake regulator) is an iron-responsive transcriptional regulator in many bacterial species, and the fur mutant of Burkholderia multivorans ATCC 17616 exhibits pleiotropic phenotypes, such as an inability to efficiently use several carbon sources, as well as high sensitivity to hydrogen peroxide (H(2)O(2)), paraquat (a superoxide-producing compound) and nitric oxide (NO). To gain more insight into the pleiotropic role of the Fur protein of ATCC 17616, spontaneous suppressor mutants of the ATCC 17616 fur mutant that restored tolerance to NO were isolated and characterized in this study. The microarray-based comparative genomic analysis and subsequent sequencing analysis indicated that such suppressor mutants had a 2 bp deletion in the oxyR gene, whose orthologues encode H(2)O(2)-responsive transcriptional regulators in other bacterial species. The suppressor mutants and the reconstructed fur-oxyR double-deletion mutant showed indistinguishable phenotypes in that they were all (i) more resistant than the fur mutant to H(2)O(2), superoxide, NO and streptonigrin (an iron-activated antibiotic) and (ii) able to use carbon sources that cannot efficiently support the growth of the fur mutant. These results clearly indicate that the oxyR mutation suppressed the pleiotropic effect of the B. multivorans fur mutant. The fur-oxyR double mutants were found to overexpress the KatG (catalase/peroxidase) and AhpC1 and AhpD (alkyl hydroperoxide reductase subunits C and D) proteins, and their enzymic activities to remove reactive oxygen and nitrogen species were suggested to be responsible for the suppression of phenotypes caused by the fur mutation.

  13. Autism spectrum disorder phenotype and intellectual disability in females with epilepsy and PCDH-19 mutations.

    PubMed

    Breuillard, Delphine; Leunen, Dorothée; Chemaly, Nicole; Auclair, Laurent; Pinard, Jean Marc; Kaminska, Anna; Desguerre, Isabelle; Ouss, Lisa; Nabbout, Rima

    2016-07-01

    Autism features and various degrees of cognitive deficit are reported in patients with PCDH-19 mutations and epilepsy. Autism spectrum disorder (ASD) and, often, cognitive profile are usually assessed clinically. We studied autism phenotype and cognitive outcome in a series of patients using standardized tools for development and ASD. We aimed to describe the phenotype of ASD in this series and to understand whether ASD is strictly linked to intellectual disability (ID) or is present as a comorbidity. Eight females aged 5 to 17years old with PCDH-19 mutations and epilepsy were recruited. For ASD diagnosis, the Autism Diagnostic Interview - Revised (ADI-R) and the Autism Diagnosis Observation Schedule (ADOS) were administered. Patients underwent a neuropsychological examination with tests measuring global intellectual efficiency (WPPSI-III and WISC-IV), language, and executive and social cognition abilities. Parental adaptive behavioral questionnaires were also obtained (VABS, CBCL, and BRIEF). Six out of eight patients presented with ASD and ID. Two patients had neither ASD nor ID, and both had the latest age of onset for their epilepsy. All cognitive functions were deficient, but theory-of-mind abilities compared to other cognitive features were even impaired. Features of ASD lacked major repetitive and stereotyped behaviors and show some differences with the classical ASD features related to ID. Our results show a large spectrum of ID and a very high rate of ASD in patients with epilepsy and PCDH-19 mutations. Autism spectrum disorder seems to be a genuine comorbidity, more than a consequence of ID. It highlights the importance of standardized psychiatric and cognitive evaluation in order to establish a tailored rehabilitation program. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Specific point mutations in Lactobacillus casei ATCC 27139 cause a phenotype switch from Lac- to Lac+.

    PubMed

    Tsai, Yu-Kuo; Chen, Hung-Wen; Lo, Ta-Chun; Lin, Thy-Hou

    2009-03-01

    Lactose metabolism is a changeable phenotype in strains of Lactobacillus casei. In this study, we found that L. casei ATCC 27139 was unable to utilize lactose. However, when exposed to lactose as the sole carbon source, spontaneous Lac(+) clones could be obtained. A gene cluster (lacTEGF-galKETRM) involved in the metabolism of lactose and galactose in L. casei ATCC 27139 (Lac(-)) and its Lac(+) revertant (designated strain R1) was sequenced and characterized. We found that only one nucleotide, located in the lacTEGF promoter (lacTp), of the two lac-gal gene clusters was different. The protein sequence identity between the lac-gal gene cluster and those reported previously for some L. casei (Lac(+)) strains was high; namely, 96-100 % identity was found and no premature stop codon was identified. A single point mutation located within the lacTp promoter region was also detected for each of the 41 other independently isolated Lac(+) revertants of L. casei ATCC 27139. The revertants could be divided into six classes based on the positions of the point mutations detected. Primer extension experiments conducted on transcription from lacTp revealed that the lacTp promoter of these six classes of Lac(+) revertants was functional, while that of L. casei ATCC 27139 was not. Northern blotting experiments further confirmed that the lacTEGF operon of strain R1 was induced by lactose but suppressed by glucose, whereas no blotting signal was ever detected for L. casei ATCC 27139. These results suggest that a single point mutation in the lacTp promoter was able to restore the transcription of a fully functional lacTEGF operon and cause a phenotype switch from Lac(-) to Lac(+) for L. casei ATCC 27139.

  15. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations

    PubMed Central

    Orthmann-Murphy, Jennifer L.; Salsano, Ettore; Abrams, Charles K.; Bizzi, Alberto; Uziel, Graziella; Freidin, Mona M.; Lamantea, Eleonora; Zeviani, Massimo; Scherer, Steven S.

    2009-01-01

    Recessive mutations in GJA12/GJC2, the gene that encodes the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), an early onset dysmyelinating disorder of the CNS, characterized by nystagmus, psychomotor delay, progressive spasticity and cerebellar signs. Here we describe three patients from one family with a novel recessively inherited mutation, 99C>G (predicted to cause an Ile>Met amino acid substitution; I33M) that causes a milder phenotype. All three had a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. The mutant protein forms gap junction plaques at cell borders similar to wild-type (WT) Cx47 in transfected cells, but fails to form functional homotypic channels in scrape-loading and dual whole-cell patch clamp assays. I33M forms overlapping gap junction plaques and functional channels with Cx43, however, I33M/Cx43 channels open only when a large voltage difference is applied to paired cells. These channels probably do not function under physiological conditions, suggesting that Cx47/Cx43 channels between astrocytes and oligodendrocytes are disrupted, similar to the loss-of-function endoplasmic reticulum-retained Cx47 mutants that cause PMLD. Thus, GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known. PMID:19056803

  16. Highly prevalent LIPH founder mutations causing autosomal recessive woolly hair/hypotrichosis in Japan and the genotype/phenotype correlations.

    PubMed

    Tanahashi, Kana; Sugiura, Kazumitsu; Kono, Michihiro; Takama, Hiromichi; Hamajima, Nobuyuki; Akiyama, Masashi

    2014-01-01

    Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH), and the 2 missense mutations c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn) are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016), and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024). In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH.

  17. Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations.

    PubMed

    Alcalay, Roy N; Mirelman, Anat; Saunders-Pullman, Rachel; Tang, Ming-X; Mejia Santana, Helen; Raymond, Deborah; Roos, Ernest; Orbe-Reilly, Martha; Gurevich, Tanya; Bar Shira, Anat; Gana Weisz, Mali; Yasinovsky, Kira; Zalis, Maayan; Thaler, Avner; Deik, Andres; Barrett, Matthew James; Cabassa, Jose; Groves, Mark; Hunt, Ann L; Lubarr, Naomi; San Luciano, Marta; Miravite, Joan; Palmese, Christina; Sachdev, Rivka; Sarva, Harini; Severt, Lawrence; Shanker, Vicki; Swan, Matthew Carrington; Soto-Valencia, Jeannie; Johannes, Brooke; Ortega, Robert; Fahn, Stanley; Cote, Lucien; Waters, Cheryl; Mazzoni, Pietro; Ford, Blair; Louis, Elan; Levy, Oren; Rosado, Llency; Ruiz, Diana; Dorovski, Tsvyatko; Pauciulo, Michael; Nichols, William; Orr-Urtreger, Avi; Ozelius, Laurie; Clark, Lorraine; Giladi, Nir; Bressman, Susan; Marder, Karen S

    2013-12-01

    The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P < 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P < 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P < 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for >5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

  18. CYP24A1 loss of function: Clinical phenotype of monoallelic and biallelic mutations.

    PubMed

    Carpenter, Thomas O

    2017-01-16

    CYP24A1, encoding the vitamin D-24-hydroxylase, is of major clinical and physiologic importance, serving to regulate the catabolism of 1,25-(OH)2D, the physiologically active vitamin D metabolite. In addition to facilitating catabolism of 1,25-(OH)2D, CYP24A1 also enhances the turnover and elimination of 25-OHD, the abundant precursor metabolite and storage form of the vitamin. CYP24A1 can be stimulated hormonally by 1,25-(OH)2D and by FGF23, whereas CYP27B1, encoding the vitamin D-1α-hydroxylase, is stimulated hormonally by parathyroid hormone (PTH) and downregulated by FGF23. Thus CYP24A1 and CYP27B1, together, provide for alternate and regulated fates of 25-OHD, and control the availability of the active metabolite, 1,25-(OH)2D, depending upon physiologic needs. These two enzymes, are therefore central to the homeostatic control of vitamin D metabolism, and as a result affect calcium metabolism in critical ways. Disruption of CYP24A1 in mice results in elevated circulating 1,25-(OH)2D, substantiating the importance of the enzyme in the maintenance of vitamin D metabolism. The consequential skeletal phenotype in these mice further demonstrates the biologic sequelae of the disruption of the vitamin D pathway, and illustrates a specific developmental pathology mediated largely by oversupply of 1,25-(OH)2D. More recent evidence has identified loss of function mutations in CYP24A1 in association with hypercalcemia, hypercalciuria and nephrolithiasis in humans. Initial reports described certain variant mutations in CYP24A1 as an unrecognized cause of "Idiopathic Infantile Hypercalcemia," and more recently older children and adults have been identified with a similar phenotype. Over 25 likely disease-causing variants are described. Homozygous and compound heterozygote mutations account for the overwhelming majority of cases, however the heterozygous loss-of-function mutations of CYP24A1 do not appear to consistently result in symptomatic hypercalcemia. Considerations

  19. Expression of a novel missense mutation found in the A4GALT gene of Amish individuals with the p phenotype.

    PubMed

    Hellberg, Asa; Schmidt-Melbye, Anne-Christine; Reid, Marion E; Olsson, Martin L

    2008-03-01

    The rare p phenotype is found at a higher frequency in Amish people than in other populations. Different mutations in the 4-alpha-galactosyltransferase gene (A4GALT), responsible for synthesis of P(k) (Gb(3)) antigen, have been found to cause the P(k)-deficient p phenotype. The aim of this study was to explore the molecular background of the p phenotype in people of Amish origin. Twenty blood samples with the p phenotype, 19 of them from Amish individuals and 1 Pakistani, were investigated. Amplification of genomic DNA by polymerase chain reaction (PCR) and sequencing by capillary electrophoresis were performed. Blood donors of different geographic origin were screened with PCR-allele-specific primer to investigate whether the novel mutation occurs among individuals with common phenotypes. The mutation was also cloned into an expression vector and transfected to Namalwa cells, which do not normally express P(k). P(k) expression on the transfected cells and P/P(k) on red blood cells (RBCs), both with p and with common phenotypes, were analyzed by flow cytometry. All 20 samples were homozygous for 299C>T changing serine to leucine in a region that is highly conserved in homologous genes across species borders. The mutation was not found in any of the 500 alleles of blood donors investigated. P(k) expression was neither observed by serology and flow cytometry on p RBCs from Amish individuals nor following transfection of cells with constructs containing the novel missense mutation. A novel A4GALT missense mutation causes the p phenotype in Amish individuals.

  20. X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype.

    PubMed

    Holden, Kenton R; Zuñiga, Oscar F; May, Melanie M; Su, Humberto; Molinero, Marco R; Rogers, R Curtis; Schwartz, Charles E

    2005-10-01

    We report a family with X-linked mental retardation that has a novel mutation in the monocarboxylate transporter 8 (MCT8) gene associated with a characteristic neurodevelopmental phenotype with early childhood hypotonia that progresses to spasticity and global developmental delays. Affected patients experience moderate to severe psychomotor delays and congenital hypotonia, develop a myopathic facies, have diminished muscle bulk and generalized muscle weakness, develop progressive spasticity and movement disorders, and have limited speech but alert, affable personalities. Acquired microcephaly and abnormal myelination on brain magnetic resonance imaging can be present. Normal monocarboxylate transporter 8 gene functioning appears to be necessary for normal thyroid-associated metabolism in neurons. Abnormal thyroid function tests appear to be a consistent finding in the absence of typical signs of thyroid dysfunction. Although the phenotype appears to be consistent, and although the neurotoxic effects of abnormal central and peripheral neuromuscular system thyroid metabolism might be partly or wholly responsible for the neurologic phenotype reported, the exact mechanism remains unclear.

  1. [Formation of para-Bombay phenotype caused by homozygous or heterozygous mutation of FUT1 gene].

    PubMed

    Zhang, Jin-Ping; Zheng, Yan; Sun, Dong-Ni

    2014-02-01

    This study was aimed to explore the molecular mechanisms for para-Bombay phenotype formation. The H antigen of these individuals were identified by serological techniques. The full coding region of alpha (1, 2) fucosyltransferase (FUT1) gene of these individuals was amplified by high-fidelity polymerase chain reaction (PCR). PCR product was identified by TOPO cloning sequencing. Analysis and comparison were used to explore the mechanisms of para-bombay phenotype formation in individuals. The results indicated that the full coding region of FUT1 DNA was successfully amplified by PCR and gel electrophoresis. DNA sequencing and analysis found that h1 (547-552delAG) existed in one chromosome and h4 (35C > T) existed in the other chromosome of NO.1 individual. Meantime, h1 (547-552delAG) was found in two chromosomes of NO.2 and NO.3 individual. It also means that FUT1 gene of NO.1 individual was h1h4 heterozygote, FUT1 gene of NO.2 and NO.3 individuals were h1h1 homozygote. It is concluded that homozygous and heterozygous mutation of FUT1 gene can lead to the formation of para-Bombay phenotype.

  2. A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation

    PubMed Central

    Yang, Shao H.; Meta, Margarita; Qiao, Xin; Frost, David; Bauch, Joy; Coffinier, Catherine; Majumdar, Sharmila; Bergo, Martin O.; Young, Stephen G.; Fong, Loren G.

    2006-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus. Progerin is targeted to the nuclear envelope and causes misshapen nuclei. Protein farnesyltransferase inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the frequency of misshapen nuclei. To determine whether an FTI would ameliorate disease phenotypes in vivo, we created gene-targeted mice with an HGPS mutation (LmnaHG/+) and then examined the effect of an FTI on disease phenotypes. LmnaHG/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. Osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness. These studies suggest that FTIs could be useful for treating humans with HGPS. PMID:16862216

  3. Gene Therapy for Retinitis Pigmentosa Caused by MFRP Mutations: Human Phenotype and Preliminary Proof of Concept

    PubMed Central

    Dinculescu, Astra; Estreicher, Jackie; Zenteno, Juan C.; Aleman, Tomas S.; Schwartz, Sharon B.; Huang, Wei Chieh; Roman, Alejandro J.; Sumaroka, Alexander; Li, Qiuhong; Deng, Wen-Tao; Min, Seok-Hong; Chiodo, Vince A.; Neeley, Andy; Liu, Xuan; Shu, Xinhua; Matias-Florentino, Margarita; Buentello-Volante, Beatriz; Boye, Sanford L.; Cideciyan, Artur V.

    2011-01-01

    Abstract Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy. PMID:22142163

  4. Impact of a mutator phenotype on motility and cell adherence in Salmonella Heidelberg.

    PubMed

    Le Bars, Hervé; Le Gall-David, Sandrine; Renoux, Virginie Madeleine; Bonnaure-Mallet, Martine; Jolivet-Gougeon, Anne; Bousarghin, Latifa

    2012-09-14

    In this study, we investigated adherence and motility of the hypermutator Salmonella enterica Heidelberg B182 bovine strain related to a 12bp deletion in mutS. This mutator phenotype was associated with increased adherence to epithelial cells and with high expression of fimA as shown by real-time RT-PCR. Motility studies showed that fliC were up-regulated in the B182 strain, while fljA and fljB were down-regulated. In order to determine if mutated mutS is implicated in this genes expression, isogenic strains, derived from a WT strain, containing the 12bp deletion in mutS (Δ12bpmutS) or an inactivated mutS (ΔmutS) were generated. Δ12bpmutS and ΔmutS strains showed a spontaneous mutation rate similar to the environmental strain B182, but exhibited lower adherence capacity and fimA expression. In contrast to the fimbriae genes, in Δ12bpmutS, fliC expression was up-regulated, but fljA and fljB expression were decreased, as in the B182 strain. Only fljB expression was increased in ΔmutS mutants. Taken together, our data suggest that mutS alteration does not influence fimbriae expression but can impact flagella genes.

  5. Phenotype of retinitis pigmentosa associated with the Ser50Thr mutation in the NRL gene.

    PubMed

    Bessant, David A R; Holder, Graham E; Fitzke, Frederick W; Payne, Annette M; Bhattacharya, Shomi S; Bird, Alan C

    2003-06-01

    We previously reported an Ser50Thr mutation in the NRL gene as a cause of autosomal dominant retinitis pigmentosa. To determine the characteristic features of the autosomal dominant retinitis pigmentosa phenotype associated with the NRL Ser50Thr mutation in affected individuals from 4 related families. Clinical records were available for 21 affected individuals; 7 underwent more extensive electrophysiologic and psychophysical testing. Night blindness was the first symptom to manifest, with onset between birth and age 16 years. Difficulty with peripheral vision was experienced between 20 and 37 years of age. Visual acuity was well preserved in younger individuals, but those older than 30 years frequently had substantial visual loss (6/36 or worse) associated with macular atrophy. Electrophysiologic testing revealed a nondetectable scotopic electroretinogram with relative preservation of the photopic electroretinogram and pattern electroretinography in the 3 youngest patients tested (aged 15-18 years). In older individuals, all components of the electroretinogram were nondetectable. Dark-adapted visual fields in younger individuals were greatly impaired, but their photopic fields remained relatively well preserved. Older patients had photopic fields limited to just a few degrees. Distinctive peripapillary chorioretinal atrophy seems to develop as the disorder progresses. The NRL Ser50Thr mutation is associated with selective loss of scotopic function before age 20 years. With time, however, the photopic system becomes affected, leading to loss of the photopic visual field and of visual acuity.

  6. Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept.

    PubMed

    Dinculescu, Astra; Estreicher, Jackie; Zenteno, Juan C; Aleman, Tomas S; Schwartz, Sharon B; Huang, Wei Chieh; Roman, Alejandro J; Sumaroka, Alexander; Li, Qiuhong; Deng, Wen-Tao; Min, Seok-Hong; Chiodo, Vince A; Neeley, Andy; Liu, Xuan; Shu, Xinhua; Matias-Florentino, Margarita; Buentello-Volante, Beatriz; Boye, Sanford L; Cideciyan, Artur V; Hauswirth, William W; Jacobson, Samuel G

    2012-04-01

    Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.

  7. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter

    PubMed Central

    Borzutzky, Arturo; Crompton, Brian; Bergmann, Anke K.; Giliani, Silvia; Baxi, Sachin; Martin, Madelena; Neufeld, Ellis J.; Notarangelo, Luigi D.

    2009-01-01

    Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naïve T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion. PMID:19740703

  8. Novel mutation in Sjogren-Larsson syndrome is associated with divergent neurologic phenotypes.

    PubMed

    Davis, Kathleen; Holden, Kenton R; S'Aulis, Dana; Amador, Claudia; Matheus, M Gisele; Rizzo, William B

    2013-10-01

    Sjögren-Larsson syndrome is an inherited disorder of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, which results in accumulation of fatty aldehydes and alcohols and is characterized by ichthyosis, intellectual disability, and spastic diplegia/quadriplegia. The authors describe 2 unrelated Honduran patients who carried the same novel homozygous nonsense mutation (c.1309A>T, p.K437X) and ALDH3A2 DNA haplotype, but widely differed in disease severity. One patient exhibited spastic quadriplegia with unusual neuroregression, whereas the other patient had the usual static form of spastic diplegia with neurodevelopmental disabilities. Biochemical analyses showed a similar profound deficiency of fatty aldehyde dehydrogenase activity and impaired fatty alcohol metabolism in both patients' cultured fibroblasts. These results indicate that variation in the neurologic phenotype of Sjögren-Larsson syndrome is not strictly determined by the ALDH3A2 mutation or the biochemical defect as expressed in cultured fibroblasts, but by unidentified epigenetic/environmental factors, gene modifiers, or other mechanisms.

  9. Natural and laboratory mutations in kuzbanian are associated with zinc stress phenotypes in Drosophila melanogaster

    PubMed Central

    Le Manh, Hung; Guio, Lain; Merenciano, Miriam; Rovira, Quirze; Barrón, Maite G.; González, Josefa

    2017-01-01

    Organisms must cope with altered environmental conditions such as high concentrations of heavy metals. Stress response to heavy metals is mediated by the metal-responsive transcription factor 1 (MTF-1), which is conserved from Drosophila to humans. MTF-1 binds to metal response elements (MREs) and changes the expression of target genes. kuzbanian (kuz), a metalloendopeptidase that activates the evolutionary conserved Notch signaling pathway, has been identified as an MTF-1 target gene. We have previously identified a putatively adaptive transposable element in the Drosophila melanogaster genome, named FBti0019170, inserted in a kuz intron. In this work, we investigated whether a laboratory mutant stock overexpressing kuz is associated with zinc stress phenotypes. We found that both embryos and adult flies overexpressing kuz are more tolerant to zinc compared with wild-type flies. On the other hand, we found that the effect of FBti0019170 on zinc stress tolerance depends on developmental stage and genetic background. Moreover, in the majority of the genetic backgrounds analyzed, FBti0019170 has a deleterious effect in unpolluted environments in pre-adult stages. These results highlight the complexity of natural mutations and suggest that besides laboratory mutations, natural mutations should be studied in order to accurately characterize gene function and evolution. PMID:28218276

  10. Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome

    PubMed Central

    Wang, Li; Lin, Qiong-Fen; Wang, Hong-Yang; Guan, Jing; Lan, Lan; Xie, Lin-Yi; Yu, Lan; Yang, Ju; Zhao, Cui; Liang, Jin-Long; Zhou, Han-Lin; Yang, Huan-Ming; Xiong, Wen-Ping; Zhang, Qiu-Jing; Wang, Da-Yong; Wang, Qiu-Ju

    2017-01-01

    Background: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. Methods: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided. Results: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations. Conclusions: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated. PMID:28303854

  11. The Tyr-265-to-Cys mutator mutant of DNA polymerase β induces a mutator phenotype in mouse LN12 cells

    PubMed Central

    Clairmont, Caroline A.; Narayanan, Latha; Sun, Ka-Wai; Glazer, Peter M.; Sweasy, Joann B.

    1999-01-01

    DNA polymerase β functions in both base excision repair and meiosis. Errors committed by polymerase β during these processes could result in mutations. Using a complementation system, in which rat DNA polymerase β substitutes for DNA polymerase I of Escherichia coli, we previously isolated a DNA polymerase β mutant in which Tyr-265 was altered to Cys (Y265C). The Y265C mutant is dominant to wild-type DNA polymerase β and possesses an intrinsic mutator activity. We now have expressed the wild-type DNA polymerase and the Y265C mutator mutant in mouse LN12 cells, which have endogenous DNA polymerase β activity. We demonstrate that expression of the Y265C mutator mutant in the LN12 cells results in an 8-fold increase in the spontaneous mutation frequency of λcII mutants compared with expression of the wild-type protein. Expression of Y265C results in at least a 40-fold increase in the frequency of deletions of three bases or more and a 7-fold increase in point mutations. Our results suggest that the mutations we observe in vivo result directly from the action of the mutator polymerase. To our knowledge, this is the first demonstration of a mutator phenotype resulting from expression of a DNA polymerase mutator mutant in mammalian cells. This work raises the possibility that variant polymerases may act in a dominant fashion in human cells, leading to genetic instability and carcinogenesis. PMID:10449735

  12. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes.

    PubMed

    Pitteloud, Nelly; Meysing, Astrid; Quinton, Richard; Acierno, James S; Dwyer, Andrew A; Plummer, Lacey; Fliers, Eric; Boepple, Paul; Hayes, Frances; Seminara, Stephanie; Hughes, Viriginia A; Ma, Jinghong; Bouloux, Pierre; Mohammadi, Moosa; Crowley, William F

    2006-07-25

    Kallmann's syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described. One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed

  13. Null mutations at the p66 and bradykinin 2 receptor loci induce divergent phenotypes in the diabetic kidney

    PubMed Central

    Vashistha, Himanshu; Singhal, Pravin C.; Malhotra, Ashwani; Husain, Mohammad; Mathieson, Peter; Saleem, Moin A.; Kuriakose, Cyril; Seshan, Surya; Wilk, Anna; DelValle, Luis; Peruzzi, Francesca; Giorgio, Marco; Pelicci, Pier Giuseppe; Smithies, Oliver; Kim, Hyung-Suk; Kakoki, Masao; Reiss, Krzysztof

    2012-01-01

    Candidate genes have been identified that confer increased risk for diabetic glomerulosclerosis (DG). Mice heterozygous for the Akita (Ins2+/C96Y) diabetogenic mutation with a second mutation introduced at the bradykinin 2 receptor (B2R−/−) locus express a disease phenotype that approximates human DG. Src homology 2 domain transforming protein 1 (p66) controls mitochondrial metabolism and cellular responses to oxidative stress, aging, and apoptosis. We generated p66-null Akita mice to test whether inactivating mutations at the p66 locus will rescue kidneys of Akita mice from disease-causing mutations at the Ins2 and B2R loci. Here we show null mutations at the p66 and B2R loci interact with the Akita (Ins2+/C96Y) mutation, independently and in combination, inducing divergent phenotypes in the kidney. The B2R−/− mutation induces detrimental phenotypes, as judged by increased systemic and renal levels of oxidative stress, histology, and urine albumin excretion, whereas the p66-null mutation confers a powerful protection phenotype. To elucidate the mechanism(s) of the protection phenotype, we turned to our in vitro system. Experiments with cultured podocytes revealed previously unrecognized cross talk between p66 and the redox-sensitive transcription factor p53 that controls hyperglycemia-induced ROS metabolism, transcription of p53 target genes (angiotensinogen, angiotensin II type-1 receptor, and bax), angiotensin II generation, and apoptosis. RNA-interference targeting p66 inhibits all of the above. Finally, protein levels of p53 target genes were upregulated in kidneys of Akita mice but unchanged in p66-null Akita mice. Taken together, p66 is a potential molecular target for therapeutic intervention in DG. PMID:23019230

  14. Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

    PubMed Central

    Böhm, Johann; Biancalana, Valérie; DeChene, Elizabeth T.; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.; Barger, Melissa A.; Mahoney, Lane J.; Kang, Peter B.; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Ousager, Lilian Bomme; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S. B.; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Aldea, Juan José Poza; Michel, Fabrice; Furby, Alain; Llona, Jose E. Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; Béroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A. H.; Smith, Stephen A.; Roggenbuck, Jennifer; Crowe, Carol A.; Spitale, Allison Brennan; Johal, Sheila C.; Amato, Anthony A.; Demmer, Laurie A.; Jonas, Jessica; Darras, Basil T.; Bird, Thomas D.; Laurino, Mercy; Welt, Selman I.; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H.; Laporte, Jocelyn

    2012-01-01

    Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. PMID:22396310

  15. Identification of novel FBN1 and TGFBR2 mutations in 65 probands with Marfan syndrome or Marfan-like phenotypes.

    PubMed

    Chung, Brian Hon-Yin; Lam, Stephen Tak-Sum; Tong, Tony Ming-For; Li, Susanna Yuk-Han; Lun, Kin-Shing; Chan, Daniel Hon-Chuen; Fok, Susanna Fung-Shan; Or, June Siu-Fong; Smith, David Keith; Yang, Wanling; Lau, Yu-Lung

    2009-07-01

    Marfan syndrome is an autosomal dominant connective tissue disorder, and mutations in the FBN1 and TGFBR2 genes have been identified in probands with MFS and related phenotypes. Using DHPLC and sequencing, we studied the mutation spectrum in 65 probands with Marfan syndrome and related phenotypes. A total of 24 mutations in FBN1 were identified, of which 19 (nine missense, six frameshift, two nonsense and two affecting splice junctions) were novel. In the remaining 41 probands, six were identified to have novel TGFBR2 mutations (one frameshift and five missense mutations). All novel mutations found in this study were confirmed to be absent in 50 unrelated normal individuals of the same ethnic background. In probands who fulfilled the Ghent criteria (n = 16), mutations in FBN1 were found in 81% of cases. None of those with TGFBR2 mutations fulfilled the Ghent criteria. Novel missense mutations of unknown significance were classified according to the latest ACMG guidelines and their likelihood to be causative was evaluated.

  16. Mutation Analysis in Glycogen Storage Disease Type III Patients in the Netherlands: Novel Genotype-Phenotype Relationships and Five Novel Mutations in the AGL Gene.

    PubMed

    Sentner, Christiaan P; Vos, Yvonne J; Niezen-Koning, Klary N; Mol, Bart; Smit, G Peter A

    2013-01-01

    Glycogen Storage Disease type III (GSD III) is an autosomal recessive disorder in which a mutation in the AGL gene causes deficiency of the glycogen debranching enzyme. In childhood, it is characterized by hepatomegaly, keto-hypoglycemic episodes after short periods of fasting, and hyperlipidemia. In adulthood, myopathy, cardiomyopathy, and liver cirrhosis are the main complications. To determine the genotype of the GSD III patients (n = 14) diagnosed and treated in our center, mutation analysis was performed by either denaturing gradient gel electrophoresis or full gene sequencing. We developed, validated and applied both methods, and in all patients a mutation was identified on both alleles. Five novel pathogenic mutations were identified in seven patients, including four missense mutations (c.643G>A, p.Asp215Asn; c.655A>G, p.Asn219Asp; c.1027C>T, p.Arg343Trp; c.1877A>G, p.His626Arg) and one frameshift mutation (c.3911delA, p.Asn1304fs). The c.643G>A, p.Asp215Asn mutation is related with type IIIa, as this mutation was found homozygously in two type IIIa patients. In addition to five novel mutations, we present new genotype-phenotype relationships for c.2039G>A, p.Trp680X; c.753_756delCAGA, p.Asp251fs; and the intron 32 c.4260-12A>G splice site mutation. The p.Trp680X mutation was found homozygously in four patients, presenting a mild IIIa phenotype with mild skeletal myopathy, elevated CK values, and no cardiomyopathy. The p.Asp251fs mutation was found homozygously in one patient presenting with a severe IIIa phenotype, with skeletal myopathy, and severe symptomatic cardiomyopathy. The c.4260-12A>G mutation was found heterozygously, together with the p.Arg343Trp mutation in a severe IIIb patient who developed liver cirrhosis and hepatocellular carcinoma, necessitating an orthotopic liver transplantation.

  17. Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.

    PubMed

    Filges, I; Nosova, E; Bruder, E; Tercanli, S; Townsend, K; Gibson, W T; Röthlisberger, B; Heinimann, K; Hall, J G; Gregory-Evans, C Y; Wasserman, W W; Miny, P; Friedman, J M

    2014-09-01

    Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes.

    PubMed

    Martinez, Francisco; Marín-Reina, Purificación; Sanchis-Calvo, Amparo; Perez-Aytés, Antonio; Oltra, Silvestre; Roselló, Mónica; Mayo, Sonia; Monfort, Sandra; Pantoja, Jorge; Orellana, Carmen

    2015-11-01

    Only 15 point mutations in NFIX gene have been reported so far, nine of them cause the Marshall-Smith syndrome (MSS) and the remaining mutations lead to an overgrowth disorder with a less severe phenotype, defined as Sotos-like. The clinical findings in three patients with MSS and two patients with a Sotos-like phenotype are presented. Analysis of the NFIX gene was performed both by conventional or next-generation sequencing. Five de novo mutations in NFIX gene were identified, four of them not previously reported. Two frameshift mutations and a donor-splice one caused MSS, while two missense mutations in the DNA binding/dimerisation domain entailed an overgrowth syndrome with some clinical features resembling Sotos syndrome, accompanied by a marfanoid habitus, very low BMI, long narrow face, or arachnodactyly. Marshall-Smith mutations are scattered through exons 6-10 of NFIX gene, while most point mutations causing an overgrowth syndrome are clustered in exon 2. Clinical features of this overgrowth syndrome may well be considered an intermediate phenotype between Sotos and Marfan syndromes.

  19. Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum

    PubMed Central

    Thorwarth, Anne; Schnittert-Hübener, Sarah; Schrumpf, Pamela; Müller, Ines; Jyrch, Sabine; Dame, Christof; Biebermann, Heike; Kleinau, Gunnar; Katchanov, Juri; Schuelke, Markus; Ebert, Grit; Steininger, Anne; Bönnemann, Carsten; Brockmann, Knut; Christen, Hans-Jürgen; Crock, Patricia; deZegher, Francis; Griese, Matthias; Hewitt, Jacqueline; Ivarsson, Sten; Hübner, Christoph; Kapelari, Klaus; Plecko, Barbara; Rating, Dietz; Stoeva, Iva; Ropers, Hans-Hilger; Grüters, Annette; Ullmann, Reinhard; Krude, Heiko

    2017-01-01

    Background NKX2-1 encodes a transcription factor with large impact on the development of brain, lung and thyroid. Germline mutations of NKX2-1 can lead to dysfunction and malformations of these organs. Starting from the largest coherent collection of patients with a suspected phenotype to date, we systematically evaluated frequency, quality and spectrum of phenotypic consequences of NKX2-1 mutations. Methods After identifying mutations by Sanger sequencing and array CGH, we comprehensively reanalysed the phenotype of affected patients and their relatives. We employed electrophoretic mobility shift assay (EMSA) to detect alterations of NKX2-1 DNA binding. Gene expression was monitored by means of in situ hybridisation and compared with the expression level of MBIP, a candidate gene presumably involved in the disorders and closely located in close genomic proximity to NKX2-1. Results Within 101 index patients, we detected 17 point mutations and 10 deletions. Neurological symptoms were the most consistent finding (100%), followed by lung affection (78%) and thyroidal dysfunction (75%). Novel symptoms associated with NKX2-1 mutations comprise abnormal height, bouts of fever and cardiac septum defects. In contrast to previous reports, our data suggest that missense mutations in the homeodomain of NKX2-1 not necessarily modify its DNA binding capacity and that this specific type of mutations may be associated with mild pulmonary phenotypes such as asthma. Two deletions did not include NKX2-1, but MBIP, whose expression spatially and temporarily coincides with NKX2-1 in early murine development. Conclusions The high incidence of NKX2-1 mutations strongly recommends the routine screen for mutations in patients with corresponding symptoms. However, this analysis should not be confined to the exonic sequence alone, but should take advantage of affordable NGS technology to expand the target to adjacent regulatory sequences and the NKX2-1 interactome in order to maximise the

  20. A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia.

    PubMed

    Torraco, A; Bianchi, M; Verrigni, D; Gelmetti, V; Riley, L; Niceta, M; Martinelli, D; Montanari, A; Guo, Y; Rizza, T; Diodato, D; Di Nottia, M; Lucarelli, B; Sorrentino, F; Piemonte, F; Francisci, S; Tartaglia, M; Valente, E M; Dionisi-Vici, C; Christodoulou, J; Bertini, E; Carrozzo, R

    2017-03-01

    NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.

  1. Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene.

    PubMed

    Sanmaneechai, Oranee; Feely, Shawna; Scherer, Steven S; Herrmann, David N; Burns, Joshua; Muntoni, Francesco; Li, Jun; Siskind, Carly E; Day, John W; Laura, Matilde; Sumner, Charlotte J; Lloyd, Thomas E; Ramchandren, Sindhu; Shy, Rosemary R; Grider, Tiffany; Bacon, Chelsea; Finkel, Richard S; Yum, Sabrina W; Moroni, Isabella; Piscosquito, Giuseppe; Pareyson, Davide; Reilly, Mary M; Shy, Michael E

    2015-11-01

    We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for

  2. Genotype–phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene

    PubMed Central

    Feely, Shawna; Scherer, Steven S.; Herrmann, David N.; Burns, Joshua; Muntoni, Francesco; Li, Jun; Siskind, Carly E.; Day, John W.; Laura, Matilde; Sumner, Charlotte J.; Lloyd, Thomas E.; Ramchandren, Sindhu; Shy, Rosemary R.; Grider, Tiffany; Bacon, Chelsea; Finkel, Richard S.; Yum, Sabrina W.; Moroni, Isabella; Piscosquito, Giuseppe; Pareyson, Davide; Reilly, Mary M.; Shy, Michael E.

    2015-01-01

    We aimed to characterize genotype–phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot–Marie–Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and the Charcot–Marie–Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot–Marie–Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3–84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot–Marie–Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required

  3. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8.

    PubMed

    Jansen, Jurgen; Friesema, Edith C H; Kester, Monique H A; Schwartz, Charles E; Visser, Theo J

    2008-05-01

    Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T(3) levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T(3) and T(4) uptake, T(3) metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T(3), immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T(3) uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity. RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T(3); L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations.

  4. Genotype-Phenotype Relationship in Patients with Mutations in Thyroid Hormone Transporter MCT8

    PubMed Central

    Jansen, Jurgen; Friesema, Edith C. H.; Kester, Monique H. A.; Schwartz, Charles E.; Visser, Theo J.

    2008-01-01

    Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T3 levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T3 and T4 uptake, T3 metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T3, immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T3 uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity. RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T3; L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations. PMID:18187543

  5. Mutation frequency and genotype/phenotype correlation among phenylketonuria patients from Georgia

    SciTech Connect

    Woo, S.L.C.; Martinez, D.; Kuozmine, A.

    1994-09-01

    Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). To determine the molecular basis of PKU in the state of Georgia, thirty-five Georgian PKU patients representing sixty independent alleles were examined by a combination of DGGE and direct sequence analysis. At present, this approach has led to the identification of 55/60 or about 92% of all mutant alleles. The relatively high frequencies of mutations common to the British Isles (R408W, I65T and L348V) are compatible with 1990 census data showing that 34% of the general Georgian population claim Irish, English or Scottish ancestors. Three new mutations, E76A (1/60), R241L (2/60), and R400R (2/60), were also detected in this study. Although the nucleotide substitution in codon 400 (AGG{r_arrow}CGG) did not change the amino acid sequence, it was the only base change detected in a scan of all 13 exons of two independent alleles. Since codon 400 is split between exons 11 and 12, this change may exert some effect on splicing, as has previously been seen in the PAH gene for the silent mutation Q304Q and the nonsense mutation Y356X, each of which effect codons immediately adjacent to splicing signals. This hypothesis remains to be tested by expression analysis or studies of ectopic transcripts. The remaining 19 characterized alleles contained one of 15 previously identified mutations. Twenty-five of the thirty non-related patients examined in this study were completely genotyped, and there was a strong correlation between mutant PAH genotype, PAH activity predicted from in vitro expression studies where known, and PKU or HPA phenotype. For mutations not yet studied by expression analysis, this correlation suggests that L213P, R241L, Y277D may drastically reduce residual PAH activity while F39L and E76A may retain significant amounts of PAH activity.

  6. Variable phenotypes in a family with mitochondrial encephalomyopathy harboring a 3291T > C mutation in mitochondrial DNA.

    PubMed

    Sunami, Yoko; Sugaya, Keizo; Chihara, Norio; Goto, Yu-ichi; Matsubara, Shiro

    2011-10-01

    We present a Japanese family suffering from mitochondrial encephalomyopathy associated with a T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 3291. Clinical manifestations of the patients include cerebellar ataxia with myopathy, recurrent headache, and myoclonus and epilepsy. The phenotypic variation among the affected members of a single family and the mutational analysis showing maternal inheritance in a heteroplasmic fashion are consistent with well-recognized phenomena associated with many pathogenic point mutations of mtDNA tRNA genes. The 3291 mutation is a rare mtDNA mutation whose clinical presentation had only been reported in three sporadic cases. This is the first report of a family segregating the 3291 mutation with multigenerational matrilinear recurrence of mitochondrial encephalopathy. Our findings provide conclusive evidence for the pathogenicity of the 3291T > C mutation in mtDNA and its characteristic clinical heterogeneity.

  7. Gastrointestinal stromal tumors with KIT exon 9 mutations: Update on genotype-phenotype correlation and validation of a high-resolution melting assay for mutational testing.

    PubMed

    Künstlinger, Helen; Huss, Sebastian; Merkelbach-Bruse, Sabine; Binot, Elke; Kleine, Michaela Angelika; Loeser, Heike; Mittler, Jens; Hartmann, Wolfgang; Hohenberger, Peter; Reichardt, Peter; Büttner, Reinhard; Wardelmann, Eva; Schildhaus, Hans-Ulrich

    2013-11-01

    KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502_Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9-mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance.

  8. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU.

    PubMed

    Depienne, Christel; Nava, Caroline; Keren, Boris; Heide, Solveig; Rastetter, Agnès; Passemard, Sandrine; Chantot-Bastaraud, Sandra; Moutard, Marie-Laure; Agrawal, Pankaj B; VanNoy, Grace; Stoler, Joan M; Amor, David J; Billette de Villemeur, Thierry; Doummar, Diane; Alby, Caroline; Cormier-Daire, Valérie; Garel, Catherine; Marzin, Pauline; Scheidecker, Sophie; de Saint-Martin, Anne; Hirsch, Edouard; Korff, Christian; Bottani, Armand; Faivre, Laurence; Verloes, Alain; Orzechowski, Christine; Burglen, Lydie; Leheup, Bruno; Roume, Joelle; Andrieux, Joris; Sheth, Frenny; Datar, Chaitanya; Parker, Michael J; Pasquier, Laurent; Odent, Sylvie; Naudion, Sophie; Delrue, Marie-Ange; Le Caignec, Cédric; Vincent, Marie; Isidor, Bertrand; Renaldo, Florence; Stewart, Fiona; Toutain, Annick; Koehler, Udo; Häckl, Birgit; von Stülpnagel, Celina; Kluger, Gerhard; Møller, Rikke S; Pal, Deb; Jonson, Tord; Soller, Maria; Verbeek, Nienke E; van Haelst, Mieke M; de Kovel, Carolien; Koeleman, Bobby; Monroe, Glen; van Haaften, Gijs; Attié-Bitach, Tania; Boutaud, Lucile; Héron, Delphine; Mignot, Cyril

    2017-04-01

    Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

  9. Genetic Selection for Context-Dependent Stochastic Phenotypes: Sp1 and TATA Mutations Increase Phenotypic Noise in HIV-1 Gene Expression

    PubMed Central

    Shah, Priya S.; Arkin, Adam P.; Schaffer, David V.

    2013-01-01

    The sequence of a promoter within a genome does not uniquely determine gene expression levels and their variability; rather, promoter sequence can additionally interact with its location in the genome, or genomic context, to shape eukaryotic gene expression. Retroviruses, such as human immunodeficiency virus-1 (HIV), integrate their genomes into those of their host and thereby provide a biomedically-relevant model system to quantitatively explore the relationship between promoter sequence, genomic context, and noise-driven variability on viral gene expression. Using an in vitro model of the HIV Tat-mediated positive-feedback loop, we previously demonstrated that fluctuations in viral Tat-transactivating protein levels generate integration-site-dependent, stochastically-driven phenotypes, in which infected cells randomly ‘switch’ between high and low expressing states in a manner that may be related to viral latency. Here we extended this model and designed a forward genetic screen to systematically identify genetic elements in the HIV LTR promoter that modulate the fraction of genomic integrations that specify ‘Switching’ phenotypes. Our screen identified mutations in core promoter regions, including Sp1 and TATA transcription factor binding sites, which increased the Switching fraction several fold. By integrating single-cell experiments with computational modeling, we further investigated the mechanism of Switching-fraction enhancement for a selected Sp1 mutation. Our experimental observations demonstrated that the Sp1 mutation both impaired Tat-transactivated expression and also altered basal expression in the absence of Tat. Computational analysis demonstrated that the observed change in basal expression could contribute significantly to the observed increase in viral integrations that specify a Switching phenotype, provided that the selected mutation affected Tat-mediated noise amplification differentially across genomic contexts. Our study thus

  10. Genetic selection for context-dependent stochastic phenotypes: Sp1 and TATA mutations increase phenotypic noise in HIV-1 gene expression.

    PubMed

    Miller-Jensen, Kathryn; Skupsky, Ron; Shah, Priya S; Arkin, Adam P; Schaffer, David V

    2013-01-01

    The sequence of a promoter within a genome does not uniquely determine gene expression levels and their variability; rather, promoter sequence can additionally interact with its location in the genome, or genomic context, to shape eukaryotic gene expression. Retroviruses, such as human immunodeficiency virus-1 (HIV), integrate their genomes into those of their host and thereby provide a biomedically-relevant model system to quantitatively explore the relationship between promoter sequence, genomic context, and noise-driven variability on viral gene expression. Using an in vitro model of the HIV Tat-mediated positive-feedback loop, we previously demonstrated that fluctuations in viral Tat-transactivating protein levels generate integration-site-dependent, stochastically-driven phenotypes, in which infected cells randomly 'switch' between high and low expressing states in a manner that may be related to viral latency. Here we extended this model and designed a forward genetic screen to systematically identify genetic elements in the HIV LTR promoter that modulate the fraction of genomic integrations that specify 'Switching' phenotypes. Our screen identified mutations in core promoter regions, including Sp1 and TATA transcription factor binding sites, which increased the Switching fraction several fold. By integrating single-cell experiments with computational modeling, we further investigated the mechanism of Switching-fraction enhancement for a selected Sp1 mutation. Our experimental observations demonstrated that the Sp1 mutation both impaired Tat-transactivated expression and also altered basal expression in the absence of Tat. Computational analysis demonstrated that the observed change in basal expression could contribute significantly to the observed increase in viral integrations that specify a Switching phenotype, provided that the selected mutation affected Tat-mediated noise amplification differentially across genomic contexts. Our study thus demonstrates a

  11. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype

    PubMed Central

    Martinelli, Simone; De Luca, Alessandro; Stellacci, Emilia; Rossi, Cesare; Checquolo, Saula; Lepri, Francesca; Caputo, Viviana; Silvano, Marianna; Buscherini, Francesco; Consoli, Federica; Ferrara, Grazia; Digilio, Maria C.; Cavaliere, Maria L.; van Hagen, Johanna M.; Zampino, Giuseppe; van der Burgt, Ineke; Ferrero, Giovanni B.; Mazzanti, Laura; Screpanti, Isabella; Yntema, Helger G.; Nillesen, Willy M.; Savarirayan, Ravi; Zenker, Martin; Dallapiccola, Bruno; Gelb, Bruce D.; Tartaglia, Marco

    2010-01-01

    RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies. PMID:20619386

  12. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene

    SciTech Connect

    Putnam, E.A.; Cho, M.; Milewicz, D.M.

    1996-03-29

    Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 mutations in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling. 49 refs., 4 figs., 2 tabs.

  13. Grey, a novel mutation in the murine Lyst gene, causes the beige phenotype by skipping of exon 25.

    PubMed

    Runkel, Fabian; Büssow, Heinrich; Seburn, Kevin L; Cox, Gregory A; Ward, Diane McVey; Kaplan, Jerry; Franz, Thomas

    2006-03-01

    The murine beige mutant phenotype and the human Chediak-Higashi syndrome are caused by mutations in the murine Lyst (lysosomal trafficking regulator) gene and the human CHS gene, respectively. In this report we have analyzed a novel murine mutant Lyst allele, called Lyst(bg-grey), that had been found in an ENU mutation screen and named grey because of the grey coat color of affected mice. The phenotype caused by the Lyst(bg-grey) mutation was inherited in a recessive fashion. Melanosomes of melanocytes associated with hair follicles and the choroid layer of the eye, as well as melanosomes in the neural tube-derived pigment epithelium of the retina, were larger and irregularly shaped in homozygous mutants compared with those of wild-type controls. Secretory vesicles in dermal mast cells of the mutant skin were enlarged as well. Test crosses with beige homozygous mutant mice (Lyst(bg)) showed that double heterozygotes (Lyst(bg)/Lyst(bg-grey)) were phenotypically indistinguishable from either homozygous parent, demonstrating that the ENU mutation was an allele of the murine Lyst gene. RT-PCR analyses revealed the skipping of exon 25 in Lyst(bg-grey) mutants, which is predicted to cause a missense D2399E mutation and the loss of the following 77 amino acids encoded by exon 25 but leave the C-terminal end of the protein intact. Analysis of the genomic Lyst locus around exon 25 showed that the splice donor at the end of exon 25 showed a T-to-C transition point mutation. Western blot analysis suggests that the Lyst(bg-grey) mutation causes instability of the LYST protein. Because the phenotype of Lyst(bg) and Lyst(bg-grey) mutants is indistinguishable, at least with respect to melanosomes and secretory granules in mast cells, the Lyst(bg-grey) mutation defines a critical region for the stability of the murine LYST protein.

  14. Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability.

    PubMed

    Medina-Trillo, Cristina; Sánchez-Sánchez, Francisco; Aroca-Aguilar, José-Daniel; Ferre-Fernández, Jesús-José; Morales, Laura; Méndez-Hernández, Carmen-Dora; Blanco-Kelly, Fiona; Ayuso, Carmen; García-Feijoo, Julián; Escribano, Julio

    2015-01-01

    Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3%) were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG) or hypomorphic (p.I126S) alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG) and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability.

  15. Hypo- and Hypermorphic FOXC1 Mutations in Dominant Glaucoma: Transactivation and Phenotypic Variability

    PubMed Central

    Medina-Trillo, Cristina; Sánchez-Sánchez, Francisco; Aroca-Aguilar, José-Daniel; Ferre-Fernández, Jesús-José; Morales, Laura; Méndez-Hernández, Carmen-Dora; Blanco-Kelly, Fiona; Ayuso, Carmen; García-Feijoo, Julián; Escribano, Julio

    2015-01-01

    Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3%) were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG) or hypomorphic (p.I126S) alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG) and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability. PMID:25786029

  16. Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2.

    PubMed

    Teebi, Ahmad S; Kennedy, Shelley; Chun, Kathy; Ray, Peter N

    2002-01-01

    Pfeiffer syndrome is clinically and genetically heterogeneous. Three clinical subtypes have been delineated based on the severity of acrocephalysyndactyly and associated manifestations. Severe cases are usually sporadic and caused by a number of different mutations in exons IIIa and IIIc of the fibroblast growth factor receptor 2 (FGFR2) gene. Mild cases are either sporadic or familial and are caused by mutations in FGFR2 or FGFR1, respectively. We report on two individuals with different novel de novo mutations in FGFR2. The first is a 17-year-old male who has a severe phenotype, within the spectrum of subtype 1 including severe ocular proptosis, elbow ankylosis, visceral anomalies, and normal intelligence. This patient was found to have a novel complex mutation at the 3' acceptor site of exon IIIc of FGFR2, denoted as C952-3 del10insACC. The other patient, a 2-year-old female, has a mild phenotype, typical of the classic subtype 1 including brachycephaly with coronal synostosis and hypertelorism. She was also found to have a mutation at the 3' acceptor site (the same splice site) of exon IIIc of FGFR2, a point mutation designated as 952-1G-->A. Speculation on the molecular mechanisms that cause severe and mild phenotypes is presented in relation to these two cases.

  17. Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes.

    PubMed

    Marini, Juan C; Erez, Ayelet; Castillo, Leticia; Lee, Brendan

    2007-12-01

    The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mice from different genetic backgrounds (B6 and ICR) were infused intravenously with [(13)C(18)O]urea, l-[(15)N(2)]arginine, l-[5,5 D(2)]ornithine, l-[6-(13)C, 4,4,5,5, D(4)]citrulline, and l-[ring-D(5)]phenylalanine to investigate the interaction between genetic background and spf-ash mutation on ureagenesis, arginine metabolism, and nitric oxide production. ICR(spf-ash) mice maintained ureagenesis (5.5 +/- 0.3 mmol.kg(-1).h(-1)) and developed mild hyperammonemia (145 +/- 19 micromol/l) when an unbalanced nitrogen load was imposed; however, B6(spf-ash) mice became hyperammonemic (671 +/- 15 micromol/l) due to compromised ureagenesis (3.4 +/- 0.1 mmol.kg(-1).h(-1)). Ornithine supplementation restored ureagenesis and mitigated hyperammonemia. A reduction in citrulline entry rate was observed due to the mutation in both genetic backgrounds (wild-type: 128, spf-ash: 60; SE 4.0 micromol.kg(-1).h(-1)). Arginine entry rate was only reduced in B6(spf-ash) mice (B6(spf-ash): 332, ICR(spf-ash): 453; SE 20.6 micromol.kg(-1).h(-1)). Genetic background and mutation had an effect on nitric oxide production (B6: 3.4, B6(spf-ash): 2.8, ICR: 9.0, ICR(spf-ash): 4.6, SE 0.7 micromol.kg(-1).h(-1)). Protein breakdown was the main source of arginine during the postabsorptive state and was higher in ICR(spf-ash) than in B6(spf-ash) mice (phenylalanine entry rate 479 and 327, respectively; SE 18 micromol.kg(-1).h(-1)). Our results highlight the importance of the interaction between mutation and genetic background on ureagenesis, arginine metabolism, and nitric oxide production. These observations help explain the wide phenotypic variation of ornithine transcarbamylase deficiency in the human

  18. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association.

    PubMed

    Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

    2015-01-01

    Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

  19. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association

    PubMed Central

    Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

    2015-01-01

    Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

  20. Mutator Phenotype and DNA Double-Strand Break Repair in BLM Helicase-Deficient Human Cells

    PubMed Central

    Suzuki, Tetsuya; Yasui, Manabu

    2016-01-01

    Bloom syndrome (BS), an autosomal recessive disorder of the BLM gene, predisposes sufferers to various cancers. To investigate the mutator phenotype and genetic consequences of DNA double-strand breaks (DSBs) in BS cells, we developed BLM helicase-deficient human cells by disrupting the BLM gene. Cells with a loss of heterozygosity (LOH) due to homologous recombination (HR) or nonhomologous end joining (NHEJ) can be restored with or without site-directed DSB induction. BLM cells exhibited a high frequency of spontaneous interallelic HR with crossover, but noncrossover events with long-tract gene conversions also occurred. Despite the highly interallelic HR events, BLM cells predominantly produced hemizygous LOH by spontaneous deletion. These phenotypes manifested during repair of DSBs. Both NHEJ and HR appropriately repaired DSBs in BLM cells, resulting in hemizygous and homozygous LOHs, respectively. However, the magnitude of the LOH was exacerbated in BLM cells, as evidenced by large deletions and long-tract gene conversions with crossover. BLM helicase suppresses the elongation of branch migration and crossover of double Holliday junctions (HJs) during HR repair, and a deficiency in this enzyme causes collapse, abnormal elongation, and/or preferable resolution to crossover of double HJs, resulting in a large-scale LOH. This mechanism underlies the predisposition for cancer in BS. PMID:27601585

  1. Mutator Phenotype and DNA Double-Strand Break Repair in BLM Helicase-Deficient Human Cells.

    PubMed

    Suzuki, Tetsuya; Yasui, Manabu; Honma, Masamitsu

    2016-12-01

    Bloom syndrome (BS), an autosomal recessive disorder of the BLM gene, predisposes sufferers to various cancers. To investigate the mutator phenotype and genetic consequences of DNA double-strand breaks (DSBs) in BS cells, we developed BLM helicase-deficient human cells by disrupting the BLM gene. Cells with a loss of heterozygosity (LOH) due to homologous recombination (HR) or nonhomologous end joining (NHEJ) can be restored with or without site-directed DSB induction. BLM cells exhibited a high frequency of spontaneous interallelic HR with crossover, but noncrossover events with long-tract gene conversions also occurred. Despite the highly interallelic HR events, BLM cells predominantly produced hemizygous LOH by spontaneous deletion. These phenotypes manifested during repair of DSBs. Both NHEJ and HR appropriately repaired DSBs in BLM cells, resulting in hemizygous and homozygous LOHs, respectively. However, the magnitude of the LOH was exacerbated in BLM cells, as evidenced by large deletions and long-tract gene conversions with crossover. BLM helicase suppresses the elongation of branch migration and crossover of double Holliday junctions (HJs) during HR repair, and a deficiency in this enzyme causes collapse, abnormal elongation, and/or preferable resolution to crossover of double HJs, resulting in a large-scale LOH. This mechanism underlies the predisposition for cancer in BS. Copyright © 2016 Suzuki et al.

  2. Mutational analysis and genotype-phenotype relation in familial hypercholesterolemia: The SAFEHEART registry.

    PubMed

    Bourbon, Mafalda; Alves, Ana Catarina; Alonso, Rodrigo; Mata, Nelva; Aguiar, Pedro; Padró, Teresa; Mata, Pedro

    2017-07-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disease of cholesterol metabolism that confers an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Therefore, early identification and treatment of these patients can improve prognosis and reduce the burden of cardiovascular mortality. The aim of this work was to perform the mutational analysis of the SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) registry. The study recruited 2938 individuals with genetic diagnosis of FH belonging to 775 families. Statistical analysis was performed using SPSS v23. A total of 194 variants have been detected in this study, 24 of them were never described before. About 88% of the patients have a pathogenic or likely pathogenic variant. Patients with null variants have a more severe phenotype than patients with defective variants, presenting with significantly higher levels of atherogenic particles (total cholesterol, LDL-cholesterol and apolipoprotein B). This study shows the molecular characteristics of the FH patients included in the SAFEHEART registry and the relationship with the phenotypic expression. The majority of the genetic variants are considered to be pathogenic or likely pathogenic, which confers a high level of confidence to the entry and follow-up data analysis performed with this registry concerning FH patients' prognosis, treatment and survival. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Identification of a novel ZNF469 mutation in a large family with Ehlers-Danlos phenotype.

    PubMed

    Al-Owain, Mohammed; Al-Dosari, Mohammed S; Sunker, Asma; Shuaib, Taghreed; Alkuraya, Fowzan S

    2012-12-15

    Brittle cornea syndrome (BCS) is a genetically heterogeneous disorder characterized by extreme corneal fragility and thinning, which may lead to spontaneous or trauma-induced corneal rupture. BCS-1 and BCS-2 are caused by recessive mutations in ZNF469 and PRDM5, respectively. Both genes play a role in the regulatory pathway of corneal development and maintenance. We report a consanguineous family with five patients affected with the cardinal ocular features of BCS and significant musculoskeletal findings primarily in the form of joint hypermobility and severe kyphoscoliosis. The patients had thin velvety skin, hallux valgus, variable sensorineural hearing loss and arachnodactyly. Interestingly, one of the patients additionally had phenylketonuria and showed a milder ophthalmological and musculoskeletal phenotype than his affected siblings. The urinary pyridinoline and deoxypyridinoline concentrations and their ratios were mildly elevated indicating increased bone-collagen turnover. A novel homozygous 14 bp duplication in exon 2 of ZNF469 (c.8817_8830dup) was uncovered by direct sequencing. This family highlights the phenotypic overlap between BCS and Ehlers-Danlos syndrome.

  4. Phenotypic characterization of spontaneously mutated rats showing lethal dwarfism and epilepsy.

    PubMed

    Suzuki, Hiroetsu; Takenaka, Motoo; Suzuki, Katsushi

    2007-08-01

    We have characterized the phenotype of spontaneously mutated rats, found during experimental inbreeding in a closed colony of Wistar Imamichi rats. Mutant rats showed severe dwarfism, short lifespan (early postnatal lethality), and high incidence of epileptic seizures. Mutant rats showed growth retardation after 3 d of age, and at 21 d their weight was about 56% that of normal rats. Most mutant rats died without reaching maturity, and 95% of the mutant rats had an ataxic gait. About 34% of the dwarf rats experienced epileptic seizures, most of which started as 'wild running' convulsions, progressing to generalized tonic-clonic convulsions. At age 28 d, the relative weight of the testes was significantly lower, and the relative weight of the brain was significantly higher, in mutant than in normal rats. Histologically, increased apoptotic germ cells, lack of spermatocytes, and immature Leydig cells were found in the mutant testes, and extracellular vacuoles of various sizes were present in the hippocampus and amygdala of the mutant brain. Mutant rats had significantly increased concentrations of plasma urea nitrogen, creatinine, and inorganic phosphate, as well as decreased concentrations of plasma growth hormone. Hereditary analysis showed that the defects were inherited as a single recessive trait. We have named the hypothetically mutated gene as lde (lethal dwarfism with epilepsy).

  5. Behavioral phenotype in Costello syndrome with atypical mutation: a case report.

    PubMed

    Alfieri, Paolo; Caciolo, Cristina; Piccini, Giorgia; D'Elia, Lidia; Valeri, Giovanni; Menghini, Deny; Tartaglia, Marco; Digilio, Maria Cristina; Dallapiccola, Bruno; Vicari, Stefano

    2015-01-01

    Costello syndrome (CS) is a rare genetic disorder caused, in the majority of cases, by germline missense HRAS mutations affecting Gly(12) promoting enhanced signaling through the MAPK and PI3K-AKT signaling cascades. In general, the cognitive profile in CS is characterized by intellectual disability ranging from mild to severe impairment. The first published descriptions of behavior in CS children underlined the presence of irritability and shyness at younger ages with sociable personality and good empathic skills after 4-5 years of age, however some recent studies have reported autistic traits. We report on a 7-year-old boy heterozygous for a rare duplication of codon 37 (p.E37dup) in HRAS, manifesting impaired social interaction and non-verbal communication and with circumscribed interests. These additional features improve phenotype delineation in individuals with rare HRAS mutations, facilitating the development of specific behavioral treatments which could lead to improvement in cases of autism spectrum disorder. © 2014 Wiley Periodicals, Inc.

  6. A novel mutation at the JK locus causing Jk null phenotype in a Chinese family.

    PubMed

    Meng, Yan; Zhou, Xueyan; Li, Yang; Zhao, Dan; Liang, Shuyuan; Zhao, Xuejian; Yang, Baoxue

    2005-12-01

    Urea transporters are a group of proteins that facilitate urea movement across biological membranes. Kidd blood group (Jk antigen) and urea transporter of human erythrocytes are carried by the same protein UT-B. To investigate the molecular basis of the Jk null phenotype in the Chinese population, blood samples from Chinese individuals were screened using the 2 mol/L urea solution hemolysis test. Urea and water permeability of erythrocytes membrane was measured by stopped-flow light scattering. Genomic DNA was extracted from lymphocytes. UT-B gene of JKnnu's family was analyzed using genomic PCR by primers designed to cover sequences of all exons and exon-intron boundaries in human UT-B gene. One Jk null subject was found from twenty thousand screened Chinese individuals, and it was confirmed that this individual did not express the erythrocyte urea transporter. Genomic sequence analysis of the Jk null individual showed that there were two point mutations, G-->C, which is novel, and G-->A, at the 3'-acceptor splice site (AG) of intron 5 of UT-B gene. Exon 6 is spliced out in the UT-B transcript due to either of these mutations. Water permeability in Jk null erythrocytes (Pf, -0.00037 cm/s) was significantly lower than that in normal erythrocytes (Pf, -0.00062 cm/s) after HgCl2 incubation, providing evidence for UT-B facilitated water transport in human erythrocytes.

  7. Abetalipoproteinemia in an infant with severe clinical phenotype and a novel mutation.

    PubMed

    Uslu, Nuray; Gürakan, Figen; Yüce, Aysel; Demir, Hülya; Tarugi, Patrizia

    2010-01-01

    Abetalipoproteinemia (ABL) is a rare autosomal disorder characterized by extremely low levels of plasma lipids and apolipoprotein B (apoB) with a variable phenotype. Mutations in the MTP gene encoding the microsomal triglyceride transfer protein (MTP) cause the disease. A five-month-old boy, born from consanguineous parents, with chronic diarrhea and severe malnutrition had extremely low plasma lipids and apoB levels suggesting the diagnosis of ABL. He was not responsive to treatment with low-fat diet and fat-soluble vitamins and died at 13 months of age with severe malnutrition. Analysis of the MTP gene showed that he was homozygous for a two nucleotide deletion in exon 4 (c.398-399delAA) expected to cause a frameshift in the mRNA leading to a premature termination codon. The normolipidemic proband's parents were found to be heterozygous for the mutation. This observation underscores that in some cases, ABL can be extremely severe from early post-natal life and poorly responsive to treatment.

  8. 'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation.

    PubMed

    Boissé Lomax, Lysa; Bayly, Marta A; Hjalgrim, Helle; Møller, Rikke S; Vlaar, Annemarie M; Aaberg, Kari M; Marquardt, Iris; Gandolfo, Luke C; Willemsen, Michèl; Kamsteeg, Erik-Jan; O'Sullivan, John D; Korenke, G Christoph; Bloem, Bastiaan R; de Coo, Irenaeus F; Verhagen, Judith M A; Said, Ines; Prescott, Trine; Stray-Pedersen, Asbjørg; Rasmussen, Magnhild; Vears, Danya F; Lehesjoki, Anna-Elina; Corbett, Mark A; Bahlo, Melanie; Gecz, Jozef; Dibbens, Leanne M; Berkovic, Samuel F

    2013-04-01

    We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.

  9. Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

    PubMed Central

    Quarello, Paola; Garelli, Emanuela; Carando, Adriana; Brusco, Alfredo; Calabrese, Roberto; Dufour, Carlo; Longoni, Daniela; Misuraca, Aldo; Vinti, Luciana; Aspesi, Anna; Biondini, Laura; Loreni, Fabrizio; Dianzani, Irma; Ramenghi, Ugo

    2010-01-01

    Background Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients. Design and Methods In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations. Results About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. Conclusions Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations. PMID:19773262

  10. The chemical chaperone phenylbutyrate rescues MCT8 mutations associated with milder phenotypes in patients with AHDS.

    PubMed

    Braun, Doreen; Schweizer, Ulrich

    2016-12-15

    Mutations in the thyroid hormone transporter MCT8 prevent appropriate entry of thyroid hormones into brain cells during development and cause severe mental retardation in affected patients. Current treatment options are thyromimetic compounds that enter the brain independent of MCT8. Some MCT8 deficient patients (e.g. those carrying MCT8(delF501)) are not as severely affected than most others. We have shown that MCT8(delF501) protein has decreased protein stability, but significant residual function once it reaches the plasma membrane. We were able to rescue protein expression and function of MCT8(delF501) in a MDCK1 cell model by application of the chemical chaperone sodium phenylbutyrate (NaPB), a drug that has been used to treat patients with cystic fibrosis and urea cycle defects over extended periods of time. Here we extend our previous study and report on the NaPB dependent rescue of a series of other pathogenic MCT8 mutants that are associated with milder patient phenotypes. We show that NaPB can functionally rescue expression and activities of Ser194Phe, Ser290Phe, Leu434Trp, Arg445Cys, Leu492Pro, and Leu568Pro mutations in MCT8 in a dose-dependent manner. The soy isoflavone genistein, a dietary supplement, which was effective in MCT8(delF501), was also effective in increasing expression and transport of these MCT8 mutants, but the effect size differed among mutants. Kinetic analyses revealed that Michaelis constants of the mutants towards the primary substrate T3 were not much different from the wild type value suggesting that these mutants are not impaired in their interaction with substrate, but rather destabilized by the mutation and degraded.

  11. The Phenotype of the Musculocontractural Type of Ehlers-Danlos Syndrome due to CHST14 Mutations

    PubMed Central

    Janecke, Andreas R.; Li, Ben; Boehm, Manfred; Krabichler, Birgit; Rohrbach, Marianne; Müller, Thomas; Fuchs, Irene; Golas, Gretchen; Katagiri, Yasuhiro; Ziegler, Shira G.; Gahl, William A.; Wilnai, Yael; Zoppi, Nicoletta; Geller, Herbert M.; Giunta, Cecilia; Slavotinek, Anne; Steinmann, Beat

    2016-01-01

    The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with biallelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients hadmildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS. PMID:26373698

  12. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations.

    PubMed

    Janecke, Andreas R; Li, Ben; Boehm, Manfred; Krabichler, Birgit; Rohrbach, Marianne; Müller, Thomas; Fuchs, Irene; Golas, Gretchen; Katagiri, Yasuhiro; Ziegler, Shira G; Gahl, William A; Wilnai, Yael; Zoppi, Nicoletta; Geller, Herbert M; Giunta, Cecilia; Slavotinek, Anne; Steinmann, Beat

    2016-01-01

    The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS.

  13. Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: Correlation with phenotypic activity

    SciTech Connect

    Cascorbi, I.; Drakoulis, N.; Brockmoeller, J.

    1995-09-01

    The polymorphic arylamine N-acetyltransferase (NAT2; EC2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had a genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2{sup *}4/{sup *}4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles {sup *}5A, {sup *}5C, and {sup *}13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of {sup *}6A, {sup *}7B, and {sup *}13 alleles than the group of {sup *}5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations. 34 refs., 4 figs., 7 tabs.

  14. Analysis of FOXL2 detects three novel mutations and an atypical phenotype of blepharophimosis-ptosis-epicanthus inversus syndrome.

    PubMed

    Krepelova, Anna; Simandlova, Martina; Vlckova, Marketa; Kuthan, Pavel; Vincent, Andrea L; Liskova, Petra

    2016-12-01

    Mutations in FOXL2 are known to cause autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), variably associated with premature ovarian failure. In this study, we report results of mutational screening in a Czech and Slovak patient population with BPES. Case series. Thirteen probands of Czech and one proband of Slovak origin with BPES and their available family members. Sanger sequencing and multiplex ligation-dependent probe amplification in 14 probands with BPES. Targeted mutational screening in first-degree relatives. Genetic characterization and phenotype evaluation in Czech and Slovak individuals with BPES and their family members. Eight different mutations were detected including three novel ones: c.5T>G; p.(Met2Arg), c.197C>A; p.(Ala66Glu) and c.701_702insTGCAGCCGCAGCGGCTGCAGCAGCTGCGGCTGCAGCCGC; p.(Ala222_Ala234dup). In one family, the molecular genetic cause of disease was not identified by the methodology used. In 13 pedigrees, a negative family history suggested a de novo origin, which could be confirmed by targeted mutational screening in four families. One 62-year-old female with the c.663_692dup30 mutation had an atypical phenotype presenting as moderate ptosis compensated by frontalis muscle contraction, no epicanthus inversus and no premature ovarian failure. The de novo mutation rate in FOXL2 is exceptionally high compared with other dominant disorders manifesting with an ocular phenotype. In cases reporting a negative family history, careful examination of both parents is important to exclude mild features of the BPES phenotype. © 2016 Royal Australian and New Zealand College of Ophthalmologists.

  15. Screening of RB1 gene mutations in Chinese patients with retinoblastoma and preliminary exploration of genotype–phenotype correlations

    PubMed Central

    He, Ming-yan; An, Yu; Qian, Xiao-wen; Li, Gang; Qian, Jiang

    2014-01-01

    Purpose Retinoblastoma (RB) sets the paradigm for hereditary cancer syndromes, for which medical care can change depending on the results of genetic testing. In this study, we screened constitutional mutations in the RB1 gene via a method combining DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), and performed a preliminary exploration of genotype–phenotype correlations. Methods The peripheral blood of 85 retinoblastoma probands, including 39 bilateral and 46 unilateral, was collected, and genomic DNA was extracted. DNA sequencing was conducted first. MLPA analysis was applied for patients with bilateral RB with negative sequencing results and unilateral probands whose age at diagnosis was less than 1 year old. Results Thirty-four distinct mutations were identified in 40 (47.1%) of the 85 probands (36 bilateral and four unilateral), of which 20% (8/40) was identified by MLPA. The total detection rate in bilateral cases was 92.3% (36/39). Of the total mutations identified, 77.5% (31/40) probands with a mean age of 10.7 months at diagnosis had null mutations, and 22.5% (9/40) with a mean age of 13.5 months at diagnosis had in-frame mutations. Of the 31 probands with null mutations, bilateral RB accounted for 96.8% (30/31). Of the nine probands with in-frame mutations, 66.7% had bilateral RB. There were seven new mutations of RB1 identified in this report, including six null mutations and one missense mutation. Clinical staging of the tumor did not show obvious differences between patients with null mutations and in-frame mutations. Conclusions Our results confirm that the type of mutation is related to age of onset and the laterality, but not staging of the retinoblastoma tumor. MLPA is a reliable method for detecting gross deletion or duplication of the RB1 gene. The combination of sequencing and MLPA improves the clinical diagnosis of RB. PMID:24791139

  16. Identification of a Novel GLA Gene Mutation, p.Ile239Met, in Fabry Disease With a Predominant Cardiac Phenotype.

    PubMed

    Csányi, Beáta; Hategan, Lidia; Nagy, Viktória; Obál, Izabella; Varga, Edina T; Borbás, János; Tringer, Annamária; Eichler, Sabrina; Forster, Tamás; Rolfs, Arndt; Sepp, Róbert

    2017-05-31

    Fabry disease (FD) is an X-linked inherited lysosomal storage disorder caused by mutations in the GLA gene, encoding for the enzyme α-galactosidase A. Although hundreds of mutations in the GLA gene have been described, many of them are variants of unknown significance. Here we report a novel GLA mutation, p.Ile239Met, identified in a large Hungarian three-generation family with FD. A 69 year-old female index patient with a clinical history of renal failure, hypertrophic cardiomyopathy, and 2nd degree AV block was screened for mutation in the GLA gene. Genetic screening identified a previously unreported heterozygous mutation in exon 5 of the GLA gene (c.717A>G; p.Ile239Met). Family screening indicated that altogether 6 family members carried the mutation (5 females, 1 male, average age: 55 ± 16 years). Three family members, including the index patient, manifested the cardiac phenotype of hypertrophic cardiomyopathy, while two other family members were diagnosed with left ventricular hypertrophy. Taking affection status as the presence of hypertrophic cardiomyopathy, left ventricular hypertrophy or elevated lyso-Gb3 levels, all affected family members carried the mutation. Linkage analysis of the family gave a two-point LOD score of 2.01 between the affection status and the p.Ile239Met GLA mutation. Lyso-Gb3 levels were elevated in all carrier family members (range: 2.4-13.8 ng/mL; upper limit of normal +2STD: ≤ 1.8 ng/mL). The GLA enzyme level was markedly reduced in the affected male family member (< 0.2 µmol/L/hour; upper limit of normal ± 2STD: ≥ 2.6 µmol/L/hour). We conclude that the p. Ile239Met GLA mutation is a pathogenic mutation for FD associated with predominant cardiac phenotype.

  17. CDH23 Mutation and Phenotype Heterogeneity: A Profile of 107 Diverse Families with Usher Syndrome and Nonsyndromic Deafness

    PubMed Central

    Astuto, L. M.; Bork, J. M.; Weston, M. D.; Askew, J. W.; Fields, R. R.; Orten, D. J.; Ohliger, S. J.; Riazuddin, S.; Morell, R. J.; Khan, S.; Riazuddin, S.; Kremer, H.; van Hauwe, P.; Moller, C. G.; Cremers, C. W. R. J.; Ayuso, C.; Heckenlively, J. R.; Rohrschneider, K.; Spandau, U.; Greenberg, J.; Ramesar, R.; Reardon, W.; Bitoun, P.; Millan, J.; Legge, R.; Friedman, T. B.; Kimberling, W. J.

    2002-01-01

    Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP–like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia. PMID:12075507

  18. Identification of a frameshift mutation responsible for the silent phenotype of human serum cholinesterase, Gly 117 (GGT----GGAG).

    PubMed Central

    Nogueira, C P; McGuire, M C; Graeser, C; Bartels, C F; Arpagaus, M; Van der Spek, A F; Lightstone, H; Lockridge, O; La Du, B N

    1990-01-01

    A frameshift mutation that causes a silent phenotype for human serum cholinesterase was identified in the DNA of seven individuals of two unrelated families. The mutation, identified using the polymerase chain reaction, causes a shift in the reading frame from Gly 117, where GGT (Gly)----GGAG (Gly+ 1 base) to a new stop codon created at position 129. This alteration is upstream of the active site (Ser 198), and, if any protein were made, it would represent only 22% of the mature enzyme found in normal serum. Results of analysis of the enzymatic activities in serum agreed with the genotypes inferred from the nucleotide sequence. Rocket immunoelectrophoresis using alpha-naphthyl acetate to detect enzymatic activity showed an absence of cross-reactive material, as expected. One additional individual with a silent phenotype did not show the same frameshift mutation. This was not unexpected, since there must be considerable molecular heterogeneity involved in causes for the silent cholinesterase phenotype. This is the first report of a molecular mechanism underlying the silent phenotype for serum cholinesterase. The analytical approach used was similar to the one we recently employed to identify the mutation that causes the atypical cholinesterase variant. Images Figure 3 Figure 5 Figure 6 PMID:2339692

  19. Expanding the phenotype of DNAJC3 mutations: A case with hypothyroidism additionally to diabetes mellitus and multisystemic neurodegeneration.

    PubMed

    Bublitz, S K; Alhaddad, B; Synofzik, M; Kuhl, V; Lindner, A; Freiberg, C; Schmidt, H; Strom, T M; Haack, T B; Deschauer, M

    2017-11-01

    Identification of this additional patient from a distant part of the originally described pedigree (Synofzik et al. 2014) confirms pathogenicity of DNAJC3 mutations. Hypothyroidism is a newly identified feature in addition to the known phenotype (diabetes with multisystemic neurodegeneration). © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Four novel mutations in the cystathionine beta-synthase gene: effect of a second linked mutation on the severity of the homocystinuric phenotype.

    PubMed

    de Franchis, R; Kraus, E; Kozich, V; Sebastio, G; Kraus, J P

    1999-01-01

    Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is frequently caused by missense mutations. In this article, we report four novel missense mutations in the CBS gene: 172C-->T (R58W) linked in cis with A114V; 376A-->G (M126V); 904G-->A (E302K); and 1006C-->T (R336C). The CBS activity of the corresponding mutant enzymes expressed in Escherichia coli was greatly diminished, confirming the pathogenicity of these mutations. Western analysis showed that the R58W+A114V and M126V mutant enzymes were unstable in E. coli, while the E302K subunits were partially degraded to shorter products. Using site-directed mutagenesis we found that CBS containing either the R58W or A114V as the only mutations demonstrated 18% and 46% of normal activity, respectively. Both mutant forms of CBS were stable in E. coli. When these two mutations were expressed in cis, the resultant mutant protein exhibited activity 1.3% that of a control. All these in vitro results were in good agreement with the clinical manifestation in these patients. The Italian patient 2241, an A114V+R58W/M126V compound heterozygote, exhibited severe pyridoxine nonresponsive homocystinuria, while another Italian patient 2242, with an A114V/E302K genotype, responded to pyridoxine treatment and had a much milder phenotype. The third patient 3064, an English compound heterozygote for two severe mutations R336C and G307S, was B6 nonresponsive. This report of a ninth homocystinuric allele carrying two mutations in cis raises the possibility that double mutant alleles may be underestimated in homocystinuric patients. In this context, a search for additional mutations in cis may sometimes be necessary to establish a good genotype-phenotype relationship.

  1. Mismatch repair genes of Streptococcus pneumoniae: HexA confers a mutator phenotype in Escherichia coli by negative complementation.

    PubMed

    Prudhomme, M; Méjean, V; Martin, B; Claverys, J P

    1991-11-01

    DNA repair systems able to correct base pair mismatches within newly replicated DNA or within heteroduplex molecules produced during recombination are widespread among living organisms. Evidence that such generalized mismatch repair systems evolved from a common ancestor is particularly strong for two of them, the Hex system of the gram-positive Streptococcus pneumoniae and the Mut system of the gram-negative Escherichia coli and Salmonella typhimurium. The homology existing between HexA and MutS and between HexB and MutL prompted us to investigate the effect of expressing hex genes in E. coli. Complementation of mutS or mutL mutations, which confer a mutator phenotype, was assayed by introducing on a multicopy plasmid the hexA and hexB genes, under the control of an inducible promoter, either individually or together in E. coli strains. No decrease in mutation rate was conferred by either hexA or hexB gene expression. However, a negative complementation effect was observed in wild-type E. coli cells: expression of hexA resulted in a typical Mut- mutator phenotype. hexB gene expression did not increase the mutation rate either individually or in conjunction with hexA. Since expression of hexA did not affect the mutation rate in mutS mutant cells and the hexA-induced mutator effect was recA independent, it is concluded that this effect results from inhibition of the Mut system. We suggest that HexA, like its homolog MutS, binds to mismatches resulting from replication errors, but in doing so it protects them from repair by the Mut system. In agreement with this hypothesis, an increase in mutS gene copy number abolished the hexA-induced mutator phenotype. HexA protein could prevent repair either by being unable to interact with Mut proteins or by producing nonfunctional repair complexes.

  2. Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without {alpha}-thalassemia

    SciTech Connect

    Villard, L.; Lossi, A.M.; Fontes, M.

    1996-03-01

    We have previously reported the isolation of a gene from Xq13 that codes for a putative regulator of transcription (XNP) and has now been shown to be the gene involved in the X-linked {alpha}-thalassemia with mental retardation (ATR-X) syndrome. The widespread expression and numerous domains present in the putative protein suggest that this gene could be involved in other phenotypes. The predominant expression of the gene in the developing brain, as well as its association with neuron differentiation, indicates that mutations of this gene might result in a mental retardation (MR) phenotype. In this paper we present a family with a splice junction mutation in XNP that results in the skipping of an exon and in the introduction of a stop codon in the middle of the XNP-coding sequence. Only the abnormal transcript is expressed in two first cousins presenting the classic ATR-X phenotype (with {alpha}-thalassemia and HbH inclusions). In a distant cousin presenting a similar dysmorphic MR phenotype but not having thalassemia, {approximately}30% of the XNP transcripts are normal. These data demonstrate that the mode of action of the XNP gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis and suggest that other dysmorphic mental retardation phenotypes, such as Juberg-Marsidi or some sporadic cases of Coffin-Lowry, could be due to mutations in XNP. 20 refs., 5 figs., 2 tabs.

  3. A novel lamin A/C gene mutation causing spinal muscular atrophy phenotype with cardiac involvement: report of one case.

    PubMed

    Iwahara, Naotoshi; Hisahara, Shin; Hayashi, Takashi; Kawamata, Jun; Shimohama, Shun

    2015-02-20

    Mutations of the lamin A/C gene have been associated with several diseases such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Charcot-Marie-Tooth disease, referred to as laminopathies. Only one report of spinal muscular atrophy and cardiomyopathy phenotype with lamin A/C gene mutations has been published. The concept that lamin A/C gene mutations cause spinal muscular atrophy has not been established. We report a man aged 65 years who presented with amyotrophy of lower limbs, arrhythmia and cardiac hypofunction. He showed gait disturbance since childhood, and his family showed similar symptoms. Neurological and electrophysiological findings suggested spinal muscular atrophy type 3. Gene analysis of lamin A/C gene showed a novel nonsense mutation p.Q353X (c.1057C > T). Further investigations revealed that he and his family members had cardiac diseases including atrioventricular block. We report the first Japanese case of spinal muscular atrophy phenotype associated with lamin A/C mutation. When a patient presents a spinal muscular atrophy phenotype and unexplained cardiac disease, especially when the family history is positive, gene analysis of lamin A/C gene should be considered.

  4. [NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease].

    PubMed

    Tamzaourte, Mouna; Errabih, Ikram; Krami, Hayat; Maha, Fadlouallah; Maria, Lahmiri; Benzzoubeir, Nadia; Ouazzani, Laaziza; Sefiani, Ahmed; Ouazzani, Houria

    2017-01-01

    The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease.

  5. A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: Genotype/phenotype correlations

    SciTech Connect

    Superti-Furga, A.; Steinmann, B.; Gitzelmann, R.; Rossi, A.

    1996-05-03

    Achondrogenesis type 1B (ACG-1B), atelosteogenesis type 2 (AO-2), and diastrophic dysplasia (DTD) are recessively inherited chondrodysplasia of decreasing severity caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene on chromosome 5. In these conditions, sulfate transport across the cell membrane is impaired which results in insufficient sulfation of cartilage proteoglycans and thus in an abnormally low sulfate content of cartilage. The severity of the phenotype correlates well with the predicted effect of the underlying DTDST mutations: homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type 1B, while other structural or regulatory mutations usually result in one of the less severe phenotypes. The chondrodysplasia arising at the DTDST locus constitute a bone dysplasia family with recessive inheritance. 28 refs., 2 tabs.

  6. Clinical Relevance and Molecular Phenotypes in Gastric Cancer, of TP53 Mutations and Gene Expressions, in Combination With Other Gene Mutations

    PubMed Central

    Park, Sungjin; Lee, Jinhyuk; Kim, Yon Hui; Park, Jaheun; Shin, Jung-Woog; Nam, Seungyoon

    2016-01-01

    While altered TP53 is the most frequent mutation in gastric cancer (GC), its association with molecular or clinical phenotypes (e.g., overall survival, disease-free survival) remains little known. To that end, we can use genome-wide approaches to identify altered genes significantly related to mutated TP53. Here, we identified significant differences in clinical outcomes, as well as in molecular phenotypes, across specific GC tumor subpopulations, when combining TP53 with other signaling networks, including WNT and its related genes NRXN1, CTNNB1, SLITRK5, NCOR2, RYR1, GPR112, MLL3, MTUS2, and MYH6. Moreover, specific GC subpopulations indicated by dual mutation of NRXN1 and TP53 suggest different drug responses, according to the Connectivity Map, a pharmacological drug-gene association tool. Overall, TP53 mutation status in GC is significantly relevant to clinical or molecular categories. Thus, our approach can potentially provide a patient stratification strategy by dissecting previously unknown multiple TP53-mutated patient groups. PMID:27708434

  7. ATM gene mutations result in both recessive and dominant expression phenotypes of genes and microRNAs.

    PubMed

    Smirnov, Denis A; Cheung, Vivian G

    2008-08-01

    The defining characteristic of recessive disorders is the absence of disease in heterozygous carriers of the mutant alleles. However, it has been recognized that recessive carriers may differ from noncarriers in some phenotypes. Here, we studied ataxia telangiectasia (AT), a classical recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. We compared the gene and microRNA expression phenotypes of noncarriers, AT carriers who have one copy of the ATM mutations, and AT patients with two copies of ATM mutations. We found that some phenotypes are more similar between noncarriers and AT carriers compared to AT patients, as expected for a recessive disorder. However, for some expression phenotypes, AT carriers are more similar to the patients than to the noncarriers. Analysis of one of these expression phenotypes, TNFSF4 level, allowed us to uncover a regulatory pathway where ATM regulates TNFSF4 expression through MIRN125B (also known as miR-125b or miR125b) [corrected] In AT carriers and AT patients, this pathway is disrupted. As a result, the level of MIRN125B is lower and the level of its target gene, TNFSF4, is higher than in noncarriers. A decreased level of MIRN125B is associated with breast cancer, and an elevated level of TNFSF4 is associated with atherosclerosis. Thus, our findings provide a mechanistic suggestion for the increased risk of breast cancer and heart disease in AT carriers. By integrating molecular and computational analyses of gene and microRNA expression, we show the complex consequences of a human gene mutation.

  8. Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families.

    PubMed

    Hebrard, Maxime; Manes, Gaël; Bocquet, Béatrice; Meunier, Isabelle; Coustes-Chazalette, Delphine; Hérald, Emilie; Sénéchal, Audrey; Bolland-Augé, Anne; Zelenika, Diana; Hamel, Christian P

    2011-12-01

    Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.

  9. HSP90 Stabilizes Auxin-Responsive Phenotypes by Masking a Mutation in the Auxin Receptor TIR1.

    PubMed

    Watanabe, Etsuko; Mano, Shoji; Nomoto, Mika; Tada, Yasuomi; Hara-Nishimura, Ikuko; Nishimura, Mikio; Yamada, Kenji

    2016-11-01

    Heat shock protein 90 (HSP90) is a molecular chaperone that is required for the function of various substrate proteins, also known as client proteins. It is proposed that HSP90 buffers or hides phenotypic variations in animals and plants by masking mutations in some of its client proteins. However, none of the client proteins with cryptic mutations has been identified to date. Here, we identify the first client protein example by which HSP90 buffers a mutation: the auxin receptor transport inhibitor response 1 (TIR1). TIR1 interacts with HSP90 in the nucleus. An HSP90-specific inhibitor abolished the nuclear localization of TIR1 and the auxin-induced degradation of a TIR1-substrate, indicating that TIR1 is an HSP90 client protein. Plants with a null mutation in the TIR1 gene had a defect in auxin response, whereas plants with a point mutation in the TIR1 gene responded to auxin treatment in young seedlings, but a cryptic defect in its auxin response was exposed with HSP90 inhibitor treatment. These results demonstrate that HSP90 masks a point mutation in the auxin receptor TIR1 and thereby buffers auxin-responsive phenotypes.

  10. The phenotype in Norwegian patients with Bardet-Biedl syndrome with mutations in the BBS4 gene.

    PubMed

    Riise, Ruth; Tornqvist, Kristina; Wright, Alan F; Mykytyn, Kirk; Sheffield, Val C

    2002-10-01

    To describe the phenotype of the Bardet-Biedl syndrome in patients with mutations in the BBS4 gene. We examined 3 pairs of siblings with Bardet-Biedl syndrome in whom 3 different mutations in the BBS4 gene were detected, 2 of which were homozygous for the mutation. All patients had an increased body mass index. The obesity varied between families from moderate to severe. All of the males had hypogenitalism. All had brachydactyly and similar dental anomalies. Polydactyly was present in 5 of the 6 patients. The number and location of the extra digits varied even between siblings. The intelligence varied between families and was within the normal range in 4 individuals. One male had spinal stenosis with paraparesis of his legs. Four patients had increased blood pressure, but only 1 had impaired renal function. Severe retinitis pigmentosa with onset in early childhood was present in all patients. There were few abnormal retinal pigmentary deposits even at advanced stages. The phenotype of patients with BBS4 mutations consists of severe retinitis pigmentosa, variable obesity, brachydactyly with variable polydactyly, small or missing teeth, genital hypoplasia, and cardiovascular disease. The combinations of clinical signs are mostly independent of the individual BBS4 mutation and can vary even within pairs of siblings. It is possible that there is a characteristic appearance of the ocular fundus in patients with BBS4 mutations.

  11. The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes

    PubMed Central

    Garver, William S.; Jelinek, David; Meaney, F. John; Flynn, James; Pettit, Kathleen M.; Shepherd, Glen; Heidenreich, Randall A.; Vockley, Cate M. Walsh; Castro, Graciela; Francis, Gordon A.

    2010-01-01

    Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lysosomal storage disorder characterized by neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration. The present study provides the lipid profiles, mutations, and corresponding associations with the biochemical phenotype obtained from NPC1 patients who participated in the National NPC1 Disease Database. Lipid profiles were obtained from 34 patients (39%) in the survey and demonstrated significantly reduced plasma LDL cholesterol (LDL-C) and increased plasma triglycerides in the majority of patients. Reduced plasma HDL cholesterol (HDL-C) was the most consistent lipoprotein abnormality found in male and female NPC1 patients across age groups and occurred independent of changes in plasma triglycerides. A subset of 19 patients for whom the biochemical severity of known NPC1 mutations could be correlated with their lipid profile showed a strong inverse correlation between plasma HDL-C and severity of the biochemical phenotype. Gene mutations were available for 52 patients (59%) in the survey, including 52 different mutations and five novel mutations (Y628C, P887L, I923V, A1151T, and 3741_3744delACTC). Together, these findings provide novel information regarding the plasma lipoprotein changes and mutations in NPC1 disease, and suggest plasma HDL-C represents a potential biomarker of NPC1 disease severity. PMID:19744920

  12. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I.

    PubMed

    Li, Kairong; Turner, Ashley N; Chen, Min; Brosius, Stephanie N; Schoeb, Trenton R; Messiaen, Ludwine M; Bedwell, David M; Zinn, Kurt R; Anastasaki, Corina; Gutmann, David H; Korf, Bruce R; Kesterson, Robert A

    2016-07-01

    Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1(Arg681*) and missense NF1(Gly848Arg) mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1(Gly848Arg) mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1(Arg681*) mutation are not viable. Mice with one Nf1(Arg681*) allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf1(4F/Arg681*); DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  13. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I

    PubMed Central

    Li, Kairong; Turner, Ashley N.; Chen, Min; Brosius, Stephanie N.; Schoeb, Trenton R.; Messiaen, Ludwine M.; Bedwell, David M.; Zinn, Kurt R.; Anastasaki, Corina; Gutmann, David H.; Korf, Bruce R.

    2016-01-01

    ABSTRACT Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681* allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F/Arg681*; DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1. PMID:27482814

  14. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.

    PubMed

    Brashear, Allison; Dobyns, William B; de Carvalho Aguiar, Patricia; Borg, Michel; Frijns, C J M; Gollamudi, Seema; Green, Andrew; Guimaraes, João; Haake, Bret C; Klein, Christine; Linazasoro, Gurutz; Münchau, Alexander; Raymond, Deborah; Riley, David; Saunders-Pullman, Rachel; Tijssen, Marina A J; Webb, David; Zaremba, Jacek; Bressman, Susan B; Ozelius, Laurie J

    2007-03-01

    Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.

  15. Genotype-phenotype analysis of a rare type of osteogenesis imperfecta in four Chinese families with WNT1 mutations.

    PubMed

    Liu, Yi; Song, Lijie; Ma, Doudou; Lv, Fang; Xu, Xiaojie; Wang, Jianyi; Xia, Weibo; Jiang, Yan; Wang, Ou; Song, Yuwen; Xing, Xiaoping; Asan; Li, Mei

    2016-10-01

    Osteogenesis imperfecta (OI) is a rare inherited disease characterized by increased bone fragility and vulnerability to fractures. Recently, WNT1 is identified as a new candidate gene for OI, here we detect pathogenic mutations in WNT1 and analyze the genotype-phenotype association in four Chinese families with OI. We designed a targeted next generation sequencing panel with known fourteen OI-related genes. We applied the approach to detect pathogenic mutations in OI patients and confirmed the mutations with Sanger sequencing and cosegregation analysis. Clinical fractures, bone mineral density (BMD) and the other clinical manifestations were evaluated. We also observed the effects of bisphosphonates in OI patients with WNT1 mutations. Four compound heterozygous mutations (c.110T>C; c.505 G>T; c. 385G>A; c.506 G>A) in WNT1 were detected in three unrelated families. These four mutations had not been reported yet. A recurrent homozygous mutation (c.506dupG) was identified in the other two families. These patients had moderate to severe OI, white to blue sclera, absence of dentinogenesis imperfecta and no brain malformation. We did not observe clear genotype-phenotype correlation in WNT1 mutated OI patients. Though bisphosphonates increased BMD in WNT1 related OI patients, height did not increase and fracture continued. We reported four novel heterozygous variants and confirmed a previous reported WNT1 mutation in four Chinese families with a clinical diagnosis of OI. Our study expanded OI spectrum and confirmed moderate to severe bone fragility induced by WNT1 defects. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Polymorphisms, Chromosomal Rearrangements, and Mutator Phenotype Development during Experimental Evolution of Lactobacillus rhamnosus GG

    PubMed Central

    Douillard, François P.; Ribbera, Angela; Xiao, Kun; Ritari, Jarmo; Rasinkangas, Pia; Paulin, Lars; Palva, Airi; Hao, Yanling

    2016-01-01

    ABSTRACT Lactobacillus rhamnosus GG is a lactic acid bacterium widely marketed by the food industry. Its genomic analysis led to the identification of a gene cluster encoding mucus-binding SpaCBA pili, which is located in a genomic island enriched in insertion sequence (IS) elements. In the present study, we analyzed by genome-wide resequencing the genomic integrity of L. rhamnosus GG in four distinct evolutionary experiments conducted for approximately 1,000 generations under conditions of no stress or salt, bile, and repetitive-shearing stress. Under both stress-free and salt-induced stress conditions, the GG population (excluding the mutator lineage in the stress-free series [see below]) accumulated only a few single nucleotide polymorphisms (SNPs) and no frequent chromosomal rearrangements. In contrast, in the presence of bile salts or repetitive shearing stress, some IS elements were found to be activated, resulting in the deletion of large chromosomal segments that include the spaCBA-srtC1 pilus gene cluster. Remarkably, a high number of SNPs were found in three strains obtained after 900 generations of stress-free growth. Detailed analysis showed that these three strains derived from a founder mutant with an altered DNA polymerase subunit that resulted in a mutator phenotype. The present work confirms the stability of the pilus production phenotype in L. rhamnosus GG under stress-free conditions, highlights the possible evolutionary scenarios that may occur when this probiotic strain is extensively cultured, and identifies external factors that affect the chromosomal integrity of GG. The results provide mechanistic insights into the stability of GG in regard to its extensive use in probiotic and other functional food products. IMPORTANCE Lactobacillus rhamnosus GG is a widely marketed probiotic strain that has been used in numerous clinical studies to assess its health-promoting properties. Hence, the stability of the probiotic functions of L. rhamnosus GG

  17. Polymorphisms, Chromosomal Rearrangements, and Mutator Phenotype Development during Experimental Evolution of Lactobacillus rhamnosus GG.

    PubMed

    Douillard, François P; Ribbera, Angela; Xiao, Kun; Ritari, Jarmo; Rasinkangas, Pia; Paulin, Lars; Palva, Airi; Hao, Yanling; de Vos, Willem M

    2016-07-01

    Lactobacillus rhamnosus GG is a lactic acid bacterium widely marketed by the food industry. Its genomic analysis led to the identification of a gene cluster encoding mucus-binding SpaCBA pili, which is located in a genomic island enriched in insertion sequence (IS) elements. In the present study, we analyzed by genome-wide resequencing the genomic integrity of L. rhamnosus GG in four distinct evolutionary experiments conducted for approximately 1,000 generations under conditions of no stress or salt, bile, and repetitive-shearing stress. Under both stress-free and salt-induced stress conditions, the GG population (excluding the mutator lineage in the stress-free series [see below]) accumulated only a few single nucleotide polymorphisms (SNPs) and no frequent chromosomal rearrangements. In contrast, in the presence of bile salts or repetitive shearing stress, some IS elements were found to be activated, resulting in the deletion of large chromosomal segments that include the spaCBA-srtC1 pilus gene cluster. Remarkably, a high number of SNPs were found in three strains obtained after 900 generations of stress-free growth. Detailed analysis showed that these three strains derived from a founder mutant with an altered DNA polymerase subunit that resulted in a mutator phenotype. The present work confirms the stability of the pilus production phenotype in L. rhamnosus GG under stress-free conditions, highlights the possible evolutionary scenarios that may occur when this probiotic strain is extensively cultured, and identifies external factors that affect the chromosomal integrity of GG. The results provide mechanistic insights into the stability of GG in regard to its extensive use in probiotic and other functional food products. Lactobacillus rhamnosus GG is a widely marketed probiotic strain that has been used in numerous clinical studies to assess its health-promoting properties. Hence, the stability of the probiotic functions of L. rhamnosus GG is of importance, and

  18. Phenotype-genotype correlations in mouse models of amelogenesis imperfecta caused by Amelx and Enam mutations.

    PubMed

    Coxon, Thomas Liam; Brook, Alan Henry; Barron, Martin John; Smith, Richard Nigel

    2012-01-01

    Mutations in human and in mouse orthologous genes Amelx and Enam result in a diverse range of enamel defects. In this study we aimed to investigate the phenotype-genotype correlation between the mutants and the wild-type controls in mouse models of amelogenesis imperfecta using novel measurement approaches. Ten hemi-mandibles and incisors were dissected from each group of Amelx(WT), Amelx(X/Y64H), Amelx(Y/Y64H), Amelx(Y64H/Y64H), and Enam(WT), Enam(Rgsc395) heterozygous and Enam(Rgsc395) homozygous mice. Their macro-morphology, colour and micro-topography were assessed using bespoke 2D and 3D image analysis systems and customized colour and whiteness algorithms. The novel methods identified significant differences (p ≤ 0.05) between the Amelx groups for mandible and incisor size and enamel colour and between the Enam groups for incisor size and enamel colour. The Amelx(WT) mice had the largest mandibles and incisors, followed in descending order of size by the Amelx(X/Y64H), Amelx(Y/Y64H) and Amelx(Y64H/Y64H) mice. Within the Enam groups the Enam(WT) incisors were largest and the Enam(Rgsc395) heterozygous mice were smallest. The effect on tooth morphology was also reflected by the severity of the enamel defects in the colour and whiteness assessment. Amelogenin affected mandible morphology and incisor enamel formation, while enamelin only affected incisors, supporting the multifunctional role of amelogenin. The enamelin mutation was associated with earlier forming enamel defects. The study supported the critical involvement of amelogenin and enamelin in enamel mineralization.

  19. Expanding the Phenotype Associated With the NEFL Mutation Neuromuscular Disease in a Family with Overlapping Myopathic and Neurogenic Findings

    PubMed Central

    Agrawal, Pankaj B.; Joshi, Mugdha; Marinakis, Nicholas S.; Schmitz-Abe, Klaus; Ciarlini, Pedro D. S. C.; Sargent, Jane C.; Markianos, Kyriacos; De Girolami, Umberto; Chad, David A.; Beggs, Alan H.

    2014-01-01

    Importance Newer sequencing technologies in combination with traditional gene mapping techniques, such as linkage analysis, can help identify the genetic basis of disease for patients with rare disorders of uncertain etiology. This approach may expand the phenotypic spectrum of disease associated with those genetic mutations. Objective To elucidate the molecular cause of a neuromuscular disease among a family in which 4 members, a mother and her 3 sons, were affected. Design, Setting, and Participants Two of 4 affected members manifested nemaline myopathy, a common subtype of congenital myopathy, while the other 2 had a nonspecific myopathy. Single-nucleotide polymorphism–based linkage analysis was performed on DNA samples from the 4 affected family members, and whole-genome sequencing was performed in the proband. Real-time quantitative reverse transcription–polymerase chain reaction, immunofluorescence, and Western blot analysis were performed on muscle biopsy specimens. Main outcomes and Measures Whole-genome sequencing and linkage analysis identified a variant in a gene that explains the phenotype. Results We identified a novel neurofilament light polypeptide (NEFL) nonsense mutation in all affected members. NEFL mutations have been previously linked to Charcot-Marie-Tooth disease in humans. This led us to reevaluate the diagnosis, and we recognized that several of the findings, especially those related to the muscle biopsy specimens and electromyography, were consistent with a neurogenic disease. Conclusions and Relevance NEFL mutations are known to cause Charcot-Marie-Tooth disease in humans and motor neuron disease in mice. We report the identification of an NEFL mutation in a family clinically manifesting congenital myopathy. We also describe potential overlap between myopathic and neurogenic findings in this family. These findings expand the phenotypic spectrum of diseases associated with NEFL mutations. This study is an example of the power of genomic

  20. Aromatase deficiency: a novel compound heterozygous mutation identified in a Chinese girl with severe phenotype and obvious maternal virilization.

    PubMed

    Zhu, Wen-Jiao; Cheng, Tong; Zhu, Hui; Han, Bing; Fan, Meng-Xia; Gu, Ting; Zhao, Shuang-Xia; Liu, Yang; Cheng, Kai-Xiang; Song, Huai-Dong; Qiao, Jie

    2016-09-15

    Aromatase deficiency is a rare autosomal recessive disorder that is caused by an impairment of androgen conversion to estrogens. Affected 46, XX individuals generally present with virilization of external genitalia at birth and mutations in CYP19A1 gene. This study described the clinical features and molecular basis of a Chinese 46, XX girl born with ambiguous genitalia and investigated the functional alteration of two novel mutations of the CYP19A1 gene. Obvious prepartum virilization and remarkably elevated testosterone were observed in the mother, who was initially suspected to have a testosterone-producing ovarian tumor. Clinical phenotypes and hormone profiles of the patient and her mother were investigated. Genotyping analyses of the CYP19A1 gene were performed in the patient and her parents. Functional impairment of the mutations was explored using three-dimensional computer model and mutagenesises in vitro transfection assays. A compound heterozygous mutation of the CYP19A1 gene was revealed in the patient, with a G deletion in nucleotide 264 of exon 3 in one allele and a 23-bp insertion in exon 9 in another allele; both mutations resulted in reading frame-shifts that led to truncated proteins of 87 and 360 amino acids, respectively. Molecular modeling analysis suggested that the two renascent truncated proteins lacked crucial amino acids that were involved in substrate access and catalysis as well as heme-binding region. Functional studies in transfected HEK-293T cells exhibited a nearly complete abolishment of enzyme activity, which may underlie the phenotype and hormone profile. Two novel CYP19A1 mutations were identified in a Chinese girl born with ambiguous genitalia and severe maternal virilization during pregnancy. Maternal virilization should prompt consideration of aromatase deficiency, preventing unnecessary interventions in pregnancy. This study broadens the spectrum of phenotype and genetic mutations of this rare disorder. Copyright © 2016

  1. Compound Mutations Cause Increased Cardiac Events in Children with Long QT Syndrome: Can the Sequence Homology-Based Tools be Applied for Prediction of Phenotypic Severity?

    PubMed

    Izumi, Gaku; Hayama, Emiko; Yamazawa, Hirokuni; Inai, Kei; Shimada, Mitsuyo; Furutani, Michiko; Nishizawa, Tsutomu; Furutani, Yoshiyuki; Matsuoka, Rumiko; Nakanishi, Toshio

    2016-06-01

    Long QT syndrome (LQTS) can cause syncope, ventricular fibrillation, and death. Recently, several disease-causing mutations in ion channel genes have been identified, and compound mutations have also been detected. It is unclear whether children who are carriers of compound mutations exhibit a more severe phenotype than those with single mutations. Although predicting phenotypic severity is clinically important, the availability of prediction tools for LQTS is unknown. To determine whether the severity of the LQTS phenotype can be predicted by the presence of compound mutations in children is needed. We detected 97 single mutations (Group S) and 13 compound mutations (Group C) between 1998 and 2012, age at diagnosis ranging 0-19 years old (median age is 9.0) and 18.0 years of follow-up period. The phenotypes and Kaplan-Meier event-free rates of the two groups were compared for cardiac events. This study investigated phenotypic severity in relation to the location of mutations in the protein sequence, which was analyzed using two sequence homology-based tools. In results, compound mutations in children were associated with a high incidence of syncope within the first decade (Group S: 32 % vs. Group C: 61 %), requiring an ICD in the second decade (Group S: 3 % vs. Group C: 56 %). Mortality in these patients was high within 5 years of birth (23 %). Phenotypic prediction tools correctly predicted the phenotypic severity in both Groups S and C, especially by using their coupling method. The coupling prediction method is useful in the initial evaluation of phenotypes both with single and compound mutations of LQTS patients. However, it should be noted that the compound mutation makes more severe phenotype.

  2. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?

    PubMed Central

    Neeve, Vivienne C. M.; Samuels, David C.; Bindoff, Laurence A.; van den Bosch, Bianca; Van Goethem, Gert; Smeets, Hubert; Lombès, Anne; Jardel, Claude; Hirano, Michio; DiMauro, Salvatore; De Vries, Maaike; Smeitink, Jan; Smits, Bart W.; de Coo, Ireneus F. M.; Saft, Carsten; Klopstock, Thomas; Keiling, Bianca-Cortina; Czermin, Birgit; Abicht, Angela; Lochmüller, Hanns; Hudson, Gavin; Gorman, Grainne G.; Turnbull, Doug M.; Taylor, Robert W.; Holinski-Feder, Elke; Chinnery, Patrick F.

    2012-01-01

    Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported

  3. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?

    PubMed

    Neeve, Vivienne C M; Samuels, David C; Bindoff, Laurence A; van den Bosch, Bianca; Van Goethem, Gert; Smeets, Hubert; Lombès, Anne; Jardel, Claude; Hirano, Michio; Dimauro, Salvatore; De Vries, Maaike; Smeitink, Jan; Smits, Bart W; de Coo, Ireneus F M; Saft, Carsten; Klopstock, Thomas; Keiling, Bianca-Cortina; Czermin, Birgit; Abicht, Angela; Lochmüller, Hanns; Hudson, Gavin; Gorman, Grainne G; Turnbull, Doug M; Taylor, Robert W; Holinski-Feder, Elke; Chinnery, Patrick F; Horvath, Rita

    2012-12-01

    Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported

  4. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.

    PubMed

    Marlin, Sandrine; Feldmann, Delphine; Blons, Hélène; Loundon, Natalie; Rouillon, Isabelle; Albert, Sébastien; Chauvin, Pierre; Garabédian, Eréa-Noël; Couderc, Rémy; Odent, Sylvie; Joannard, Alain; Schmerber, Sébastien; Delobel, Bruno; Leman, Jacques; Journel, Hubert; Catros, Hélène; Lemarechal, Cédric; Dollfus, Hélène; Eliot, Marie-Madeleine; Delaunoy, Jean-Louis; David, Albert; Calais, Catherine; Drouin-Garraud, Valérie; Obstoy, Marie-Françoise; Goizet, Cyril; Duriez, Françoise; Fellmann, Florence; Hélias, Jocelyne; Vigneron, Jacqueline; Montaut, Bettina; Matin-Coignard, Dominique; Faivre, Laurence; Baumann, Clarisse; Lewin, Patricia; Petit, Christine; Denoyelle, Françoise

    2005-06-01

    To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with DFNB1. Case series. Collaborative study in referral centers, institutional practice. Patients A total of 256 hearing-impaired patients selected on the basis of the presence of biallelic mutations in GJB2 or the association of 1 GJB2 mutation with the GJB6 deletion (GJB6-D13S1830)del. The prevalence of GJB2 mutations and the GJB6 deletion and audiometric phenotypes related to the most frequent genotypes. Twenty-nine different GJB2 mutations were identified. Allelic frequency of 35delG was 69%, and the other common mutations, 313del14, E47X, Q57X, and L90P, accounted for 2.6% to 2.9% of the variants. Concerning GJB6, (GJB6-D13S1830)del accounted for 5% of all mutated alleles and was observed in 25 of 93 compound heterozygous patients. Three novel GJB2 mutations, 355del9, V95M, and 573delCA, were identified. Hearing impairment was frequently less severe in compound heterozygotes 35delG/L90P and 35delG/N206S than in 35delG homozygotes. Moderate or mild hearing impairment was more frequent in patients with 1 or 2 noninactivating mutations than in patients with 2 inactivating mutations. Of 93 patients, hearing loss was stable in 73, progressive in 21, and fluctuant in 2. Progressive hearing loss was more frequent in patients with 1 or 2 noninactivating mutations than in those with 2 inactivating mutations. In 49 families, hearing loss was compared between siblings with similar genotypes, and variability in terms of severity was found in 18 families (37%). Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness.

  5. Germline mutations and genotype-phenotype associations in head and neck paraganglioma patients with negative family history in China.

    PubMed

    Zhu, W D; Wang, Z Y; Chai, Y C; Wang, X W; Chen, D Y; Wu, H

    2015-09-01

    The aim of this study was to assess the frequency of germline mutations and to explore genotype-phenotype associations in Chinese head and neck paraganglioma (HNPGL) patients without family history. Twenty-six Chinese patients with a diagnosis of HNPGL(14 male and 12 female, respectively)were recruited, who were followed up from 2000 to 2012. Genomic DNA was obtained from resected tumor tissues and peripheral blood samples. Seven genes, Succinate dehydrogenase complex A,B,C,D (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), TMEM127 (transmembrane protein 127) and VHL (Von Hippel-Lindau), were screened by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) was performed to search for potential large deletions or duplications of SDHB, SDHC, SDHD, SDHAF1 and SDHAF2. The total frequency of germline mutations was 30.8% (8/26), including 5 cases with missense mutation p.Met1Ile in SDHD, 1 case with missense mutation p.Tyr216Cys in SDHB, and 1 case with a novel truncation mutation p.Gln44Ter in SDHAF2. MLPA showed one patient with malignant HNPGL had heterozygous deletions of exon1, 2, 3, 7 and 8 in SDHB. Mutations in SDHD were the leading cause of HNPGL in this study. Mutation carriers were younger than non-mutation carriers (p < 0.01) and more likely to suffer from multiple tumors (p = 0.048), especially with mutations in SDHD. The presence of mutation was associated with the development of larger tumors (p = 0.021). This study confirmed that the missense mutation p.Met1Ile at the start codon in SDHD was a hotspot in chinese patients with HNPGLs. We recommend genetic analysis in patients below 45 years, especially SDHD gene.

  6. Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation.

    PubMed

    Zuela, Noam; Zwerger, Monika; Levin, Tal; Medalia, Ohad; Gruenbaum, Yosef

    2016-05-01

    There are roughly 14 distinct heritable autosomal dominant diseases associated with mutations in lamins A/C, including Emery-Dreifuss muscular dystrophy (EDMD). The mechanical model proposes that the lamin mutations change the mechanical properties of muscle nuclei, leading to cell death and tissue deterioration. Here, we developed an experimental protocol that analyzes the effect of disease-linked lamin mutations on the response of nuclei to mechanical strain in living Caenorhabditis elegans We found that the EDMD mutation L535P disrupts the nuclear mechanical response specifically in muscle nuclei. Inhibiting lamin prenylation rescued the mechanical response of the EDMD nuclei, reversed the muscle phenotypes and led to normal motility. The LINC complex and emerin were also required to regulate the mechanical response of C. elegans nuclei. This study provides evidence to support the mechanical model and offers a potential future therapeutic approach towards curing EDMD. © 2016. Published by The Company of Biologists Ltd.

  7. Molecular immunity to mycobacteria: knowledge from the mutation and phenotype spectrum analysis of Mendelian susceptibility to mycobacterial diseases

    PubMed Central

    Qu, Hui-Qi; Fisher-Hoch, Susan P.; McCormick, Joseph B.

    2011-01-01

    Summary Understanding molecular immunity against mycobacterial infection is critical for the development of effective strategies to control tuberculosis (TB), which is a major health issue in the developing world. Host immunogenetic studies represent an indispensable approach to understand the molecular mechanisms against mycobacterial infection. A superb paradigm is the identification of rare mutations causing Mendelian susceptibility to mycobacterial diseases (MSMD). Mutations in the interferon-gamma (IFN-γ) receptor genes are highly specific (although not exclusive) for mycobacterial infection. Only dominant negative mutations of STAT1 have specific susceptibility to mycobacterial infection. Mutations in the interleukin-12 (IL-12) signaling genes have phenotypes with non-specificity. Current studies highlight a complex molecular network in antimycobacterial immunity, centered on IFN-γ signaling. PMID:21330176

  8. A strong loss-of-function mutation in RAN1 results in constitution activation of the ethylene response pathway as well as a rosette-lethal phenotype

    Treesearch

    Keith Woeste; Joseph J. Kieber

    2000-01-01

    A recessive mutation was identified that constitutively activated the ethylene response pathway in Arabidopsis and resuited in a rosette-lethal phenotype. Positional cloning of the gene corresponding to this mutation revealed that it was allelic to responsive to antagonist1 (ran1), a mutation that causes seedlings to respond in a positive manner to what is normally a...

  9. Phenotypic characterization of the Komeda miniature rat Ishikawa, an animal model of dwarfism caused by a mutation in Prkg2.

    PubMed

    Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

    2008-12-01

    The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BNxKMI-mri/mri)F1xKMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII.

  10. Phenotypic Characterization of the Komeda Miniature Rat Ishikawa, an Animal Model of Dwarfism Caused by a Mutation in Prkg2

    PubMed Central

    Tsuchida, Atsuko; Yokoi, Norihide; Namae, Misako; Fuse, Masanori; Masuyama, Taku; Sasaki, Masashi; Kawazu, Shoji; Komeda, Kajuro

    2008-01-01

    The Komeda miniature rat Ishikawa (KMI) is a spontaneous animal model of dwarfism caused by a mutation in Prkg2, which encodes cGMP-dependent protein kinase type II (cGKII). This strain has been maintained as a segregating inbred strain for the mutated allele mri. In this study, we characterized the phenotype of the KMI strain, particularly growth traits, craniofacial measurements, and organ weights. The homozygous mutant (mri/mri) animals were approximately 70% to 80% of the size of normal, heterozygous (mri/+) animals in regard to body length, weight, and naso-occipital length of the calvarium, and the retroperitoneal fat of mri/mri rats was reduced greatly. In addition, among progeny of the (BN×KMI-mri/mri)F1×KMI-mri/mri backcross, animals with the KMI phenotype (mri/mri) were easily distinguished from those showing the wild-type phenotype (mri/+) by using growth traits such as body length and weight. Genetic analysis revealed that all of the backcrossed progeny exhibiting the KMI phenotype were homozygous for the KMI allele in the 1.2-cM region between D14Rat5 and D14Rat80 on chromosome 14, suggesting strongly that mri acts in a completely recessive manner. The KMI strain is the first and only rat model with a confirmed mutation in Prkg2 and is a valuable model for studying dwarfism and longitudinal growth traits in humans and for functional studies of cGKII. PMID:19149413

  11. Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.

    PubMed

    Nouioua, Sonia; Hamadouche, Tarik; Funalot, Benoit; Bernard, Rafaëlle; Bellatache, Nora; Bouderba, Radia; Grid, Djamel; Assami, Salima; Benhassine, Traki; Levy, Nicolas; Vallat, Jean-Michel; Tazir, Meriem

    2011-08-01

    Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.

  12. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.

    PubMed

    Masurel-Paulet, Alice; Piton, Amélie; Chancenotte, Sophie; Redin, Claire; Thauvin-Robinet, Christel; Henrenger, Yvan; Minot, Delphine; Creppy, Audrey; Ruffier-Bourdet, Marie; Thevenon, Julien; Kuentz, Paul; Lehalle, Daphné; Curie, Aurore; Blanchard, Gaelle; Ghosn, Ezzat; Bonnet, Marlene; Archimbaud-Devilliers, Mélanie; Huet, Frédéric; Perret, Odile; Philip, Nicole; Mandel, Jean-Louis; Faivre, Laurence

    2016-08-01

    Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc.

  13. Opposite Clinical Phenotypes of Glucokinase Disease: Description of a Novel Activating Mutation and Contiguous Inactivating Mutations in Human Glucokinase (GCK) Gene

    PubMed Central

    Barbetti, Fabrizio; Cobo-Vuilleumier, Nadia; Dionisi-Vici, Carlo; Toni, Sonia; Ciampalini, Paolo; Massa, Ornella; Rodriguez-Bada, Pablo; Colombo, Carlo; Lenzi, Lorenzo; Garcia-Gimeno, María A.; Bermudez-Silva, Francisco J.; Rodriguez de Fonseca, Fernando; Banin, Patrizia; Aledo, Juan C.; Baixeras, Elena; Sanz, Pascual; Cuesta-Muñoz, Antonio L.

    2009-01-01

    Glucokinase is essential for glucose-stimulated insulin release from the pancreatic β-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported. PMID:19884385

  14. Acquired somatic ATRX mutations in myelodysplastic syndrome associated with alpha thalassemia (ATMDS) convey a more severe hematologic phenotype than germline ATRX mutations.

    PubMed

    Steensma, David P; Higgs, Douglas R; Fisher, Chris A; Gibbons, Richard J

    2004-03-15

    Acquired somatic mutations in ATRX, an X-linked gene encoding a chromatin-associated protein, were recently identified in 4 patients with the rare subtype of myelodysplastic syndrome (MDS) associated with thalassemia (ATMDS). Here we describe a series of novel point mutations in ATRX detected in archival DNA samples from marrow and/or blood of patients with ATMDS by use of denaturing high-performance liquid chromatography (DHPLC), a technique sensitive to low-level mosaicism. Two of the new mutations result in changes in amino acids altered in previously described pedigrees with germ line ATRX mutations (ATR-X syndrome), but the hematologic abnormalities were much more severe in the patients with ATMDS than in the corresponding constitutional cases. In one ATMDS case where DNA samples from several time points were available, the proportion of ATRX-mutant subclones correlated with changes in the amount of hemoglobin H. This study strengthens the link between acquired, somatic ATRX mutations and ATMDS, illustrates how molecular defects associated with MDS and other hematologic malignancies masked by somatic mosaicism may be detected by DHPLC, and shows that additional factors increase the severity of the hematologic phenotype of ATRX mutations in ATMDS.

  15. Mutations in collagen 18A1 and their relevance to the human phenotype.

    PubMed

    Passos-Bueno, Maria Rita; Suzuki, Oscar T; Armelin-Correa, Lucia M; Sertié, Andréa L; Errera, Flavia I V; Bagatini, Kelly; Kok, Fernando; Leite, Katia R M

    2006-03-01

    Collagen XVIII, a proteoglycan, is a component of basement membranes (BMs). There are three distinct isoforms that differ only by their N-terminal, but with a specific pattern of tissue and developmental expression. Cleavage of its C-terminal produces endostatin, an inhibitor of angiogenesis. In its N-terminal, there is a frizzled motif which seems to be involved in Wnt signaling. Mutations in this gene cause Knobloch syndrome KS), an autosomal recessive disorder characterized by vitreoretinal and macular degeneration and occipital encephalocele. This review discusses the effect of both rare and polymorphic alleles in the human phenotype, showing that deficiency of one of the collagen XVIII isoforms is sufficient to cause KS and that null alleles causing deficiency of all collagen XVIII isoforms are associated with a more severe ocular defect. This review besides illustrating the functional importance of collagen XVIII in eye development and its structure maintenance throughout life, it also shows its role in other tissues and organs, such as nervous system and kidney.

  16. A Unique Mutation in a MYB Gene Cosegregates with the Nectarine Phenotype in Peach

    PubMed Central

    Dondini, Luca; Pacheco, Igor; Dettori, Maria Teresa; Gazza, Laura; Scalabrin, Simone; Strozzi, Francesco; Tartarini, Stefano; Bassi, Daniele; Verde, Ignazio; Rossini, Laura

    2014-01-01

    Nectarines play a key role in peach industry; the fuzzless skin has implications for consumer acceptance. The peach/nectarine (G/g) trait was described as monogenic and previously mapped on chromosome 5. Here, the position of the G locus was delimited within a 1.1 cM interval (635 kb) based on linkage analysis of an F2 progeny from the cross ‘Contender’ (C, peach) x ‘Ambra’ (A, nectarine). Careful inspection of the genes annotated in the corresponding genomic sequence (Peach v1.0), coupled with variant discovery, led to the identification of MYB gene PpeMYB25 as a candidate for trichome formation on fruit skin. Analysis of genomic re-sequencing data from five peach/nectarine accessions pointed to the insertion of a LTR retroelement in exon 3 of the PpeMYB25 gene as the cause of the recessive glabrous phenotype. A functional marker (indelG) developed on the LTR insertion cosegregated with the trait in the CxA F2 progeny and was validated on a broad panel of genotypes, including all known putative donors of the nectarine trait. This marker was shown to efficiently discriminate between peach and nectarine plants, indicating that a unique mutational event gave rise to the nectarine trait and providing a useful diagnostic tool for early seedling selection in peach breeding programs. PMID:24595269

  17. Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

    PubMed Central

    Strickland, Alleene V.; Schabhüttl, Maria; Offenbacher, Hans; Synofzik, Matthis; Hauser, Natalie S.; Brunner-Krainz, Michaela; Gruber-Sedlmayr, Ursula; Moore, Steven A.; Windhager, Reinhard; Bender, Benjamin; Harms, Matthew; Klebe, Stephan; Young, Peter; Kennerson, Marina; Garcia, Avencia Sanchez Mejias; Gonzalez, Michael A.; Züchner, Stephan; Schule, Rebecca; Shy, Michael E.; Auer-Grumbach, Michaela

    2015-01-01

    Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development (MCD), and Charcot-Marie-Tooth disease, type 2O (CMT2O). We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore we analysed our database of 1,024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways. PMID:26100331

  18. Expanding the SHOC2 Mutation Associated Phenotype of Noonan Syndrome with Loose Anagen Hair: Structural Brain Anomalies and Myelofibrosis

    PubMed Central

    Gripp, Karen W.; Zand, Dina J.; Demmer, Laurie; Anderson, Carol E.; Dobyns, William B.; Zackai, Elaine H.; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L.; Sol-Church, Katia

    2013-01-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4) (75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. PMID:23918763

  19. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

    PubMed

    Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

    2013-10-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis.

  20. Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency

    PubMed Central

    Felgentreff, Kerstin; Lee, Yu Nee; Frugoni, Francesco; Du, Likun; van der Burg, Mirjam; Giliani, Silvia; Tezcan, Ilhan; Reisli, Ismail; Mejstrikova, E; Villartay, JP; Sleckman, Barry P; Manis, John; Notarangelo, Luigi D

    2015-01-01

    Background The endonuclease ARTEMIS, encoded by the DCLRE1C gene, is a component of the non-homologous end-joining (NHEJ) pathway, and participates in hairpin opening during the V(D)J recombination process and repair of a subset of DNA double strand breaks. Patients with ARTEMIS deficiency usually present with severe combined immunodeficiency (SCID) and cellular radiosensitivity, but hypomorphic mutations may cause milder phenotypes (leaky SCID). Objective We sought to correlate the functional impact of human DCLRE1C mutations on phenotypic presentation in patients with ARTEMIS deficiency. Methods We studied recombination and DNA repair activity of 41 human DCLRE1C mutations in Dclre1c−/− v-abl kinase transformed pro-B cells retrovirally engineered with a construct that allows quantification of recombination activity by flow-cytometry. For assessment of DNA repair efficacy, resolution of γH2AX accumulation was studied after ionizing radiation. Results Low or absent activity was detected for mutations causing a typical SCID phenotype. Most of leaky SCID patients were compound heterozygous for one loss of function (LOF) and one hypomorphic allele with significant residual levels of recombination and DNA repair activity. Deletions disrupting the C-terminus result in truncated, but partially functional proteins, and are often associated with leaky SCID. Overexpression of hypomorphic mutants may improve the functional defect. Conclusions Correlation between the nature and location of DCLRE1C mutations, functional activity, and the clinical phenotype, has been observed. Hypomorphic variants that have been reported in the general population may be disease-causing if combined in trans with a LOF allele. Therapeutic strategies aimed at inducing overexpression of hypomorphic alleles may be beneficial. PMID:25917813

  1. Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency.

    PubMed

    Felgentreff, Kerstin; Lee, Yu Nee; Frugoni, Francesco; Du, Likun; van der Burg, Mirjam; Giliani, Silvia; Tezcan, Ilhan; Reisli, Ismail; Mejstrikova, Ester; de Villartay, Jean-Pierre; Sleckman, Barry P; Manis, John; Notarangelo, Luigi D

    2015-07-01

    The endonuclease ARTEMIS, which is encoded by the DCLRE1C gene, is a component of the nonhomologous end-joining pathway and participates in hairpin opening during the V(D)J recombination process and repair of a subset of DNA double-strand breaks. Patients with ARTEMIS deficiency usually present with severe combined immunodeficiency (SCID) and cellular radiosensitivity, but hypomorphic mutations can cause milder phenotypes (leaky SCID). We sought to correlate the functional effect of human DCLRE1C mutations on phenotypic presentation in patients with ARTEMIS deficiency. We studied the recombination and DNA repair activity of 41 human DCLRE1C mutations in Dclre1c(-/-) v-abl kinase-transformed pro-B cells retrovirally engineered with a construct that allows quantification of recombination activity by means of flow cytometry. For assessment of DNA repair efficacy, resolution of γH2AX accumulation was studied after ionizing radiation. Low or absent activity was detected for mutations causing a typical SCID phenotype. Most of the patients with leaky SCID were compound heterozygous for 1 loss-of-function and 1 hypomorphic allele, with significant residual levels of recombination and DNA repair activity. Deletions disrupting the C-terminus result in truncated but partially functional proteins and are often associated with leaky SCID. Overexpression of hypomorphic mutants might improve the functional defect. Correlation between the nature and location of DCLRE1C mutations, functional activity, and the clinical phenotype has been observed. Hypomorphic variants that have been reported in the general population can be disease causing if combined in trans with a loss-of-function allele. Therapeutic strategies aimed at inducing overexpression of hypomorphic alleles might be beneficial. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  2. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile.

    PubMed

    McDonnell, Aoibhinn; Schulman, Betsy; Ali, Zahid; Dib-Hajj, Sulayman D; Brock, Fiona; Cobain, Sonia; Mainka, Tina; Vollert, Jan; Tarabar, Sanela; Waxman, Stephen G

    2016-04-01

    Inherited erythromelalgia, the first human pain syndrome linked to voltage-gated sodium channels, is widely regarded as a genetic model of human pain. Because inherited erythromelalgia was linked to gain-of-function changes of sodium channel Na(v)1.7 only a decade ago, the literature has mainly consisted of reports of genetic and/or clinical characterization of individual patients. This paper describes the pattern of pain, natural history, somatosensory profile, psychosocial status and olfactory testing of 13 subjects with primary inherited erythromelalgia with mutations of SCN9A, the gene encoding Na(v)1.7. Subjects were clinically profiled using questionnaires, quantitative sensory testing and olfaction testing during the in-clinic phase of the study. In addition, a detailed pain phenotype for each subject was obtained over a 3-month period at home using diaries, enabling subjects to self-report pain attacks, potential triggers, duration and severity of pain. All subjects reported pain and heat in the extremities (usually feet and/or hands), with pain attacks triggered by heat or exercise and relieved mainly by non-pharmacological manoeuvres such as cooling. A large proportion of pain attacks (355/1099; 32%) did not involve a specific trigger. There was considerable variability in the number, duration and severity of pain attacks between subjects, even those carrying the same mutation within a family, and within individuals over the 12-13 week observation period. Most subjects (11/13) had pain between attacks. For these subjects, mean pain severity between pain attacks was usually lower than that during an attack. Olfaction testing using the Sniffin'T test did not demonstrate hyperosmia. One subject had evidence of orthostatic hypotension. Overall, there was a statistically significant correlation between total Hospital Anxiety and Depression Scale scores (P= 0.005) and pain between attacks and for Hospital Anxiety and Depression Scale Depression scores and pain

  3. Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing.

    PubMed

    Tafazoli, Alireza; Eshraghi, Peyman; Pantaleoni, Francesca; Vakili, Rahim; Moghaddassian, Morteza; Ghahraman, Martha; Muto, Valentina; Paolacci, Stefano; Golyan, Fatemeh Fardi; Abbaszadegan, Mohammad Reza

    2017-09-25

    Noonan Syndrome (NS) is an autosomal dominant disorder with many variable and heterogeneous conditions. The genetic basis for 20-30% of cases is still unknown. This study evaluates Iranian Noonan patients both clinically and genetically for the first time. Mutational analysis of PTPN11 gene was performed in 15 Iranian patients, using PCR and Sanger sequencing at phase one. Then, as phase two, Next Generation Sequencing (NGS) in the form of targeted resequencing was utilized for analysis of exons from other related genes. Homology modelling for the novel founded mutations was performed as well. The genotype, phenotype correlation was done according to the molecular findings and clinical features. Previously reported mutation (p.N308D) in some patients and a novel mutation (p.D155N) in one of the patients were identified in phase one. After applying NGS methods, known and new variants were found in four patients in other genes, including: CBL (p. V904I), KRAS (p. L53W), SOS1 (p. I1302V), and SOS1 (p. R552G). Structural studies of two deduced novel mutations in related genes revealed deficiencies in the mutated proteins. Following genotype, phenotype correlation, a new pattern of the presence of intellectual disability in two patients was registered. NS shows strong variable expressivity along the high genetic heterogeneity especially in distinct populations and ethnic groups. Also possibly unknown other causative genes may be exist. Obviously, more comprehensive and new technologies like NGS methods are the best choice for detection of molecular defects in patients for genotype, phenotype correlation and disease management. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

  4. PKA-Dependent Biophysical Phenotype for V227F-KCNJ2 Mutation in Catecholaminergic Polymorphic Ventricular Tachycardia

    PubMed Central

    Vega, Amanda L.; Tester, David J.; Ackerman, Michael J.; Makielski, Jonathan C.

    2009-01-01

    Background KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, IK1. KCNJ2 mutations are associated with Andersen-Tawil syndrome (ATS) and also Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The aim of this study was to characterize the biophysical and cellular phenotype of a KCNJ2 missense mutation, V227F, found in a patient with CPVT. Methods and Results Kir2.1-wild type (WT) and V227F channels were expressed individually and together in Cos-1 cells to measure IK1 by voltage clamp. Unlike typical ATS-associated KCNJ2 mutations which show dominant negative loss of function, Kir2.1WT+V227F co-expression yielded IK1 indistinguishable from Kir2.1-WT under basal conditions. To simulate catecholamine activity, a PKA-stimulating cocktail comprised of forskolin and 3-isobutyl-1-methylxanthine (IBMX) was used to increase PKA activity. This PKA-simulated catecholaminergic stimulation caused marked reduction of outward IK1 compared to Kir2.1-WT. PKA-induced reduction in IK1 was eliminated by mutating the phosphorylation site at serine 425 (S425N). Conclusions Heteromeric Kir2.1-V227F and WT channels showed an unusual latent loss of function biophysical phenotype that depended upon PKA-dependent Kir2.1 phosphorylation. This biophysical phenotype, distinct from typical ATS mutations, suggests a specific mechanism for PKA dependent IK1 dysfunction for this KCNJ2 mutation which correlates with adrenergic conditions underlying the clinical arrhythmia. PMID:19843922

  5. Single-nucleotide polymorphism mutation spectra and resistance to quinolones in Salmonella enterica serovar Enteritidis with a mutator phenotype.

    PubMed

    Levy, Dan D; Sharma, Bhavana; Cebula, Thomas A

    2004-07-01

    Resistance to quinolone antibiotics has been associated with single-nucleotide polymorphisms (SNPs) in the quinolone resistance-determining region (QRDR) of gyrA. Mutations in the gyrA gene were compared by using mutant populations derived from wild-type Salmonella enterica serovar Enteritidis and its isogenic mutS::Tn10 mutator counterpart. Spontaneous mutants arising during nonselective growth were isolated by selection with either nalidixic acid, enrofloxacin, or ciprofloxacin. QRDR SNPs were identified in approximately 70% (512 of 695) of the isolates via colony hybridization with radiolabeled oligonucleotide probes. Notably, transition base substitution SNPs in the QRDR were dramatically increased in mutants derived from the mutS strain. Some, but not all, antibiotic-resistant mutants lacking QRDR SNPs were resistant to tetracycline and chloramphenicol, consistent with alterations in nonspecific efflux pumps or other membrane transport mechanisms. Changing the selection conditions shifted the mutation spectrum. Selection with ciprofloxacin was least likely to yield a mutant harboring either a QRDR SNP or chloramphenicol resistance. Selection with enrofloxacin was more likely to yield mutants containing Ser83-->Phe mutations, whereas selection with ciprofloxacin or nalidixic acid favored recovery of Asp87-->Gly mutants. Fluoroquinolone-resistant Salmonella strains isolated from veterinary or clinical settings frequently display a mutational spectrum with a preponderance of transition SNPs in the QRDR, the pattern found in vitro among mutS mutator mutants reported here. Both the preponderance of transition mutations and the varied mutation spectra reported for veterinary and clinical isolates suggest that bacterial mutators defective in methyl-directed mismatch repair may play a role in the emergence of quinolone and fluoroquinolone resistance in feral settings.

  6. Nucleotide selectivity defect and mutator phenotype conferred by a colon cancer-associated DNA polymerase δ mutation in human cells

    PubMed Central

    Mertz, Tony M.; Baranovskiy, Andrey G.; Wang, Jing; Tahirov, Tahir H.; Shcherbakova, Polina V.

    2017-01-01

    Mutations in the POLD1 and POLE genes encoding DNA polymerases δ (Polδ) and ε (Polε) cause hereditary colorectal cancer (CRC) and have been found in many sporadic colorectal and endometrial tumors. Much attention has been focused on POLE exonuclease domain mutations, which occur frequently in hypermutated DNA mismatch repair (MMR)-proficient tumors and appear to be responsible for the bulk of genomic instability in these tumors. In contrast, somatic POLD1 mutations are seen less frequently and typically occur in MMR-deficient tumors. Their functional significance is often unclear. Here we demonstrate that expression of the cancer-associated POLD1-R689W allele is strongly mutagenic in human cells. The mutation rate increased synergistically when the POLD1-R689W expression was combined with a MMR defect, indicating that the mutator effect of POLD1-R689W results from a high rate of replication errors. Purified human Polδ-R689W has normal exonuclease activity, but the nucleotide selectivity of the enzyme is severely impaired, providing a mechanistic explanation for the increased mutation rate in the POLD1-R689W-expressing cells. The vast majority of mutations induced by the POLD1-R689W are GC→TA transversions and GC→AT transitions, with transversions showing a strong strand bias and a remarkable preference for polypurine/polypyrimidine sequences. The mutational specificity of the Polδ variant matches that of the hypermutated CRC cell line, HCT15, in which this variant was first identified. The results provide compelling evidence for the pathogenic role of the POLD1-R689W mutation in the development of the human tumor and emphasize the need to experimentally determine the significance of Polδ variants present in sporadic tumors. PMID:28368425

  7. Inheritance of a temperature-modified phenotype of the short antennae (sa) mutation in a moth, Ephestia kuehniella (Lepidoptera: Pyralidae).

    PubMed

    Pavelka, J; Koudelová, J

    2001-01-01

    The autosomal recessive mutation short antennae (sa) causes considerable shortening of antennae in male and female Mediterranean flour moths (Ephestia kuehniella Zeller). However, the sa phenotype can be suppressed by several physical factors, making sa moths indistinguishable from wild-type moths (sa(WT)). This can be done by subjecting larva and pupa to a higher temperature (25 degrees C), to lithium ions, or to an alternate electric field. The first half of pupal development was found to be the sensitive period for the sa(WT) phenotype. The sa(WT) phenotype is stable and cannot be reverted to the original sa type by physical or chemical factors. The sa(WT) phenotype is transmitted to future generations. When crossed with typical sa moths, the sa(WT) phenotype is inherited either as a dominant character if carried by males or a semidominant character if carried by females. We compared proteins of the ejaculate, accessory gland secretions, and spermatophore in sa, sa(WT), and wild-type males and found considerable differences between sperm proteins of sa(WT), sa, and wild-type males. The sa(WT) phenotype influences the mating success of males: sa(WT) males mated successfully with any females, whereas typical sa males were less successful in mating and then mainly with females of the same phenotype.

  8. Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse.

    PubMed

    Dillon, Lloye M; Hida, Aline; Garcia, Sofia; Prolla, Tomas A; Moraes, Carlos T

    2012-01-01

    Pharmacological agents, such as bezafibrate, that activate peroxisome proliferator-activated receptors (PPARs) and PPAR γ coactivator-1α (PGC-1α) pathways have been shown to improve mitochondrial function and energy metabolism. The mitochondrial DNA (mtDNA) mutator mouse is a mouse model of aging that harbors a proofreading-deficient mtDNA polymerase γ. These mice develop many features of premature aging including hair loss, anemia, osteoporosis, sarcopenia and decreased lifespan. They also have increased mtDNA mutations and marked mitochondrial dysfunction. We found that mutator mice treated with bezafibrate for 8-months had delayed hair loss and improved skin and spleen aging-like phenotypes. Although we observed an increase in markers of fatty acid oxidation in these tissues, we did not detect a generalized increase in mitochondrial markers. On the other hand, there were no improvements in muscle function or lifespan of the mutator mouse, which we attributed to the rodent-specific hepatomegaly associated with fibrate treatment. These results showed that despite its secondary effects in rodent's liver, bezafibrate was able to improve some of the aging phenotypes in the mutator mouse. Because the associated hepatomegaly is not observed in primates, long-term bezafibrate treatment in humans could have beneficial effects on tissues undergoing chronic bioenergetic-related degeneration.

  9. Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype.

    PubMed

    Parenti, I; Gervasini, C; Pozojevic, J; Graul-Neumann, L; Azzollini, J; Braunholz, D; Watrin, E; Wendt, K S; Cereda, A; Cittaro, D; Gillessen-Kaesbach, G; Lazarevic, D; Mariani, M; Russo, S; Werner, R; Krawitz, P; Larizza, L; Selicorni, A; Kaiser, F J

    2016-01-01

    Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype–Phenotype Correlations

    PubMed Central

    Lepri, Francesca; De Luca, Alessandro; Stella, Lorenzo; Rossi, Cesare; Baldassarre, Giuseppina; Pantaleoni, Francesca; Cordeddu, Viviana; Williams, Bradley J; Dentici, Maria L; Caputo, Viviana; Venanzi, Serenella; Bonaguro, Michela; Kavamura, Ines; Faienza, Maria F; Pilotta, Alba; Stanzial, Franco; Faravelli, Francesca; Gabrielli, Orazio; Marino, Bruno; Neri, Giovanni; Silengo, Margherita Cirillo; Ferrero, Giovanni B; Torrrente, Isabella; Selicorni, Angelo; Mazzanti, Laura; Digilio, Maria C; Zampino, Giuseppe; Dallapiccola, Bruno; Gelb, Bruce D; Tartaglia, Marco

    2011-01-01

    Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype–phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies. Hum Mutat 32:760–772, 2011. © 2011 Wiley-Liss, Inc. PMID:21387466

  11. Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype.

    PubMed

    Limberg, Maren M; Zumhagen, Sven; Netter, Michael F; Coffey, Alison J; Grace, Andrew; Rogers, Jane; Böckelmann, Doris; Rinné, Susanne; Stallmeyer, Birgit; Decher, Niels; Schulze-Bahr, Eric

    2013-05-01

    Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.

  12. A distinct mutation on the alternative splice site of APC exon 9 results in attenuated familial adenomatous polyposis phenotype.

    PubMed

    Fostira, Florentia; Yannoukakos, Drakoulis

    2010-09-01

    A subset of APC mutation carriers shows a milder familial adenomatous polyposis phenotype (attenuated FAP) developing smaller number of polyps and colorectal cancer at an older age. It seems that a different mechanism to carcinogenesis is initiated according to the initial site of the germline mutation. The APC gene of a female patient with AFAP phenotypic features was analysed. A novel mutation located on the alternatively splice site of exon 9 was identified. This is the first reported mutation in the specific site. Transcripts characterization revealed disruption of splicing occurring within exon 9, resulting in the expression of a shorter mRNA transcript, which surprisingly does not affect the ratio between the two wild type transcripts, as well as the production of wild type short isoform by the mutant allele. The short wild type isoform, produced by the mutant allele, needs to be inactivated, on top of the wild type allele, for colorectal cancer to develop. These observations enhance the 'three hit hypothesis' and indicate that a distinct mechanism for the adenoma to carcinoma sequence should be followed, for truncated mutations taking place on the borderline of the alternatively spliced exon 9 of the APC gene, as well.

  13. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency

    SciTech Connect

    Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R.

    1995-05-01

    5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

  14. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities.

    PubMed

    Mahoney, My G; Sadowski, Sara; Brennan, Donna; Pikander, Pekka; Saukko, Pekka; Wahl, James; Aho, Heikki; Heikinheimo, Kristiina; Bruckner-Tuderman, Leena; Fertala, Andrzej; Peltonen, Juha; Uitto, Jouni; Peltonen, Sirkku

    2010-04-01

    Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.

  15. Ion channel mechanisms related to sudden cardiac death in phenotype-negative long-QT syndrome genotype-phenotype correlations of the KCNQ1(S349W) mutation.

    PubMed

    Horr, Samuel; Goldenberg, Ilan; Moss, Arthur J; O-Uchi, Jin; Barsheshet, Alon; Connelly, Heather; Gray, Daniel A; Zareba, Wojciech; Lopes, Coeli M B

    2011-02-01

      Data regarding possible ion channel mechanisms that predispose to ventricular tachyarrhythmias in patients with phenotype-negative long-QT syndrome (LQTS) are limited. We carried out cellular expression studies for the S349W mutation in the KCNQ1 channel, which was identified in 15 patients from the International LQTS Registry who experienced a high rate of cardiac events despite lack of significant QTc prolongation. The clinical outcome of S349W mutation carriers was compared with that of QTc-matched carriers of haploinsufficient missense (n = 30) and nonsense (n = 45) KCNQ1 mutations. The channels containing the mutant S349W subunit showed a mild reduction in current (<50%), in the haploinsuficient range, with an increase in maximal conductance compared with wild-type channels. In contrast, expression of the S349W mutant subunit produced a pronounced effect on both the voltage dependence of activation and the time constant of activation, while haploinsuficient channels showed no effect on either parameter. The cumulative probability of cardiac events from birth through age 20 years was significantly higher among S349W mutation carriers (58%) as compared with carriers of QTc-matched haploinsufficent missense (21%, P = 0.004) and nonsense (25%, P = 0.01) mutations. The S349W mutation in the KCNQ1 potassium channel exerts a relatively mild effect on the ion channel current, whereas an increase in conductance compensates for impaired voltage activation of the channel. The changes observed in voltage activation of the channel may underlie the mechanisms predisposing to arrhythmic risk among LQTS patients with a normal-range QTc. © 2010 Wiley Periodicals, Inc.

  16. Functional characterization of insulin receptor gene mutations contributing to Rabson-Mendenhall syndrome - phenotypic heterogeneity of insulin receptor gene mutations.

    PubMed

    Jiang, Shan; Fang, Qichen; Zhang, Feng; Wan, Hui; Zhang, Rong; Wang, Congrong; Bao, Yuqian; Zhang, Lei; Ma, Xiaojing; Lu, Junxi; Gao, Fei; Xiang, Kunsan; Jia, Weiping

    2011-01-01

    Rabson-Mendenhall syndrome (RMS) is a rare disorder that presents as severe insulin resistance as a result of mutations present in the insulin receptor (INSR). A Chinese girl with RMS presented with profound diabetes, hyperinsulinemia, acanthosis nigricans, hirsutism, and abnormalities of teeth and nails. Direct sequencing of the patient's INSR detected heterozygote mutations at Arg83Gln (R83Q) and Ala1028Val (A1028V), with the former representing a novel mutation. Functional studies of Chinese hamster ovary (CHO) cells transfected with wild-type (WT) and mutant forms of INSR were performed to evaluate the effects of these mutations on receptor expression and activation. Receptor expression, insulin binding activity, and phosphorylation of the R83Q variant were comparable to WT. In contrast, expression of the A1028V receptor was much lower than that of WT INSR, and impairment of insulin binding and autophosphorylation were nearly commensurate with the decrease in expression detected. Reductions in the phosphorylation of IRS-1, Akt, and Erk1/2 (60%, 40%, and 50% of WT, respectively) indicate that the A1028V receptor contributes to impaired signal transduction. In conclusion, INSR mutations associated with RMS were identified. Moreover, the A1028V mutation associated with a decrease in expression of INSR potentially accounts for loss of function of the INSR.

  17. From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2

    PubMed Central

    Sheikh, Taimoor I.; Ausió, Juan; Faghfoury, Hannah; Silver, Josh; Lane, Jane B.; Eubanks, James H.; MacLeod, Patrick; Percy, Alan K.; Vincent, John B.

    2016-01-01

    Mutations in the MECP2 gene cause Rett syndrome (RTT). MeCP2 binds to chromocentric DNA through its methyl CpG-binding domain (MBD) to regulate gene expression. In heterozygous females the variable phenotypic severity is modulated by non-random X-inactivation, thus making genotype-phenotype comparisons unreliable. However, genotype-phenotype correlations in males with hemizygousMECP2 mutations can provide more accurate insights in to the true biological effect of specific mutations. Here, we compared chromatin organization and binding dynamics for twelve MeCP2 missense mutations (including two novel and the five most common MBD missense RTT mutations) and identifiedacorrelation with phenotype in hemizygous males. We observed impaired interaction of MeCP2-DNA for mutations around the MBD-DNA binding interface, and defective chromatin clustering for distal MBD mutations. Furthermore, binding and mobility dynamics show a gradient of impairment depending on the amino acid properties and tertiary structure within the MBD. Interestingly, a wide range of phenotypic/clinical severity, ranging from neonatal encephalopathy to mild psychiatric abnormalities were observed and all are consistent with our functional/molecular results. Overall, clinical severity showed a direct correlation with the functional impairment of MeCP2. These mechanistic and phenotypic correlations of MeCP2 mutations will enable improved and individualized diagnostics, and may lead to personalized therapeutic interventions. PMID:27929079

  18. Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships.

    PubMed

    Krasnov, Kristina V; Tzetis, Maria; Cheng, Jie; Guggino, William B; Cutting, Garry R

    2008-11-01

    We have been investigating the functional consequences of rare disease-associated amino acid substitutions in the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations of the arginine residue at codon 1070 have been associated with different disease consequences; R1070P and R1070Q with "severe" pancreatic insufficient cystic fibrosis (CF) and R1070W with "mild" pancreatic sufficient CF or congenital bilateral absence of the vas deferens. Intriguingly, CFTR bearing each of these mutations is functional when expressed in nonpolarized cells. To determine whether R1070 mutations cause disease by affecting CFTR localization, we created polarized Madin Darby canine kidney (MDCK) cell lines that express either wild-type or mutant CFTR from the same genomic integration site. Confocal microscopy and biotinylation studies revealed that R1070P was not inserted into the apical membrane, R1070W was inserted at levels reduced from wild-type while R1070Q was present in the apical membrane at levels comparable to wild-type. The abnormal localization of CFTR bearing R1070P and R1070W was consistent with deleterious consequences in patients; however, the profile of CFTR R1070Q was inconsistent with a "severe" phenotype. Reanalysis of 16 patients with the R1070Q mutation revealed that 11 carried an in cis nonsense mutation, S466X. All 11 patients carrying the complex allele R1070Q-S466X had severe disease, while 4 out of 5 patients with R1070Q had "mild" disease, thereby reconciling the apparent discrepancy between the localization studies of R1070Q and the phenotype of patients bearing this mutation. Our results emphasize that localization studies in relevant model systems can greatly assist the interpretation of the disease-causing potential of rare missense mutations.

  19. ATP1A3 Mutations and Genotype-Phenotype Correlation of Alternating Hemiplegia of Childhood in Chinese Patients

    PubMed Central

    Zhang, Jie; Xu, Xiaojing; Liu, Xiaoyan; Wu, Xiru; Wei, Liping; Zhang, Yuehua

    2014-01-01

    Alternating hemiplegia of childhood (AHC) is a rare and severe neurological disorder. ATP1A3 was recently identified as the causative gene. Here we report the first genetic study in Chinese AHC cohort. We performed whole-exome sequencing on three trios and three unrelated patients, and screened additional 41 typical cases and 100 controls by PCR-Sanger sequencing. ATP1A3 mutations were detected in 95.7% of typical AHC patients. At least 93.3% were de novo. Four late onset, atypical AHC patients were also mutation positive, suggesting the need for testing ATP1A3 mutations in atypical cases. Totally, 13 novel missense mutations (T370N, G706R, L770R, T771N, T771I, S772R, L802P, D805H, M806K, P808L, I810N, L839P and G893R) were identified in our study. By homology modeling of the mutant protein structures and calculation of an extensive list of molecular features, we identified two statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. A logistic regression classifier achieved 92.9% accuracy by the average of 100 times of five-fold cross validations. Genotype-phenotype correlation analysis showed that patients with epilepsy were more likely to carry E815K mutation. In summary, ATP1A3 is the major pathogenic gene of AHC in Chinese patients; mutations have distinctive molecular features that discriminate them from neutral variants and are correlated with phenotypes. PMID:24842602

  20. Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.

    PubMed

    Attard, M; Jean, G; Forestier, L; Cherqui, S; van't Hoff, W; Broyer, M; Antignac, C; Town, M

    1999-12-01

    Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused by a defect in the transport of cystine across the lysosomal membrane and characterized by early onset of renal proximal tubular dysfunction. Late-onset cystinosis, a rarer form of the disorder, is characterized by onset of symptoms between 12 and 15 years of age. We previously characterized the cystinosis gene, CTNS, and identified pathogenic mutations in patients with infantile nephropathic cystinosis, including a common, approximately 65 kb deletion which encompasses exons 1-10. Structure predictions suggested that the gene product, cystinosin, is a novel integral lysosomal membrane protein. We now examine the predicted effect of mutations on this model of cystinosin. In this study, we screened patients with infantile nephropathic cystinosis, those with late-onset cystinosis and patients whose phenotype does not fit the classical definitions. We found 23 different mutations in CTNS; 14 are novel mutations. Out of 25 patients with infantile nephropathic cystinosis, 12 have two severely truncating mutations, which is consistent with a loss of functional protein, and 13 have missense or in-frame deletions, which would result in disruption of transmembrane domains and loss of protein function. Mutations found in two late-onset patients affect functionally unimportant regions of cystinosin, which accounts for their milder phenotype. For three patients, the age of onset of cystinosis was <7 years but the course of the disease was milder than the infantile nephropathic form. This suggests that the missense mutations found in these individuals allow production of functional protein and may also indicate regions of cystinosin which are not functionally important.

  1. Genotype–phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I

    PubMed Central

    Rauch, Frank; Lalic, Liljana; Roughley, Peter; Glorieux, Francis H

    2010-01-01

    Osteogenesis imperfecta (OI) is a heritable disorder with bone fragility that is often associated with short stature, tooth abnormalities (dentinogenesis imperfecta), and blue sclera. The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the α1 or the α2 chain of collagen type I. In this study, we compared the results of genotype analysis and clinical examination in 161 OI patients (median age: 13 years) who had glycine mutations in the triple helical domain of α1(I) (n=67) or α2(I) (n=94). Serine substitutions were the most frequently encountered type of mutation in both chains. Compared with patients with serine substitutions in α2(I) (n=40), patients with serine substitutions in α1(I) (n=42) on average were shorter (median height z-score −6.0 vs −3.4; P=0.005), indicating that α1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the α2(I) chain but not in the α1(I) chain. Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90 and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. These data should be useful to predict disease phenotype in newly diagnosed OI patients. PMID:20087402

  2. Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy.

    PubMed

    Thibodeau, My Linh; Peters, Colin H; Townsend, Katelin N; Shen, Yaoqing; Hendson, Glenda; Adam, Shelin; Selby, Kathryn; Macleod, Patrick M; Gershome, Cynthia; Ruben, Peter; Jones, Steven J M; Friedman, Jan M; Gibson, William T; Horvath, Gabriella A

    2017-09-12

    TRPV4 encodes a polymodal calcium-permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4-related neuromuscular disease, our study suggests a role for compound heterozygosity and loss-of-function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was also noted in both affected children, suggesting that TRPV4 may be necessary for normal brain development. © 2017 Wiley Periodicals, Inc.

  3. Deep intronic mis-splicing mutation in JAK3 gene underlies T-B+NK- severe combined immunodeficiency phenotype.

    PubMed

    Stepensky, Polina; Keller, Baerbel; Shamriz, Oded; NaserEddin, Adeeb; Rumman, Nisreen; Weintraub, Michael; Warnatz, Klaus; Elpeleg, Orly; Barak, Yaacov

    2016-02-01

    Severe combined immune deficiency (SCID) is a group of genetically heterogeneous diseases caused by an early block in T cell differentiation and present with life threatening infections, often within the first year of life. Janus kinase (JAK)3 gene mutations have been found to cause autosomal recessive T-B+ SCID phenotype. In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes. We present the cases and discuss the current literature. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA

    PubMed Central

    Haack, Tobias B.; Hogarth, Penelope; Kruer, Michael C.; Gregory, Allison; Wieland, Thomas; Schwarzmayr, Thomas; Graf, Elisabeth; Sanford, Lynn; Meyer, Esther; Kara, Eleanna; Cuno, Stephan M.; Harik, Sami I.; Dandu, Vasuki H.; Nardocci, Nardo; Zorzi, Giovanna; Dunaway, Todd; Tarnopolsky, Mark; Skinner, Steven; Frucht, Steven; Hanspal, Era; Schrander-Stumpel, Connie; Héron, Delphine; Mignot, Cyril; Garavaglia, Barbara; Bhatia, Kailash; Hardy, John; Strom, Tim M.; Boddaert, Nathalie; Houlden, Henry H.; Kurian, Manju A.; Meitinger, Thomas; Prokisch, Holger; Hayflick, Susan J.

    2012-01-01

    Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration. PMID:23176820

  5. [Nuclear gene involves in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation].

    PubMed

    Zhao, Su Ying; Zhang, Hai Jun; Xu, Chun Hong; Shan, Xiang Nian

    2006-02-01

    The human mitochondrial 12S rRNA gene mutation at position 1555 associated with non-syndromic deafness and aminoglycoside-induced deafness. Family of Huaiyin in Jiangsu is one of the biggest non-syndromic deafness family in the world. In this family, deafness is maternally inherited. After establishing immortal lymphoblastoid cell lines of the family by EB virus, we analysed 17 lymphoblastoid cell lines derived, respectively, from symptomatic, asymptomatic and controll members of the family. Compared with control members, symptomatic and asymptomatic members both exhibited significant decreases in the rate of growth as well as in the rates of mitochondrial protein synthesis. But the extent of decreases is different and