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1

Clinical Polymorphism of Stargardt Disease in a Large Consanguineous Tunisian Family; Implications for Nosology  

PubMed Central

Purpose To describe the polymorphic expression of Stargardt disease in a large Tunisian family with clinical intra- and interfamilial variation of the condition. Methods Twelve subjects from two related families with autosomal recessive Stargardt disease were enrolled. A detailed clinical examination including visual acuity and visual field measurement, fundus photography, fluorescein angiography, electroretinography (ERG) and color vision testing was performed for all subjects. Results The youngest child from family A manifested typical Stargardt disease while her two brothers presented with Stargardt disease-fundus flavimaculatus (STGD-FFM) and her two sisters demonstrated a peculiar phenotype overlapping Stargardt disease and cone-rod dystrophy; their phenotypic manifestation corresponded well with ERG groups I, II and III, respectively. This uncommon occurrence of an age-related decline in ERG amplitude and worsening of fundus changes is suggestive of a grading pattern in Stargardt disease. Their two cousins in family B, displayed the STGD-FFM phenotype. Despite clinically similar STGD-FFM patterns in both families, age of onset and progression of the phenotype in family B differed from family A. Conclusion This is the first report on phenotypic variation of Stargardt disease in a large Tunisian family. Regarding phenotype and severity of visual symptoms, family A demonstrated Stargardt disease at various stages of progression. In addition, STGD-FFM appeared to be an independent clinical entity in family B. These findings imply that further parameters are required to classify Stargardt’s disease.

El Matri, Leila; Ouechtati, Farah; Chebil, Ahmed; Largueche, Leila; Abdelhak, Sonia

2013-01-01

2

Fragile X syndrome screening of families with consanguineous and non-consanguineous parents in the Iranian population.  

PubMed

Fragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentally retarded males, the frequency of fragile X syndrome is approximately 2-3 percent, but little is known about its proportion in mentally retarded patients from countries where parental consanguinity is common. The objective of this study was to estimate the frequency of fragile X syndrome (FXS) in mentally retarded patients from Iran. We examined a total of 508 families with MR that had been referred to the Genetics Research Center (GRC) in Tehran of which 467 families had at least two mentally retarded children. In 384 families, the parents were related and in 124 they were not related of which most of them had putative or established X-linked inheritance pattern. Full FMR1 mutations were found in 32 of the 508 families studied (6.3%), in 19 out of 124 families with apparently unrelated parents (15.3%), and in 13 of the 384 consanguineous families (3.4%). Thus, in Iran, the relative frequency of FXS seems to be high, and in patients with unrelated parents is much higher. We also show that even in families with consanguineous parents, FXS has to be ruled out before assuming that familial MR is due to autosomal recessive gene defects. Molecular studies are in progress to explain the high proportion of FMR1 mutations in mentally retarded offspring of unrelated Iranian parents. PMID:19361583

Pouya, Ali Reza; Abedini, Seyedeh Sedigheh; Mansoorian, Neda; Behjati, Farkhondeh; Nikzat, Nooshin; Mohseni, Marzieh; Nieh, Sahar Esmaeeli; Abbasi Moheb, Lia; Darvish, Hossein; Monajemi, Gholamreza Bahrami; Banihashemi, Susan; Kahrizi, Kimia; Ropers, Hans Hilger; Najmabadi, Hossein

2009-01-01

3

Moroccan consanguineous family with Becker myotonia and review.  

PubMed

Myotonia congenita is a genetic muscle disorder characterized by clinical and electrical myotonia, muscle hypertrophy, and stiffness. It is inherited as either autosomal-dominant or -recessive, known as Thomsen and Becker diseases, respectively. These diseases are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease and causes more severe muscle stiffness and pain. Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, have been found in both types. We report here the case of a Moroccan consanguineous family with a myotonic autosomal-recessive condition in two children. The molecular studies showed that the patients reported here are homozygous for mutation p.Gly482Arg in the CLCN1 gene. The parents were heterozygote carriers for mutation p.Gly482Arg. This diagnosis allowed us to provide an appropriate management to the patients and to make a genetic counselling to their family. PMID:22346025

Ratbi, Ilham; Elalaoui, Siham Chafai; Escudero, Adela; Kriouile, Yamina; Molano, Jesus; Sefiani, Abdelaziz

2011-10-01

4

Moroccan consanguineous family with Becker myotonia and review  

PubMed Central

Myotonia congenita is a genetic muscle disorder characterized by clinical and electrical myotonia, muscle hypertrophy, and stiffness. It is inherited as either autosomal-dominant or –recessive, known as Thomsen and Becker diseases, respectively. These diseases are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease and causes more severe muscle stiffness and pain. Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, have been found in both types. We report here the case of a Moroccan consanguineous family with a myotonic autosomal-recessive condition in two children. The molecular studies showed that the patients reported here are homozygous for mutation p.Gly482Arg in the CLCN1 gene. The parents were heterozygote carriers for mutation p.Gly482Arg. This diagnosis allowed us to provide an appropriate management to the patients and to make a genetic counselling to their family.

Ratbi, Ilham; Elalaoui, Siham Chafai; Escudero, Adela; Kriouile, Yamina; Molano, Jesus; Sefiani, Abdelaziz

2011-01-01

5

Myotonia congenita in a large consanguineous Arab family: insight into the clinical spectrum of carriers and double heterozygotes of a novel mutation in the chloride channel CLCN1 gene.  

PubMed

The aims of this study were to (1) characterize the clinical phenotype, (2) define the causative mutation, and (3) correlate the clinical phenotype with genotype in a large consanguineous Arab family with myotonia congenita. Twenty-four family members from three generations were interviewed and examined. Genomic DNA was extracted from peripheral blood samples for sequencing the exons of the CLCN1 gene. Twelve individuals with myotonia congenita transmitted the condition in an autosomal dominant manner with incomplete penetrance. A novel missense mutation [568GG>TC (G190S)] was found in a dose-dependent clinical phenotype. Although heterozygous individuals were asymptomatic or mildly affected, the homozygous individuals were severely affected. The mutation is a glycine-to-serine residue substitution in a well-conserved motif in helix D of the CLC-1 chloride channel in the skeletal muscle plasmalemma. A novel mutation, 568GG>TC (G190S) in the CLCN1 gene, is responsible for autosomal dominant myotonia congenita with a variable phenotypic spectrum. PMID:19697366

Shalata, Adel; Furman, Haya; Adir, Vardit; Adir, Noam; Hujeirat, Yasir; Shalev, Stavit A; Borochowitz, Zvi U

2010-04-01

6

Consanguinity profile in the Gaza Strip of Palestine: large-scale community-based study.  

PubMed

Consanguineous marriages which have been practiced throughout history continue to be practiced within different ethnic, religious and social groups to varying degrees with highest prevalences in North Africa, Middle East and central and south Asia. In the Gaza Strip of Palestine, little is known about the consanguinity profile, so the present large-scale study aims to explore the consanguinity profile of two generations using data from the ?-thalassemia premarital screening program. Sociodemographic data analysis included 156,635 (141,200 males and 15,435 females) persons and their parents, representing 141,200 couples who were referred to the Thalassemia and Hemophilia Center for premarital testing. In addition, the consanguinity characteristics of parents of 217 transfusion-dependent ?-thalassemic non-sibling patients were analyzed. Results revealed a significant decrease in the overall prevalence of consanguineous (first- and second-cousin) marriages between the previous (fathers') generation (45.2%) and the current (groom/bride) generation (39.9%). Among the five governorates of the Gaza Strip, records of Gaza Governorate revealed the lowest occurrence (36.9% current generation and 42.1% previous generation) of consanguineous marriages, as compared to all others. Consanguineous marriages are significantly higher in semi-urban areas (41.6%) than in urban areas (39.1%) in the current generation (previous generation, 46.4% vs 44.7%, respectively). Compound consanguinity (two generation) and a single level of consanguinity were seen in 20.7% and 43.7%, respectively, of the cases. The average age of those with first-cousin marriages is significantly lower (22.4±4.4 years) than those with second-cousin marriages (24.3±6.1 years) and the non-consanguineous (26.5±8.2 years). The rate of consanguineous marriages among never married people (42.2%) is significantly much higher than the rate of people with multiple marriages (18.1%). About 74.7% of the non-sibling thalassemic patients of the Gaza Strip are associated with consanguineous parents, of them 54.4% first-cousins and 20.3% second-cousins. In conclusion, although there is a decline in the consanguinity profile in the present compared to previous generation, consanguineous marriages are still a common practice in the Gaza Strip, which rationalizes the necessity for more awareness and counseling efforts about the potential health-related risks of consanguinity on individual lives and the population overall. PMID:24468669

Sirdah, Mahmoud M

2014-02-01

7

Genetics of acheiropodia ("The handless and footless families of Brazil"): IV. Sex ratio, consanguinity and birth order.  

PubMed

The sex ratio among acheiropods is shown to be not significantly different from the sex ratio among their normal sibs, as well as among other segments of the family (parental sibships, cousin sibships and other sibships). The frequency of consanguineous marriages among the parents of acheiropods (82%) is one of the highest thus far reported among parents of individuals affected with rare autosomal recessive anomalies or diseases. No evidence was found of any overall positive or negative birth order effect on the incidence of acheiropodia. These results further strengthen the hypothesis of a simple genetic mechanism for acheiropodia, namely autosomal recessive inheritance, without any detectable complication as regards sex ratio, consanguinity and birth order. Although the family size from heterozygous parents (producing at least one acheiropod) was twice as large as family sizes in other segments of the families (8 against 4), we have at present no evidence to support either heterozygous advantage or reproductive compensation. PMID:1052763

Freire-Maia, A; Chakraborty, R

1975-10-01

8

Influence of Consanguinity on the Pattern of Familial Aggregation of Congenital Cardiovascular Anomalies in an Outpatient Population  

Microsoft Academic Search

Background: Familial aggregation of congenital heart disease (CHD) has been well described in different populations, in particular those with a high consanguinity rate. Extensive genetic study of affected families has improved the understanding of basic genetics of different cardiac lesions. Objective: To identify the role of consanguinity as a risk factor among familial cases of CHD in a stable outpatient

Mohamed A. Seliem; Issam H. Bou-Holaigah; Nouriya Al-Sannaa

2007-01-01

9

Genetic heterogeneity in two consanguineous families segregating early onset retinal degeneration: the pitfalls of homozygosity mapping.  

PubMed

Retinitis pigmentosa is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4,000. At least 28 genes and loci have been implicated in nonsyndromic autosomal recessive retinitis pigmentosa. Here we report two extended and highly consanguineous families segregating early onset retinitis pigmentosa. Despite the consanguinity in both families, we found allelic heterogeneity in one of them, in which affected individuals were compound heterozygotes for two different mutations of the CRB1 gene. In the second family we found evidence for locus heterogeneity. A novel homozygous mutation of RDH12 was found in only 14 of 17 affected individuals in this family. Our data indicate that in the other affected individuals the disease is caused by a different gene/s. These findings demonstrate that while homozygosity mapping is an efficient tool for identification of the underlying mutated genes in inbred families, both locus and allelic heterogeneity may occur even within the same consanguineous family. These observations should be taken into account, especially when studying common and heterogeneous recessive genetic conditions. PMID:19140180

Benayoun, Liat; Spiegel, Ronen; Auslender, Noa; Abbasi, Anan H; Rizel, Leah; Hujeirat, Yasir; Salama, Ihsan; Garzozi, Hanna J; Allon-Shalev, Stavit; Ben-Yosef, Tamar

2009-02-15

10

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness.  

PubMed

Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957_9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected. PMID:17851452

Lezirovitz, Karina; Pardono, Eliete; de Mello Auricchio, Maria T B; de Carvalho E Silva, Fernando L; Lopes, Juliana J; Abreu-Silva, Ronaldo S; Romanos, Jihane; Batissoco, Ana C; Mingroni-Netto, Regina C

2008-01-01

11

Clinical evaluation of two consanguineous families with homozygous mutations in BEST1  

PubMed Central

Purpose To describe the clinical and genetic findings in two consanguineous families with Best vitelliform macular dystrophy (BVMD) and homozygous mutations in the bestrophin-1 (BEST1) gene. Methods Ophthalmologic examination was performed in eight members of two families originating from Spain and Denmark. Mutation screening was performed using the Vitelliform Macular Dystrophy mutation array from Asper Biotech, and by the directed genomic sequencing of BEST1. Results Two homozygous mutations were detected in these families. Mutation c.936C>A (p.Asp312Glu) has been reported previously in a Danish family; here, we describe four additional individuals in this family demonstrating findings compatible with a severe dominant BVMD, albeit with reduced penetrance in heterozygotes. In the Spanish family, a novel homozygous missense mutation in exon 4, c.388 C>A (p.Arg130Ser), was identified in the siblings. Homozygous siblings demonstrated evidence of multifocal vitelliform retinopathy, whereas heterozygous family members presented findings ranging from isolated reduction of the electrooculogram Arden ratio to normal values on all clinical parameters. Conclusions As demonstrated in these consanguineous families, a great clinical variability is associated with homozygous mutations in BEST1, ranging from severe dominant BVMD with reduced penetrance in heterozygotes to autosomal recessive bestrophinopathy.

Pineiro-Gallego, Teresa; Alvarez, Maria; Pereiro, Ines; Campos, Severiano; Sharon, Dror; Schatz, Patrik

2011-01-01

12

Novel mutations in RPE65 identified in consanguineous Pakistani families with retinal dystrophy  

PubMed Central

Purpose To identify pathogenic mutations responsible for retinal dystrophy in three consanguineous Pakistani families. Methods A thorough ophthalmic examination including fundus examination and electroretinography was performed, and blood samples were collected from all participating members. Genomic DNA was extracted, and genome-wide linkage and/or exclusion analyses were completed with fluorescently labeled short tandem repeat microsatellite markers. Two-point Lod scores were calculated, and coding exons along with exon-intron boundaries of RPE65 gene were sequenced, bidirectionally. Results Ophthalmic examinations of the patients affected in all three families suggested retinal dystrophy with an early, most probably congenital, onset. Genome-wide linkage and/or exclusion analyses localized the critical interval in all three families to chromosome 1p31 harboring RPE65. Bidirectional sequencing of RPE65 identified a splice acceptor site variation in intron 2: c.95–1G>A, a single base substitution in exon 3: c.179T>C, and a single base deletion in exon 5: c.361delT in the three families, respectively. All three variations segregated with the disease phenotype in their respective families and were absent from ethnically matched control chromosomes. Conclusions These results strongly suggest that causal mutations in RPE65 are responsible for retinal dystrophy in the affected individuals of these consanguineous Pakistani families.

Kabir, Firoz; Naz, Shagufta; Riazuddin, S. Amer; Naeem, Muhammad Asif; Khan, Shaheen N.; Husnain, Tayyab; Akram, Javed; Sieving, Paul A.; Hejtmancik, J. Fielding

2013-01-01

13

Clinical and genetic investigation of isolated microspherophakia in a consanguineous Tunisian family.  

PubMed

Microspherophakia seems to be the most specific feature of the Weill-Marchesani Syndrome, which could be due to mutations within the ADAMTS10 gene. As the locus responsible for isolated microspherophakia is still unknown, because the reported cases are rare, we checked whether the ADAMTS10 gene is involved in isolated microspherophakia in a Tunisian family. A consanguineous family (MSP-M), including six family members and two patients, presented with decreased vision secondary to bilateral isolated microspherophakia. A linkage analysis was carried out using microsatellite markers flanking the ADAMTS10 candidate gene. In the MSP-M family, isolated microspherophakia is likely inherited as an autosomal-recessive disease. Using a homozygosity-mapping strategy, haplotypic analysis using four STRs showed an exclusion of linkage between the ADAMTS10 gene and the disease locus in this family. Our study suggests that isolated microspherophakia and the Weill-Marchesani Syndrome are not allelic to the ADAMTS10 gene. PMID:19696795

Ben Yahia, Salim; Ouechtati, Farah; Jelliti, Bechir; Nouira, Sonia; Chakroun, Sonia; Abdelhak, Sonia; Khairallah, Moncef

2009-09-01

14

Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar.  

PubMed

Whole exome sequencing (WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease-causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease-causing mutations in four families: (i) a novel nonsense homozygous (c.1034C>G) in PHKG2 causing glycogen storage disease type 9C (GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1-bp deletion (c.915del) in NSUN2 in a male proband with Noonan-like syndrome; (iii) a homozygous SNV (c.1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease-causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ˜25% of our cases. PMID:24102521

Fahiminiya, S; Almuriekhi, M; Nawaz, Z; Staffa, A; Lepage, P; Ali, R; Hashim, L; Schwartzentruber, J; Abu Khadija, K; Zaineddin, S; Gamal, H; Majewski, J; Ben-Omran, T

2014-08-01

15

Wolcott-Rallison Syndrome Is the Most Common Genetic Cause of Permanent Neonatal Diabetes in Consanguineous Families  

PubMed Central

Context and Objective: Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes. Research Design and Methods: The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6). Results: Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group. Conclusions: WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent.

Rubio-Cabezas, Oscar; Patch, Ann-Marie; Minton, Jayne A. L.; Flanagan, Sarah E.; Edghill, Emma L.; Hussain, Khalid; Balafrej, Amina; Deeb, Asma; Buchanan, Charles R.; Jefferson, Ian G.; Mutair, Angham; Hattersley, Andrew T.; Ellard, Sian

2009-01-01

16

APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family  

PubMed Central

Background Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. Methods We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. Results A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. Conclusion The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

2012-01-01

17

Mapping of a New Locus for Autosomal Recessive Demyelinating Charcot-Marie-Tooth Disease to 19q13.1-13.3 in a Large Consanguineous Lebanese Family: Exclusion of MAG as a Candidate Gene  

PubMed Central

Autosomal recessive Charcot-Marie-Tooth disease (CMT) type 4 (CMT4) is a complex group of demyelinating hereditary motor and sensory neuropathies presenting genetic heterogeneity. Five different subtypes that correspond to six different chromosomal locations have been described. We hereby report a large inbred Lebanese family affected with autosomal recessive CMT4, in whom we have excluded linkage to the already-known loci. The results of a genomewide search demonstrated linkage to a locus on chromosome 19q13.1-13.3, over an 8.5-cM interval between markers D19S220 and D19S412. A maximum pairwise LOD score of 5.37 for marker D19S420, at recombination fraction [?] .00, and a multipoint LOD score of 10.3 for marker D19S881, at ?=.00, strongly supported linkage to this locus. Clinical features and the results of histopathologic studies confirm that the disease affecting this family constitutes a previously unknown demyelinating autosomal recessive CMT subtype known as “CMT4F.” The myelin-associated glycoprotein (MAG) gene, located on 19q13.1 and specifically expressed in the CNS and the peripheral nervous system, was ruled out as being the gene responsible for this form of CMT.

Delague, Valerie; Bareil, Corinne; Tuffery, Sylvie; Bouvagnet, Patrice; Chouery, Eliane; Koussa, Salam; Maisonobe, Thierry; Loiselet, Jacques; Megarbane, Andre; Claustres, Mireille

2000-01-01

18

A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family  

PubMed Central

Purpose Aphakia is the complete absence of any lens in the eye, either due to surgical removal of the lens as a result of a perforating wound or ulcer, or due to a congenital anomaly. The purpose of this study was to elucidate the molecular genetics for a large consanguineous Pakistani family with a clear aphakia phenotype. Methods The initial homozygosity screening of the family was extended to all the known autosomal recessive cataract loci in order to exclude the possibility of surgical cataract removal leading to aphakia. The screening was performed using polymorphic nucleotide repeat markers, followed by DNA sequencing of a possible candidate gene, the forkhead box protein E3 gene (FOXE3). The identified mutation was counter-checked by a diagnostic restriction enzyme digest of all the family members, and an analysis of the normal population. Results The initial homozygosity screening of 13 known autosomal recessive loci resulted in negative LOD (logarithm of odds) scores. The aphakia phenotype suggested a mutation in FOXE3 close to the AR-locus 1p34.3-p32.2, and sequence analyses revealed the nonsense mutation c.720C>A, changing cysteine 240 to a stop codon. Segregation in the family was shown by diagnostic restriction enzyme digest, and marker analysis of another aphakia family from Madagascar carrying the same mutation excluded the presence of a founder mutation. Clinical re-examination of the family was not possible due to the escalating security concerns and internal displacement of the population in this region of Pakistan which has prevailed for many months. Conclusions FOXE3 is responsible for the early developmental arrest of the lens placode, and the complete loss of a functional FOXE3 protein results in primary aphakia. It can also be deduced that this mutation is quite primitive in origin since the same mutation is responsible for the same phenotypic outcome in two families of geographically different descent.

Anjum, Iram; Eiberg, Hans; Baig, Shahid Mahmood; Tommerup, Niels

2010-01-01

19

Down syndrome and consanguinity  

PubMed Central

Background: Among the genetics disorders, Down syndrome (DS) is the major cause of mental retardation, congenital heart and intestinal disease. So far, no certain therapeutic method has been suggested for the treatment of this syndrome. The aim of the current survey was to investigate the frequency of parental consanguinity, maternal age in the patients with DS. Materials and Methods: This study was conducted on 38 consecutive patients with clinically and laboratory confirmed DS who referred to the genetic lab of a referral University Hospital. The G-banding method for karyotyping was employed. Results: The patients were 21 males and 17 females within the age of 16 days to 28 years old. Free trisomy (92.1%, n = 35) was the most common chromosomal abnormality. The frequency of DS was higher among the non-consanguine marriages (71.1%) in comparison with the consanguine marriages (28.9%). Mean age of the mothers in the consanguine marriages (mean = 27.1 ± 6.3) was lower than in the non-consanguine marriages (mean = 31.1 ± 7.7). Conclusion: Higher frequency of DS among the non-consanguine marriages in comparison with the consanguine marriages, may suggest that DS diagnostic tests might be done on all embryos regardless of the parents’ familial relationship.

Rezayat, Amir Akhavan; Nazarabadi, Mohammad Hassanzadeh; Andalibi, Mohammad Sobhan Sheikh; Ardabili, Hossein Mohaddes; Shokri, Maryam; Mirzaie, Salmeh; Jarahi, Lida

2013-01-01

20

Atrichia with papular lesions in two Pakistani consanguineous families resulting from mutations in the human hairless gene.  

PubMed

Atrichia with papular lesions (APL) is a rare autosomal recessive form of total alopecia, characterized by hair loss soon after birth and the development of papular lesions of keratin-filled cysts over extensive areas of the body. Mutations in the hairless (hr) gene, a putative single zinc finger transcription factor, have been implicated in the pathogenesis of this disorder. In the present study, we describe two novel deletion mutations in exons 2 and 8 of the human hairless gene leading to frameshift and downstream premature termination codons in two consanguineous Pakistani families affected with atrichia. PMID:16211417

John, Peter; Aslam, Muhammad; Rafiq, Muhammad Arshad; Amin-ud-din, Muhammad; Haque, Sayedul; Ahmad, Wasim

2005-11-01

21

Genetic Diagnosis in Consanguineous Families With Kidney Disease by Homozygosity Mapping Coupled With Whole-Exome Sequencing  

PubMed Central

Background Accurate diagnosis of the primary cause of an individual’s kidney disease can be essential for proper management. Some kidney diseases have overlapping histopathological features despite being caused by defects in different genes. In this report we describe two consanguineous Saudi Arabian families in which individuals presented with kidney failure and mixed clinical and histological features initially thought consistent with focal segmental glomerulosclerosis. Study Design Case series. Setting and participants We studied members of two apparently unrelated families from Saudi Arabia with kidney disease. Measurements Whole-genome single-nucleotide polymorphism analysis followed by targeted isolation and sequencing of exons using genomic DNA samples from affected members of these families, followed by additional focused genotyping and sequence analysis. Results The two apparently unrelated families shared a region of homozygosity on chromosome 2q13. Exome sequence from the affected individuals lacked any sequence reads from the NPHP1 gene, which is located within this homozygous region. Additional PCR based genotyping confirmed that affected individuals had NPHP1 deletions, rather than defects in a known FSGS-associated gene. Limitations The methods used here may not result in a clear genetic diagnosis in many cases of apparent familial kidney disease. Conclusions This analysis demonstrates the power of new high-throughput genotyping and sequencing technologies to aid in the rapid genetic diagnosis of individuals with an inherited form of kidney disease. We believe it is likely that such tools may become useful clinical genetic tools and alter the manner in which diagnoses are made in nephrology.

Al-Romaih, Khaldoun I.; Genovese, Giulio; Al-Mojalli, Hamad; Al-Othman, Saleh; Al-Manea, Hadeel; Al-Suleiman, Mohammed; Al-Jondubi, Mohammed; Atallah, Nourah; Al-Rodhyan, Maha; Weins, Astrid; Pollak, Martin R.; Adra, Chaker N.

2011-01-01

22

Lack of KIF21A mutations in congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families  

PubMed Central

Purpose Congenital fibrosis of the extraocular muscles type I (CFEOM1), the most common CFEOM worldwide, is characterized by bilateral ptotic hypotropia, an inability to supraduct above the horizontal midline, horizontal strabismus (typically exotropia), and ophthalmoplegia with abnormal synkinesis. This distinct non-syndromic phenotype is considered autosomal dominant and is virtually always from heterozygous missense mutations in kinesin family member 21A (KIF21A). However, there are occasional KIF21A-negative cases, opening the possibility for a recessive cause. The objective of this study is to explore this possibility by assessing CFEOM1 patients exclusively from consanguineous families, who are the most likely to have recessive cause for their phenotype if a recessive cause exists. Methods Ophthalmic examination and candidate gene direct sequencing (KIF21A, paired-like homeobox 2A [PHOX2A], tubulin beta-3 [TUBB3]) of CFEOM1 patients from consanguineous families referred for counseling from 2005 to 2010. Results All 5 probands had classic CFEOM1 as defined above. Three had siblings with CFEOM. None of the probands had mutations in KIF21A, PHOX2A, or TUBB3. Conclusions The lack of KIF21A mutations in CFEOM1 patients exclusively from consanguineous families, most of whom had siblings with CFEOM, is strong evidence for a recessive form of CFEOM1. Further studies of such families will hopefully uncover the specific locus(loci).

Shinwari, Jameela; Omar, Aisha; Al-Sharif, Latifa; Khalil, Dania S.; Alanazi, Mohammed; Al-Amri, Abdullah; Al Tassan, Nada

2011-01-01

23

Coexistence of mal de Meleda and congenital cataract in a consanguineous Tunisian family: two case reports  

PubMed Central

Introduction Mal de Meleda is a rare form of palmoplantar keratoderma, with autosomal recessive transmission. It is characterized by diffuse erythema and hyperkeratosis of the palms and soles. Recently, mutations in the ARS (component B) gene (ARS, MIM: 606119) on chromosome 8q24.3 have been identified in families with this disorder. Congenital cataract is a visual disease that may interfere with sharp imaging of the retina. Mutations in the heat-shock transcription factor 4 gene (HSF4; MIM: 602438) may result in both autosomal dominant and autosomal recessive congenital cataracts. Case presentation A Tunisian family with two female siblings aged 45 and 30 years, presented with a clinical association of mal de Meleda and congenital cataract. The two patients exhibited diffuse palmoplantar keratodermas. One of them presented with a total posterior subcapsular cataract and had a best corrected visual acuity at 1/20 in the left eye and with the right eye was only able to count fingers at a distance of one foot. The other woman had a slight posterior subcapsular lenticular opacity and her best corrected visual acuity was 8/10 in the right eye and with her left eye she was only able to count fingers at a distance of one foot. A mutational analysis of their ARS gene revealed the presence of the homozygous missense mutation C99Y and two single nucleotide polymorphisms (-55G>C and -60G>C). The splice mutation (c.1327+4A-G) within intron 12 of the HSF4 gene, which has been previously described in Tunisian families with congenital cataract, was not found in the two probands within this family. Conclusion To the best of our knowledge, such original clinical association has not been reported previously. The association of these two autosomal recessive diseases might have occurred in this family due to a high degree of inbreeding. The C99Y mutation may be specific to the Tunisian population as it has been exclusively reported so far in only three Tunisian families with mal de Meleda.

2010-01-01

24

Sporadic case of X-chromosomal Alport syndrome in a consanguineous family  

Microsoft Academic Search

Alport syndrome (AS) is a genetic disorder of basement membranes caused by mutations in type IV collagen genes that is characterized\\u000a by chronic hematuria and progressive nephropathy leading to renal failure. The main extrarenal features include sensorineural\\u000a hearing loss and ocular lesions. The mode of inheritance is X-linked dominant in about 80%–85% of the affected families, whereas\\u000a autosomal transmission is

Beate Ermisch; Oliver Gross; Kai-Olaf Netzer; Manfred Weber; Matthias Brandis; Lothar Bernd Zimmerhackl

2000-01-01

25

Identification of a novel mutation in FOXL2 gene that leads to blepharophimosis ptosis epicanthus inversus and telecanthus syndrome in a Tunisian consanguineous family.  

PubMed

Mutations in FOXL2 gene are responsible for blepharophimosis ptosis epicanthus inversus and telecanthus syndrome (BPES). The BPES syndrome is a rare autosomal dominant genetic disease characterized by eyelid malformations associated with premature ovarian failure (BPES type I) or not (BPES type II). The human FOXL2 protein (376 aa) contains a 100 amino-acid DNA-binding forkhead domain (residues 52-152) and a polyalanine tract (residues 221-234). In the present study, we report the molecular investigation of four affected members with BPES syndrome in a Tunisian consanguineous family. To identify the causative mutation, we performed a direct sequencing of the FOXL2 gene. The sequence analysis of the coding exon revealed a novel frameshift mutation g.1113 dup C, c.876 dup C, p.P292 Fs. The mutation is located downstream of the polyalanine tract and causes the protein extension to 532 aa. This study reports for the first time a novel frameshift mutation in two-generation consanguineous Tunisian family with BPES. Our results expand the spectrum of FOXL2 mutations. PMID:19929410

Chouchene, Ibtissem; Derouiche, Kaouthar; Chaabouni, Afif; Cherif, Lamia; Amouri, Ahlem; Largueche, Leila; Abdelhak, Sonia; El Matri, Leila

2010-02-01

26

A novel splice-site mutation of TULP1 underlies severe early-onset retinitis pigmentosa in a consanguineous Israeli Muslim Arab family  

PubMed Central

Purpose To investigate the genetic basis for autosomal recessive severe early-onset retinitis pigmentosa (RP) in a consanguineous Israeli Muslim Arab family. Methods Haplotype analysis for all known genes underlying autosomal recessive RP was performed. Mutation screening of the underlying gene was done by direct sequencing. An in vitro splicing assay was used to evaluate the effect of the identified mutation on splicing. Results Haplotype analysis indicated linkage to the Tubby-like protein 1 (TULP)1 gene. Direct sequencing revealed a homozygous single base insertion, c.1495+2_1495+3insT, located in the conserved donor splice-site of intron 14. This mutation co-segregated with the disease, and was not detected in 114 unrelated Israeli Muslim Arab controls. We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing. Conclusions To date, 22 distinct pathogenic mutations of TULP1 have been reported in patients with early-onset RP or Leber congenital amaurosis. Here we report a novel splice-site mutation of TULP1, c.1495+2_1495+3insT, underlying autosomal recessive early-onset RP in a consanguineous Israeli Muslim Arab family. This report expands the spectrum of pathogenic mutations of the TULP1 gene.

Abbasi, Anan H.; Garzozi, Hanna J.

2008-01-01

27

A novel splice site mutation of CDHR1 in a consanguineous Israeli Christian Arab family segregating autosomal recessive cone-rod dystrophy  

PubMed Central

Purpose To investigate the genetic basis for autosomal recessive cone-rod dystrophy in a consanguineous Israeli Christian Arab family. Methods Patients underwent a detailed ophthalmic examination, including funduscopy, electroretinography (ERG), visual field testing, and optical coherence tomography. Genome-wide homozygosity mapping using a single nucleotide polymorphism array was performed to identify homozygous regions shared between the two affected individuals. Mutation screening of the underlying gene was performed with direct sequencing. In silico analysis was used to predict the effect of the mutation on splicing. Results The family included two affected individuals. Clinical findings included progressive deterioration of visual acuity, photophobia, defective color vision, loss of central visual fields, pigmentary deposits localized mainly in the peripheral retina, a thinned and atrophic macular region, retinal vessel attenuation, absent ERG cone responses, and reduced ERG rod responses. Homozygosity mapping revealed several homozygous intervals shared among the affected individuals. One, a 12Mb interval on chromosome 10, included the CDHR1 gene. Direct sequencing revealed a single base transversion, c.1485+2T>G, located in the conserved donor splice site of Intron 13. This mutation cosegregated with the disease in the family, and was not detected in 208 Israeli Christian Arab control chromosomes. In silico analysis predicted that this mutation eliminates the Intron 13 donor splice site. Conclusions Only three distinct pathogenic mutations of CDHR1 have been reported to date in patients with autosomal recessive retinal degeneration. Here we report a novel splice site mutation of CDHR1, c.1485+2T>G, underlying autosomal recessive cone-rod dystrophy in a consanguineous Israeli Christian Arab family. This report expands the spectrum of pathogenic mutations of the CDHR1 gene.

Cohen, Ben; Chervinsky, Elena; Jabaly-Habib, Haneen; Shalev, Stavit A.; Briscoe, Daniel

2012-01-01

28

Bloom syndrome: An analysis of consanguineous families assigns the locus mutated to chromosome band 15q26. 1  

SciTech Connect

By the principle of identity by descent, parental consanguinity in individuals with rare recessively transmitted disorders dictates homozygosity not just at the mutated disease-associated locus but also at sequences that flank that locus closely. In 25 of 26 individuals with Bloom syndrome examined whose parents were related, a polymorphic tetranucleotide repeat in an intron of the protooncogene FES was homozygous far more often than expected (P < 0.0001 by x[sup 2]). Therefore, BLM, the gene that when mutated gives rise to Bloom syndrome, is tightly linked to FES, a gene whose chromosome position is known to be 15q26.1. This successful approach to the assignment of the Bloom syndrome locus to one short segment of the human genome simultaneously (i) demonstrates the power of homozygosity mapping and (ii) becomes the first step in a [open quotes]reverse[close quotes] genetics definition of the primary defect in Bloom syndrome.

German, J.; Roe, A.M.; Ellis, N.A. (New York Blood Center, NY (United States)); Leppert, M.F. (Univ. of Utah, Salt Lake City, UT (United States))

1994-07-05

29

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

PubMed

Split-hand/split-foot malformation (SHFM), representing variable degree of median clefts of hands and feet, is a genetically heterogeneous group of limb malformations with seven loci mapped on different human chromosomes. However, only 3 genes (TP63, WNT10B, DLX5) for the seven loci have been identified. The study, presented here, described three consanguineous Pakistani families segregating SHFM in autosomal recessive manner. Linkage in the families was searched by genotyping microsatellite markers and mutation screening of candidate gene was performed by Sanger DNA sequencing. Clinical features of affected members of these families exhibited SHFM phenotype with involvement of hands and feet. Genotyping using microsatellite markers mapped the families to WNT10B gene at SHFM6 on chromosome 12q13.11-q13. Subsequently, sequence analysis of WNT10B gene revealed a novel 4-bp deletion mutation (c.1165_1168delAAGT) in one family and 7-bp duplication (c.300_306dupAGGGCGG) in two other families. Structure-based analysis showed a significant conformational shift in the active binding site of mutated WNT10B (p.Lys388Glufs*36), influencing binding with Fzd8. The mutations identified in the WNT10B gene extend the body of evidence implicating it in the pathogenesis of SHFM. PMID:24211389

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

2014-01-25

30

Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.  

PubMed

The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans). PMID:16823392

Laurier, Virginie; Stoetzel, Corinne; Muller, Jean; Thibault, Christelle; Corbani, Sandra; Jalkh, Nadine; Salem, Nabiha; Chouery, Eliane; Poch, Olivier; Licaire, Serge; Danse, Jean-Marc; Amati-Bonneau, Patricia; Bonneau, Dominique; Mégarbané, André; Mandel, Jean-Louis; Dollfus, Hélène

2006-11-01

31

A novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability  

PubMed Central

Background Intellectual disability (ID) is a serious disorder of the central nervous system with a prevalence of 1-3% in a general population. In the past decades, the research focus has been predominantly on X-linked ID (68 loci and 19 genes for non syndromic X linked ID) while for autosomal recessive nonsyndromic ID (NSID) only 30 loci and 6 genes have been reported to date. Methods Genome-wide homozygosity mapping with 500 K Nsp1 array (Affymetrix), CNV analysis, PCR based breakpoint mapping and DNA sequencing was performed to explore the genetic basis of autosomal recessive nonsyndromic ID in a large Pakistani family. Results Data analysis showed linkage at 8p23 locus with common homozygous region between SNPs rs6989820 and rs2237834, spanning a region of 12.494 Mb. The subsequent CNV analysis of the data revealed a homozygous deletion of 170.673 Kb which encompassed the TUSC3 gene. Conclusion We report a novel deletion mutation in TUSC3 gene which is the second gene after TRAPPC9 in which mutation has been identified in more than one family with autosomal recessive NSID. The study will aid in exploring the molecular pathway of cognition.

2011-01-01

32

A new locus on chromosome 22q13.31 linked to recessive genetic epilepsy with febrile seizures plus (GEFS+) in a Tunisian consanguineous family  

PubMed Central

Background Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. The aim of our study was to identify the responsible locus for GEFS+ syndrome in a consanguineous Tunisian family showing three affected members, by carrying out a genome-wide single nucleotide polymorphisms (SNPs) genotyping followed by a whole-exome sequencing. We hypothesized an autosomal recessive (AR) mode of inheritance. Results Parametric linkage analysis and haplotype reconstruction identified a new unique identical by descent (IBD) interval of 527 kb, flanking by two microsatellite markers, 18GTchr22 and 15ACchr22b, on human chromosome 22q13.31 with a maximum multipoint LOD score of 2.51. Our analysis was refined by the use of a set of microsatellite markers. We showed that one of them was homozygous for the same allele in all affected individuals and heterozygous in healthy members of this family. This microsatellite marker, we called 17ACchr22, is located in an intronic region of TBC1D22A gene, which encodes a GTPase activator activity. Whole-exome sequencing did not reveal any mutation on chromosome 22q13.31 at the genome wide level. Conclusions Our findings suggest that TBC1D22A is a new locus for GEFS+.

2013-01-01

33

Large Families and Language Development  

MedlinePLUS Videos and Cool Tools

... corner of the player. Large Families and Language Development HealthDay January 27, 2014 Related MedlinePlus Pages Family ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated ...

34

Consanguineous marriages in Afghanistan.  

PubMed

The present cross-sectional study was done in order to illustrate the prevalence and types of consanguineous marriages among Afghanistan populations. Data on types of marriages were collected using a simple questionnaire. The total number of couples in the study was 7140 from the following provinces: Badakhshan, Baghlan, Balkh, Bamyan, Kabul, Kunduz, Samangan and Takhar. Consanguineous marriages were classified by the degree of relationship between couples: double first cousins, first cousins, first cousins once removed, second cousins and beyond second cousins. The coefficient of inbreeding (F) was calculated for each couple and the mean coefficient of inbreeding (?) estimated for each population. The proportion of consanguineous marriages in the country was 46.2%, ranging from 38.2% in Kabul province to 51.2% in Bamyan province. The equivalent mean inbreeding coefficient (?) was 0.0277, and ranged from 0.0221 to 0.0293 in these two regions. There were significant differences between provinces for frequencies of different types of marriages (p<0.001). First cousin marriages (27.8%) were the most common type of consanguineous marriages, followed by double first cousin (6.9%), second cousin (5.8%), beyond second cousin (3.9%) and first cousin once removed (1.8%). There were significant differences between ethnic groups for the types of marriages (?2=177.6, df=25, p<0.001). Tajiks (Soni) and Turkmens (also Pashtuns) showed the lowest (?=0.0250) and highest (?=0.0297) mean inbreeding coefficients, respectively, among the ethnic groups in Afghanistan. The study shows that Afghanistan's populations, like other Islamic populations, have a high level of consanguinity. PMID:21729362

Saify, Khyber; Saadat, Mostafa

2012-01-01

35

From "New Genetics" to Everyday Knowledge: Ideas about How Genetic Diseases Are Transmitted in Two Large Brazilian Families  

ERIC Educational Resources Information Center

This study focuses on everyday or lay understandings of inheritance. In the northeastern Brazil, 100 individuals were interviewed in order to describe how they explain the origin of genetic disorders affecting their relatives for several generations. There were involved 60 individuals from a large consanguineous family with many members affected…

Santos, Silvana; Bizzo, Nelio

2005-01-01

36

Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.  

PubMed

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2 × 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D; Mouassess, Faten; Achkar, Walid A L; Fulton, Robert S; Denny, Joshua C; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M; Pappas, Dimitrios A; Carroll, Robert J; Eyler, Anne E; Trynka, Gosia; Stahl, Eli A; Cui, Jing; Saxena, Richa; Coenen, Marieke J H; Guchelaar, Henk-Jan; Huizinga, Tom W J; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E; de Vries, Niek; Tak, Paul P; Moreland, Larry W; Bridges, S Louis; Miceli-Richard, Corinne; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A; Gregersen, Peter K; Mardis, Elaine R; Arayssi, Thurayya; Kazkaz, Layla A; Plenge, Robert M

2014-01-01

37

Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene  

PubMed Central

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P?=?0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF?=?0.042] and rs116541814 [MAF?=?0.021], combined P?=?3.2×10?6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P?=?0.049 for C-alpha test and P?=?0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.

Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D.; Mouassess, Faten; Achkar, Walid A. L.; Fulton, Robert S.; Denny, Joshua C.; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M.; Pappas, Dimitrios A.; Carroll, Robert J.; Eyler, Anne E.; Trynka, Gosia; Stahl, Eli A.; Cui, Jing; Saxena, Richa; Coenen, Marieke J. H.; Guchelaar, Henk-Jan; Huizinga, Tom W. J.; Dieude, Philippe; Mariette, Xavier; Barton, Anne; Canhao, Helena; Fonseca, Joao E.; de Vries, Niek; Tak, Paul P.; Moreland, Larry W.; Bridges, S. Louis; Miceli-Richard, Corinne; Choi, Hyon K.; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A.; Gregersen, Peter K.; Mardis, Elaine R.; Arayssi, Thurayya; Kazkaz, Layla A.; Plenge, Robert M.

2014-01-01

38

Endogamy, Consanguinity and Community Disease Profiles  

Microsoft Academic Search

Considerable attention is paid to the role of consanguineous marriage as a causative factor in the prevalence of genetic disorders. At the same time, the potential influence of community endogamy on overall levels of homozygosity and disease profiles remains largely under-investigated. With the ongoing global epidemiological transition from infectious to non-communicable disease, the impact of genetic disorders will become increasingly

Alan Bittles

2005-01-01

39

Cystic fibrosis in a large kindred family in Qatar.  

PubMed

We describe 45 patients with cystic fibrosis (CF), diagnosed between June 1987 and May 1999, seen at the Hamad Medical Corporation, Qatar in the Arabian Gulf. Twenty-six of 32 families in the study were related and belonged to the same Bedouin tribe. The parents of 98% of these cases were consanguineous. Metabolic alkalosis and/or hypo-electrolytaemia were found in a large proportion of infants with CF. Cystic fibrosis in Qatari children is phenotypically variable with mild to moderate respiratory symptoms, and none of them died during this study. Among the non-Arabic-Asian patients, pulmonary symptoms were more severe, Pseudomonas colonization was earlier, pancreatic insufficiency occurred in infancy and four died in early life. PMID:11064773

Abdul Wahab, A; Dawod, S T; al Thani, G

2000-09-01

40

Was the Darwin/Wedgwood Dynasty Adversely Affected by Consanguinity?  

NSDL National Science Digital Library

Charles Darwin, who was married to his first cousin, Emma Wedgwood, was one of the first experimentalists to demonstrate the adverse effects of inbreeding and to question the consequences of consanguineous mating. He documented the phenomenon of inbreeding depression for numerous plant species, and this caused him to worry about the health of his own children, who were often ill. To determine whether Darwin's fears were justified, we constructed a pedigree of the Darwin/Wedgwood dynasty from the large quantity of genealogical information published on these families. The inbreeding coefficients (F) computed from the pedigree show that Darwin's children were subject to a moderate level of inbreeding (F 5 0.0630), and the progeny of related families had still higher inbreeding values (e.g., F 5 0.1255 for the progeny of Henry Wedgwood, Emma Wedgwood's brother). The analysis of a sample of 25 Darwin/Wedgwood families belonging to four consecutive generations shows a statistically significant positive association between child mortality (death at or before the age of 10 years) and inbreeding coefficient detected by means of nonparametric tests (ÃÂ = 0.309, P = 0.040). Our findings suggest that the high childhood mortality experienced by the Darwin progeny (3 of his 10 children died at age 10 or younger) might be a result of increased homozygosity of deleterious recessive alleles produced by the consanguineous marriages within the Darwin/Wedgwood dynasty.

Tim Berra (The Ohio State University;Dept of Evolution, Ecology and Organismal Biology)

2010-05-03

41

Consanguinity, human evolution, and complex diseases  

PubMed Central

There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F ? 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is ?3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates.

Bittles, A. H.; Black, M. L.

2010-01-01

42

Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus  

PubMed Central

Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus.

Radhakrishna, Uppala; Ratnamala, Uppala; Deutsch, Samuel; Bartoloni, Lucia; Kuracha, Murali R; Singh, Raminder; Banwait, Jasjit; Bastola, Dhundy K; Johar, Kaid; Nath, Swapan K; Antonarakis, Stylianos E

2012-01-01

43

Consanguinity and increased risk for schizophrenia in Egypt  

PubMed Central

Background Consanguinity has been suggested as a risk factor for psychsoses in some Middle Eastern countries, but adequate control data are unavailable. Our recent studies in Egypt have shown elevated parental consanguinity rates among patients with bipolar I disorder (BP1), compared with controls. We have now extended our analyses to Schizophrenia (SZ) in the same population. Methods A case-control study was conducted at Mansoura University Hospital, Mansoura, Egypt (SZ, n = 75; controls, n = 126, and their available parents). The prevalence of consanguinity was estimated from family history data (‘self report’), followed by DNA analysis using short tandem repeat polymorphisms (STRPs, n = 63) (‘DNA-based’ rates). Results Self reported consanguinity was significantly elevated among the patients (SZ: 46.6%, controls: 19.8%, OR 3.53, 95% CI 1.88, 6.64; p = 0.000058, 1 d.f.). These differences were confirmed using DNA based estimates for coefficients of inbreeding (inbreeding coefficients as means ± standard error, cases: 0.058 ± 0.007, controls: 0.022 ± 0.003). Conclusions Consanguinity rates are signifcantly elevated among Egyptian SZ patients in the Nile delta region. The associations are similar to those observed with BP1 in our earlier study. If replicated, the substantial risk associated with consanguinity raises public health concerns. They may also pave the way for gene mapping studies.

Mansour, Hader; Fathi, Warda; Klei, Lambertus; Wood, Joel; Chowdari, Kodavali; Watson, Annie; Eissa, Ahmed; Elassy, Mai; Ali, Ibtihal; Salah, Hala; Yassin, Amal; Tobar, Salwa; El-Boraie, Hala; Gaafar, Hanan; Ibrahim, Nahed E.; Kandil, Kareem; El-Bahaei, Wafaa; El-Boraie, Osama; Alatrouny, Mohamed; El-Chennawi, Farha; Devlin, Bernie; Nimgaonkar, Vishwajit L.

2010-01-01

44

Association studies in consanguineous populations  

SciTech Connect

To study the genetic determinism of multifactorial diseases in large panmictic populations, a strategy consists in looking for an association with markers closely linked to candidate genes. A distribution of marker genotypes different in patients and controls may indicate that the candidate gene is involved in the disease. In panmictic populations, the power to detect the role of a candidate gene depends on the gametic disequilibrium with the marker locus. In consanguineous populations, we show that it depends on the inbreeding coefficient F as well. Inbreeding increases the power to detect the role of a recessive or quasi-recessive disease-susceptibility factor. The gain in power turns out to be greater for small values of the gametic disequilibrium. Moreover, even in the absence of gametic disequilibrium, the presence of inbreeding may allow to detect the role of a recessive factor. Ignoring inbreeding when it exists may lead to reject falsely a recessive model if the mode of inheritance is inferred on the distribution of genotypes among patients. 5 refs., 6 figs., 1 tab.

Genin, E.; Clerget-Darpous, F. [Institut National d`Etudes Demographiques, Paris (France)

1996-04-01

45

From new genetics to everyday knowledge: Ideas about how genetic diseases are transmitted in two large Brazilian families  

NASA Astrophysics Data System (ADS)

This study focuses on everyday or lay understandings of inheritance. In the northeastern Brazil, 100 individuals were interviewed in order to describe how they explain the origin of genetic disorders affecting their relatives for several generations. There were involved 60 individuals from a large consanguineous family with many members affected with a neurodegenerative disorder, SPOAN syndrome (spastic paraplegia, optic atrophy and neuropathy), and 40 individuals of another family living with neurofibromatosis type 1 (NF1). The results indicate that families here studied have built narratives to explain the origin of genetic diseases, saying that an ancestor infected with syphilis gave rise to disorders and birthmarks transmitted to descendents.

Santos, Silvana; Bizzo, Nelio

2005-07-01

46

The frequency and effecting factors of consanguineous marriage in a group of soldiers in Ankara.  

PubMed

This cross-sectional study was carried out to investigate the frequency of consanguineous marriage in a group of army conscripts in Ankara and the factors affecting this. Of 4153 soldiers, 387 were married. The rate of marriage between first cousins was found to be 19.1%, and the overall rate of consanguineous marriage was 24.1%. Consanguineous marriage was found to be significantly prevalent among soldiers who were born in and still living in the Eastern region; among those who lived in villages; among those whose parents as well as themselves had low educational levels; and among those whose marriages were arranged by their families. Neither the payment of bride-price nor the presence of consanguinity between parents was a significant factor for consanguineous marriage. In addition, the age of the soldier and the age at marriage were significantly lower among soldiers married to first cousins than among soldiers whose marriages were not consanguineous. PMID:16082860

Kir, Tayfun; Güleç, Mahir; Bakir, Bilal; Ho?jgönül, Esat; Tümerdem, Nazmi

2005-07-01

47

Health effects of consanguinity in Pondicherry.  

PubMed

Of 1000 pregnant women studied, consanguinity was observed in 30.8%, with a higher frequency among women from rural areas, and among Hindus. In the consanguineous group, first cousin marriages were present in 47.4%, and uncle niece marriages in 23.4% of women. Coefficient of inbreeding was highest in Harijans (0.0258), followed by non-Brahmins (0.0220) and Brahmins (0.0204). Fertility was not influenced by consanguinity. There was a significantly higher rate of still births and infant mortality in consanguineous matings as compared with non-consanguineous. Total morbidity was higher in the consanguineous group as compared with the non-consanguineous (p less than 0.01), especially that due to neonatal infections and jaundice. There was no significant difference in the prevalence of congenital malformations, chromosomal and genetic disorders between the two groups, although the number of abnormal births in this group was small. PMID:1500125

Verma, I C; Prema, A; Puri, R K

1992-06-01

48

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene.  

PubMed

Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119-69G>C, c.161+66A>T and c.875-31G>C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition. PMID:21107338

Ouechtati, Farah; Merdassi, Ahlem; Bouyacoub, Yosra; Largueche, Leila; Derouiche, Kaouther; Ouragini, Houyem; Nouira, Sonia; Tiab, Leila; Baklouti, Karim; Rebai, Ahmed; Schorderet, Daniel F; Munier, Francis L; Zografos, Leonidas; Abdelhak, Sonia; El Matri, Leila

2011-01-01

49

Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome  

Microsoft Academic Search

Mutations in myosin XVA are responsible for the shaker 2 (sh2) phenotype in mice and nonsyndromic autosomal recessive profound hearing loss DFNB3 on chromosome 17p11.2. We have ascertained seven families with profound congenital hearing loss from Pakistan and India with evidence of linkage to DFNB3 at 17p11.2. We report three novel homozygous mutations in MYO15A segregating in three of these

Nikki Liburd; Manju Ghosh; Saima Riazuddin; Sadaf Naz; Shaheen Khan; Zubair Ahmed; Sheikh Riazuddin; Yong Liang; Puthezhath S. N. Menon; Tenesha Smith; Ann C. M. Smith; Ken-Shiung Chen; James R. Lupski; Edward R. Wilcox; Lorraine Potocki; Thomas B. Friedman

2001-01-01

50

Is There a Significant Trend in Prevalence of Consanguineous Marriage in Tehran? A Review of Three Generations  

Microsoft Academic Search

Consanguineous marriage is a common practice in Iran. The present study surveyed the trend in consanguineous marriage across\\u000a three generations of Iranians. Index cases, consisting of 400 individuals attending the diabetes and osteoporosis clinic in\\u000a Shariati Hospital, were interviewed. Data on consanguinity status for 1789 marriages within the index cases’ families were\\u000a obtained. Generation 1 consisted of marriages contracted before

Seyed Mohammad Akrami; Vahideh Montazeri; Somaieh Rashid Shomali; Ramin Heshmat; Bagher Larijani

2009-01-01

51

Consanguinity in South America: Demographic Aspects  

Microsoft Academic Search

A sample of 53,552 nonmalformed liveborn infants was ascertained by the Latin-American Collaborative Study of Congenital Malformations between 1967 and 1996. The mean consanguinity rate was 0.96%, with significantly higher values in Brazil and Venezuela, and lower in Argentina. Low paternal education and occupation levels were positively associated with consanguinity. First-cousin matings represented almost half of all consanguineous couples. The

Rosa Liascovich; Mónica Rittler; Eduardo E. Castilla

2001-01-01

52

Consanguinity in South America: demographic aspects.  

PubMed

A sample of 53,552 nonmalformed liveborn infants was ascertained by the Latin-American Collaborative Study of Congenital Malformations between 1967 and 1996. The mean consanguinity rate was 0.96%, with significantly higher values in Brazil and Venezuela, and lower in Argentina. Low paternal education and occupation levels were positively associated with consanguinity. First-cousin matings represented almost half of all consanguineous couples. The consanguinity was mainly of more closely related types in Brazil, while in Venezuela more remote types predominated. This could reflect differences in migration patterns and rates between these two countries. PMID:11096268

Liascovich, R; Rittler, M; Castilla, E E

2001-01-01

53

Congenital malformations, reproductive wastage and consanguineous mating.  

PubMed

A study was undertaken in Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, South India, to understand the relation between congenital developmental disorders and consanguinity and also reproductive wastage and consanguinity. Four hundred children with existing congenital developmental disorders were studied with regard to their consanguineous parentage and compared with 1,000 randomly selected patients attending the paediatric outpatient department. There was a significantly higher prevalence of consanguinity in the study group (p < 0.001) and greater frequency in rural areas. The common types of consanguineous marriages were between first cousins (50.6%) and uncle and niece (42.4%). Frequency of consanguinity was not significantly related to religion and caste. The mean coefficient of inbreeding was 0.056. Consanguinity had no significant effect on average pregnancy rate and reproductive wastage. The frequency of consanguinity was significantly higher especially with autosomal recessive disorders (p < 0.001), congenital heart diseases (p < 0.001), multiple malformations (p < 0.001), neurological malformations (p < 0.005), chromosomal disorders (p < 0.01), genitourinary disorders (p < 0.02) and mental retardation-developmental disorders (p < 0.02). These observations stress the need for communicating the deleterious effects of inbreeding to the public through regular health education. PMID:7684587

Jain, V K; Nalini, P; Chandra, R; Srinivasan, S

1993-02-01

54

Asteroid families classification: Exploiting very large datasets  

NASA Astrophysics Data System (ADS)

The number of asteroids with accurately determined orbits increases fast, and this increase is also accelerating. The catalogs of asteroid physical observations have also increased, although the number of objects is still smaller than in the orbital catalogs. Thus it becomes more and more challenging to perform, maintain and update a classification of asteroids into families. To cope with these challenges we developed a new approach to the asteroid family classification by combining the Hierarchical Clustering Method (HCM) with a method to add new members to existing families. This procedure makes use of the much larger amount of information contained in the proper elements catalogs, with respect to classifications using also physical observations for a smaller number of asteroids. Our work is based on a large catalog of high accuracy synthetic proper elements (available from AstDyS), containing data for >330,000 numbered asteroids. By selecting from the catalog a much smaller number of large asteroids, we first identify a number of core families; to these we attribute the next layer of smaller objects. Then, we remove all the family members from the catalog, and reapply the HCM to the rest. This gives both satellite families which extend the core families and new independent families, consisting mainly of small asteroids. These two cases are discriminated by another step of attribution of new members and by merging intersecting families. This leads to a classification with 128 families and currently 87,095 members. The number of members can be increased automatically with each update of the proper elements catalog; changes in the list of families are not automated. By using information from absolute magnitudes, we take advantage of the larger size range in some families to analyze their shape in the proper semimajor axis vs. inverse diameter plane. This leads to a new method to estimate the family age, or ages in cases where we identify internal structures. The analysis of the plot above evidences some open problems but also the possibility of obtaining further information of the geometrical properties of the impact process. The results from the previous steps are then analyzed, using also auxiliary information on physical properties including WISE albedos and SDSS color indexes. This allows to solve some difficult cases of families overlapping in the proper elements space but generated by different collisional events. The families formed by one or more cratering events are found to be more numerous than previously believed because the fragments are smaller. We analyze some examples of cratering families (Massalia, Vesta, Eunomia) which show internal structures, interpreted as multiple collisions. We also discuss why Ceres has no family.

Milani, Andrea; Cellino, Alberto; Kneževi?, Zoran; Novakovi?, Bojan; Spoto, Federica; Paolicchi, Paolo

2014-09-01

55

Consanguinity and prereproductive mortality in the Utah Mormon population.  

PubMed

To test the effects of parental consanguinity on mortality among offspring, inbreeding coefficients were estimated for 303,675 members of the Utah Mormon population who were born between 1847 and 1945. Although consanguinity has been relatively rare in this population, the large sample size permitted the identification of more than 3,500 inbred offspring. Among the offspring of unrelated parents, 13.2% died before the age of 16. Significant elevations in prereproductive mortality were seen among the offspring of first-cousin marriages (22%) and among the offspring of closer unions (32%). The cor- responding relative risks are 1.70 (95% confidence limits = 1.52, 1.91) and 2.41 (95% confidence limits = 1.59, 3.41), respectively. Other categories of relationship did not produce significant elevations in offspring mortality. Similar results were obtained when a case-control approach was used to remove the effects of socioeconomic variation. Consistent with many other studies of populations with low consanguinity rates, this population experienced a relatively high absolute increase in mortality among the offspring of first-cousin marriages (9%). Preliminary evidence is offered for the hypothesis that mortality differentials are larger in populations with low inbreeding and low mortality because nongenetic causes of death do not obscure the effects of consanguinity. PMID:11474206

Jorde, L B

2001-01-01

56

Consanguineous marriage and reproductive risk: attitudes and understanding of ethnic groups practising consanguinity in Western society  

PubMed Central

Consanguineous couples should be adequately informed about their increased reproductive risk and possibilities for genetic counselling. Information may only be effective if it meets the needs of the target group. This study aimed to gain more insight into: (1) attitudes of people belonging to ethnic groups in Western society towards consanguinity and their understanding of risk for offspring; and (2) their attitudes regarding reproductive information targeted at consanguineous couples. Dutch Moroccans and Turks were invited to complete an online questionnaire by snowball sampling and by placing a link on two popular Dutch Moroccan/Turkish forum websites between September and October 2011. The questionnaire was completed by 201 individuals who were, on average, neither positive nor negative towards consanguinity. Respondents with a consanguineous partner were more positive, estimated the risk for the offspring lower and were less positive about the provision of risk information to consanguineous couples when compared with respondents without a consanguineous partner. Participants of Turkish origin had a more negative attitude towards consanguinity and estimated the reproductive risk higher than Moroccan participants. More than half of the respondents thought that information should be given before marriage, whereas only 10% thought it should never be provided. The general practitioner was most often mentioned (54%) as the designated professional to inform people. Information about genetic risks related to consanguinity should be offered early, preferably before marriage. The diversity of the target population requires various strategies to disseminate information and reach consanguineous couples with the offer of genetic counselling.

Teeuw, Marieke E; Loukili, Ghariba; Bartels, Edien AC; ten Kate, Leo P; Cornel, Martina C; Henneman, Lidewij

2014-01-01

57

Consanguinity and occurrence of cleft lip/palate: a hospital-based registry study in Riyadh.  

PubMed

This paper focuses on the influence of consanguinity on the occurrence of orofacial clefts. All patients with orofacial clefts registered at King Faisal Specialist Hospital and Research Center, Riyadh since June 1999 until December 2009 were included in this study. Patients were classified in two distinct groups: cleft lip with or without cleft palate (CL?±?P) and isolated cleft palate (CP). Chi-squared test was used to test independence of variables. Intracluster correlation coefficient was estimated to assess the degree of concordance between siblings. Among 1,171 total patients, CL?±?P was found to be more common (64.0%). Males were more likely to be affected with CL?±?P (M:F?=?1.5:1) and females were more likely to be affected with CP (M:F?=?0.9:1; P?family history of clefts; family history was more likely to be positive for patients with CL?±?P than for patients with CP (33.6% vs. 22.0%; P?Consanguineous relationships were seen in 56.8% of our patients' parents. Family history was more likely to be positive for patients whose parents were consanguineous than those who were non-consanguineous (34.2% vs. 25.8%; P?=?0.003), both for the CL?±?P and CP groups. Recurrence among siblings did not differ between those born to consanguineous versus non-consanguineous parents. Recurrence of clefts in offspring was higher among parents affected by cleft compared to those who were not affected (51.4% vs. 11.4%; P?consanguinity is important for populations with a high degree of consanguinity. PMID:22302702

Ravichandran, Kandasamy; Shoukri, Mohamed; Aljohar, Aziza; Shazia, Naz Subhani; Al-Twaijri, Yasmin; Al Jarba, Ibtisam

2012-03-01

58

Consanguinity and disorders of sex development.  

PubMed

Disorders of sex development (DSD) are defined as 'congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical' [Lee et al., Pediatrics 2006;118:e488-e500]. Studies conducted in Western countries, with low rates of consanguinity, show that truly ambiguous genitalia have an estimated incidence of 1:5,000 births. There are indications that the prevalence of DSD is higher in endogamous communities. The incidence of ambiguous genitalia in Saudi Arabia has been estimated at 1:2,500 live births; whilst in Egypt, it has been estimated at 1:3,000 live births. This may be due in part to an increase in disorders of androgen synthesis associated with 46,XX DSD. There is clearly a need for further studies to address the frequency of DSD in communities with high levels of consanguinity. This will be challenging, as an accurate diagnosis is difficult and expensive even in specialized centres. In developing countries with high levels of consanguinity, these limitations can be compounded by cultural, social and religious factors. Overall there is an indication that consanguinity may lead to an increase in incidences of both 46,XY and 46,XX DSD, and a co-ordinated study of populations with higher incidences of consanguinity/endogamy is needed to resolve this. © 2014 S. Karger AG, Basel. PMID:25060274

Bashamboo, Anu; McElreavey, Ken

2014-01-01

59

Identification of a novel ZNF469 mutation in a large family with Ehlers-Danlos phenotype  

Microsoft Academic Search

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

M. Al-Owain; M. S. Al-Dosari; A. Sunker; T. Shuaib; F. S. Alkuraya

2012-01-01

60

Large Constituent Families Help Children Parse Compounds  

ERIC Educational Resources Information Center

The family size of the constituents of compound words, or the number of compounds sharing the constituents, has been shown to affect adults' access to compound words in the mental lexicon. The present study was designed to see if family size would affect children's segmentation of compounds. Twenty-five English-speaking children between 3;7 and…

Krott, Andrea; Nicoladis, Elena

2005-01-01

61

Race, consanguinity and social features in Birmingham babies: a basis for prospective study.  

PubMed Central

STUDY OBJECTIVE--The aim of the study was to investigate the influence of consanguinity on children's health. DESIGN--The study is a prospective survey from birth to five years of a cohort of babies born in a multiracial community. This report details the initial findings on consanguinity. SETTING--Participating families live predominantly in three health districts of Birmingham, and were recruited in three local maternity hospitals. PARTICIPANTS--Babies of 2432 European mothers, 509 Afro-Caribbean mothers, 625 Indian mothers, 956 Pakistani mothers, and 216 Bangladeshi mothers have been enrolled in the study. Eighty mothers refused to participate. MEASUREMENTS AND RESULTS--Sociodemographic information was obtained using a structured questionnaire administered at interview. Interview data were supplemented with obstetric information from the medical records. The highest prevalence of parental consanguinity was in Pakistani Muslims (69%), whereas in Muslims from other countries it was 23%, and it was less than 1% in non-Muslims. In the majority of consanguineous Muslim pedigrees the degree of inbreeding was greater than that for first cousin parents. CONCLUSIONS--This prospective study will allow an assessment to be made about any ill health in childhood arising from parental consanguinity, about whether screening programmes are indicated for particular autosomal recessive diseases, and about whether premarital health education might be beneficial. The study has also documented parental ages in different races and this, together with the levels of parental consanguinity in all races, will be useful in genetic methods for assessing the frequency of recessive genes, the possibility of genetic heterogeneity, and whether or not parental age effect exists for new mutations of specific genetic disorders.

Bundey, S; Alam, H; Kaur, A; Mir, S; Lancashire, R J

1990-01-01

62

Family hierarchy and large neutrino mixings  

Microsoft Academic Search

The recent neutrino data seem to favor two large and one small mixing angles and a hierarchy of their squared mass differences. We discuss these within the context of hierarchical neutrino masses. We show that this scheme suggests a specific neutrino mass matrix with mild fine-tuning. We then present a Froggatt–Nielsen model that reproduces this matrix.

Fu-Sin Ling; Pierre Ramond

2002-01-01

63

Parental responses to consanguinity and genetic disease in Saudi Arabia.  

PubMed

In-depth interviews of 36 Saudi families whose children suffered from neuro-metabolic disorders were conducted at a specialist hospital in Riyadh in order to examine parental understanding of disease and attitudes towards future births and consanguineous marriages. Parents had difficulty accepting a genetic explanation for diseases that did not affect all children at the time of birth; they also expressed religious or folk beliefs to account for illness. Coping behaviours included denial and resignation to the situation, divorce and remarriage. Some families adopted a cautious approach to cousin marriages and future births; this was significantly related to their education level, but not to previous infant deaths. Awareness of medical facts brought little emotional comfort to parents but allowed for preventive measures through screening adult carriers and identifying affected infants. This study presents new material from Saudi Arabia to strengthen current awareness that the range of religious beliefs, social attitudes and reproductive behaviours adopted by families in a society undergoing rapid change is of direct relevance to health care. PMID:1776043

Panter-Brick, C

1991-01-01

64

Consanguinity and the Risk of Congenital Heart Disease  

PubMed Central

Consanguineous unions have been associated with an increased susceptibility to various forms of inherited disease. Although consanguinity is known to contribute to recessive diseases, the potential role of consanguinity in certain common birth defects is less clear, particularly since the disease pathophysiology may involve genetic and environmental/epigenetic factors. In this study we ask whether consanguinity affects one of the most common birth defects, congenital heart disease, and identify areas for further research into these birth defects, since consanguinity may now impact health on a near-global basis. A systematic review of consanguinity in congenital heart disease was performed, focusing on non-syndromic disease, with the methodologies and results from studies of different ethnic populations compared. The risks for congenital heart disease have been assessed and summarized collectively and by individual lesion. The majority of studies support the view that consanguinity increases the prevalence of congenital heart disease, however the study designs differed dramatically. Only a few (n = 3) population-based studies that controlled for potential sociodemographic confounding were identified, and data on individual cardiac lesions were limited by case numbers. Overall the results suggest that the risk for congenital heart disease is increased in consanguineous unions in the studied populations, principally at first cousin level and closer, a factor that should be considered in empiric risk estimates in genetic counseling. However, for more precise risk estimates a better understanding of the underlying disease factors is needed.

Shieh, Joseph T.C.; Bittles, Alan H.; Hudgins, Louanne

2012-01-01

65

Consanguineous marriages and endemic malaria: can inbreeding increase population fitness?  

Microsoft Academic Search

BACKGROUND: The practice of consanguineous marriages is widespread in countries with endemic malaria. In these regions, consanguinity increases the prevalence of ?+-thalassemia, which is protective against malaria. However, it also causes an excessive mortality amongst the offspring due to an increase in homozygosis of recessive lethal alleles. The aim of this study was to explore the overall effects of inbreeding

Srdjan Denic; Nicolas Nagelkerke; Mukesh M Agarwal

2008-01-01

66

A Novel Mutation in the Sodium\\/Iodide Symporter Gene in the Largest Family with Iodide Transport Defect  

Microsoft Academic Search

We previously reported nine children with an autosomally reces- sive form of congenital hypothyroidism due to an iodide transport defect in a large Hutterite family with extensive consanguinity living in central Canada. Since the original report, we have diagnosed con- genital hypothyroidism by newborn TSH screening in 9 additional children from the family. We performed direct sequencing of the PCR

SHINJI KOSUGI; SHELLY BHAYANA; HEATHER J. DEAN

2010-01-01

67

Little Brother Joins the Large Family  

NASA Astrophysics Data System (ADS)

On the night of 15 December 2006, the fourth and last-to-be-installed VLTI Auxiliary Telescope (AT4) obtained its 'First Light'. The first images demonstrate that AT4 will be able to deliver the excellent image quality already delivered by the first three ATs. It will soon join its siblings to perform routinely interferometric measurements. ESO PR Photo 51a/06 ESO PR Photo 51a/06 VLT Auxiliary Telescope The VLT is composed of four 8.2-m Unit Telescope (Antu, Kueyen, Melipal and Yepun). They have been progressively put into service together with a vast suite of the most advanced astronomical instruments and are operated every night in the year. Contrary to other large astronomical telescopes, the VLT was designed from the beginning with the use of interferometry as a major goal. The VLT Interferometer (VLTI) combines starlight captured by two or three 8.2- VLT Unit Telescopes, dramatically increasing the spatial resolution and showing fine details of a large variety of celestial objects. ESO PR Photo 51b/06 ESO PR Photo 51b/06 One AT Under the Sky However, most of the time the large telescopes are used for other research purposes. They are therefore only available for interferometric observations during a limited number of nights every year. Thus, in order to exploit the VLTI each night and to achieve the full potential of this unique setup, some other (smaller), dedicated telescopes were included into the overall VLT concept. These telescopes, known as the VLTI Auxiliary Telescopes (ATs), are mounted on tracks and can be placed at precisely defined "parking" observing positions on the observatory platform. From these positions, their light beams are fed into the same common focal point via a complex system of reflecting mirrors mounted in an underground system of tunnels. The Auxiliary Telescopes are real technological jewels. They are placed in ultra-compact enclosures, complete with all necessary electronics, an air conditioning system and cooling liquid for thermal control, compressed air for enclosure seals, a hydraulic plant for opening the dome shells, etc. Each AT is also fitted with a transporter that lifts the telescope and relocates it from one station to another. It moves around with its own housing on the top of Paranal, almost like a snail. The VLTI is arguably the world's most advanced optical device of this type. It has already demonstrated its powerful capabilities by addressing several key scientific issues, such as determining the size and the shape of a variety of stars (ESO PR 22/02, PR 14/03, PR 31/03, and PR 09/06), measuring distances to stars (ESO PR 25/04), probing the innermost regions of the proto-planetary discs around young stars (ESO PR 27/04 and PR 35/06) or making the first detection by infrared interferometry of an extragalactic object (ESO PR 17/03).

2006-12-01

68

Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases.  

PubMed

There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F >or= 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is approximately 3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates. PMID:19805052

Bittles, A H; Black, M L

2010-01-26

69

Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V).  

PubMed

Twenty-nine subjects (17 families) with cystic fibrosis belonging to the same Bedouin tribe were screened for cystic fibrosis transmembrane regulator gene mutations (CFTR). Homozygous I1234V mutation in exon 19 was identified in all families with a relatively high rate of consanguinity (96.6 per cent). The homozygous I1234V mutation tended to present with a variable degree of pulmonary disease, pancreatic insufficiency and electrolyte imbalance. Homozygous I1234V was found to be a common mutation in the studied Bedouin tribe in Qatar. PMID:11336127

Abdul Wahab, A; Al Thani, G; Dawod, S T; Kambouris, M; Al Hamed, M

2001-04-01

70

The impact of consanguinity on neonatal and infant health.  

PubMed

Marriage between biological relatives is widely popular in many parts of the world, with over 1000 million people living in countries where 20-50+% of unions are contracted between couples related as second cousins or closer. Consanguinity is, however, a controversial topic, in part due to public misunderstanding, complicated by often exaggerated past estimates of the adverse health outcomes. While some consanguineous couples are at high risk of conceiving a child with a genetic disorder, they are a small minority. Thus a multi-population meta-analysis has indicated an excess infant death rate of 1.1% in the progeny of first cousins, and even this figure may be compromised by inadequate control for non-genetic variables. The benefits as well as the disadvantages of consanguineous marriage are assessed and discussed, with specific consideration given to the health of migrant communities in Western countries, among whom first cousin marriage remains preferential. PMID:20832202

Bittles, A H; Black, M L

2010-11-01

71

Familial interstitial pulmonary fibrosis: A large family with atypical clinical features  

PubMed Central

A large kindred of familial pulmonary fibrosis is reported. Six members from the first two generations of this particular kindred were described more than 40 years previously; six more individuals from the third and fourth generations have also been evaluated. The proband, now 23 years of age, has mild disease; the other 11 documented affected family members all died from their disease at an average age of 37 years (range 25 to 50 years). The pathology was that of usual interstitial pneumonia, as is typical in idiopathic pulmonary fibrosis. However, the initial radiographic pattern in many of these individuals was upper lobe and nodular and, along with the young age, was atypical for idiopathic pulmonary fibrosis. Several genetic abnormalities have been associated with familial pulmonary fibrosis. The present study examined the genes coding for surfactant protein-C, ATP-binding cassette protein A3 and telomerase, and found no abnormalities.

Chibbar, Ranji; Gjevre, John A; Shih, Francis; Neufeld, Heather; Lemire, Edmond G; Fladeland, Derek A; Cockcroft, Donald W

2010-01-01

72

Oculocutaneous albinism and consanguineous marriage among Spanish Gitanos or Calé--a study of 83 cases.  

PubMed

This paper studies 83 cases of oculocutaneous albinism (OCA) in family networks of Gitanos in southeastern Spain, and analyzes their sustained inbreeding patterns and complex genealogical relationships. It is based in the family and genealogy reconstitution of the Gitano population of 22 contiguous localities using ethnographic and historical demography methods. The study found a prevalence of OCA among Gitanos in the area of about 1: 1,200. Most of the cases belong to three extended kin networks in which consanguineous marriages have been common for generations. In these networks there are other cases of visual and auditive congenital anomalies, and other birth defects such as brachydactily, polydactily, neurological defects, Potter Sequence, etc. In 61 OCA cases it was possible to trace inbreeding links with a depth of three to nine generations. For these cases the estimated alpha (average of the inbreeding coefficient, F) is 0.0222. Relationships between the parents of people affected are of three types: close, as between first or second cousins; distant, as between third or fourth cousins, and non-existent, as in mixed marriages. In most cases, however, persons with albinism are linked by multiple consanguineous links. Albinism seems to be a visible example of a high prevalence of birth defects in this minority, associated with founder effects, sustained inbreeding and high fertility rates. These conditions derive from Gitano's marriage preferences and pronatalist strategies. In turn, these strategies have to be related to the exclusion, persecution and segregation that Spanish Gypsies have suffered for centuries. PMID:24308209

Gamella, Juan F; Carrasco-Muñoz, Elisa Martín; Núñez Negrillo, Ana María

2013-09-01

73

Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees  

PubMed Central

The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We developed a web-based compound heterozygous filter that is suited for data from NGS projects and that is easy to use for non-bioinformaticians. We analyzed the power of compound heterozygous mutation filtering by deriving background distributions for healthy individuals from different ethnicities and studied the effectiveness in trios as well as more complex pedigree structures. While usually more then 30 genes harbor potential compound heterozygotes in single exomes, this number can be markedly reduced with every additional member of the pedigree that is included in the analysis. In a real data set with exomes of four family members, two sisters affected by Mabry syndrome and their healthy parents, the disease-causing gene PIGO, which harbors the pathogenic compound heterozygous variants, could be readily identified. Compound heterozygous filtering is an efficient means to reduce the number of candidate mutations in studies aiming at identifying recessive disease genes in non-consanguineous families. A web-server is provided to make this filtering strategy available at www.gene-talk.de.

Kamphans, Tom; Sabri, Peggy; Zhu, Na; Heinrich, Verena; Mundlos, Stefan; Robinson, Peter N.; Parkhomchuk, Dmitri; Krawitz, Peter M.

2013-01-01

74

Examining BCL-2 Family Function with Large Unilamellar Vesicles  

PubMed Central

The BCL-2 (B cell CLL/Lymphoma) family is comprised of approximately twenty proteins that collaborate to either maintain cell survival or initiate apoptosis1. Following cellular stress (e.g., DNA damage), the pro-apoptotic BCL-2 family effectors BAK (BCL-2 antagonistic killer 1) and/or BAX (BCL-2 associated X protein) become activated and compromise the integrity of the outer mitochondrial membrane (OMM), though the process referred to as mitochondrial outer membrane permeabilization (MOMP)1. After MOMP occurs, pro-apoptotic proteins (e.g., cytochrome c) gain access to the cytoplasm, promote caspase activation, and apoptosis rapidly ensues2. In order for BAK/BAX to induce MOMP, they require transient interactions with members of another pro-apoptotic subset of the BCL-2 family, the BCL-2 homology domain 3 (BH3)-only proteins, such as BID (BH3-interacting domain agonist)3-6. Anti-apoptotic BCL-2 family proteins (e.g., BCL-2 related gene, long isoform, BCL-xL; myeloid cell leukemia 1, MCL-1) regulate cellular survival by tightly controlling the interactions between BAK/BAX and the BH3-only proteins capable of directly inducing BAK/BAX activation7,8. In addition, anti-apoptotic BCL-2 protein availability is also dictated by sensitizer/de-repressor BH3-only proteins, such as BAD (BCL-2 antagonist of cell death) or PUMA (p53 upregulated modulator of apoptosis), which bind and inhibit anti-apoptotic members7,9. As most of the anti-apoptotic BCL-2 repertoire is localized to the OMM, the cellular decision to maintain survival or induce MOMP is dictated by multiple BCL-2 family interactions at this membrane. Large unilamellar vesicles (LUVs) are a biochemical model to explore relationships between BCL-2 family interactions and membrane permeabilization10. LUVs are comprised of defined lipids that are assembled in ratios identified in lipid composition studies from solvent extracted Xenopus mitochondria (46.5% phosphatidylcholine, 28.5% phosphatidylethanoloamine, 9% phosphatidylinositol, 9% phosphatidylserine, and 7% cardiolipin)10. This is a convenient model system to directly explore BCL-2 family function because the protein and lipid components are completely defined and tractable, which is not always the case with primary mitochondria. While cardiolipin is not usually this high throughout the OMM, this model does faithfully mimic the OMM to promote BCL-2 family function. Furthermore, a more recent modification of the above protocol allows for kinetic analyses of protein interactions and real-time measurements of membrane permeabilization, which is based on LUVs containing a polyanionic dye (ANTS: 8-aminonaphthalene-1,3,6-trisulfonic acid) and cationic quencher (DPX: p-xylene-bis-pyridinium bromide)11. As the LUVs permeabilize, ANTS and DPX diffuse apart, and a gain in fluorescence is detected. Here, commonly used recombinant BCL-2 family protein combinations and controls using the LUVs containing ANTS/DPX are described.

Asciolla, James J.; Renault, Thibaud T.; Chipuk, Jerry E.

2014-01-01

75

Examining BCL-2 family function with large unilamellar vesicles.  

PubMed

The BCL-2 (B cell CLL/Lymphoma) family is comprised of approximately twenty proteins that collaborate to either maintain cell survival or initiate apoptosis(1). Following cellular stress (e.g., DNA damage), the pro-apoptotic BCL-2 family effectors BAK (BCL-2 antagonistic killer 1) and/or BAX (BCL-2 associated X protein) become activated and compromise the integrity of the outer mitochondrial membrane (OMM), though the process referred to as mitochondrial outer membrane permeabilization (MOMP)(1). After MOMP occurs, pro-apoptotic proteins (e.g., cytochrome c) gain access to the cytoplasm, promote caspase activation, and apoptosis rapidly ensues(2). In order for BAK/BAX to induce MOMP, they require transient interactions with members of another pro-apoptotic subset of the BCL-2 family, the BCL-2 homology domain 3 (BH3)-only proteins, such as BID (BH3-interacting domain agonist)(3-6). Anti-apoptotic BCL-2 family proteins (e.g., BCL-2 related gene, long isoform, BCL-xL; myeloid cell leukemia 1, MCL-1) regulate cellular survival by tightly controlling the interactions between BAK/BAX and the BH3-only proteins capable of directly inducing BAK/BAX activation(7,8). In addition, anti-apoptotic BCL-2 protein availability is also dictated by sensitizer/de-repressor BH3-only proteins, such as BAD (BCL-2 antagonist of cell death) or PUMA (p53 upregulated modulator of apoptosis), which bind and inhibit anti-apoptotic members(7,9). As most of the anti-apoptotic BCL-2 repertoire is localized to the OMM, the cellular decision to maintain survival or induce MOMP is dictated by multiple BCL-2 family interactions at this membrane. Large unilamellar vesicles (LUVs) are a biochemical model to explore relationships between BCL-2 family interactions and membrane permeabilization(10). LUVs are comprised of defined lipids that are assembled in ratios identified in lipid composition studies from solvent extracted Xenopus mitochondria (46.5% phosphatidylcholine, 28.5% phosphatidylethanoloamine, 9% phosphatidylinositol, 9% phosphatidylserine, and 7% cardiolipin)(10). This is a convenient model system to directly explore BCL-2 family function because the protein and lipid components are completely defined and tractable, which is not always the case with primary mitochondria. While cardiolipin is not usually this high throughout the OMM, this model does faithfully mimic the OMM to promote BCL-2 family function. Furthermore, a more recent modification of the above protocol allows for kinetic analyses of protein interactions and real-time measurements of membrane permeabilization, which is based on LUVs containing a polyanionic dye (ANTS: 8-aminonaphthalene-1,3,6-trisulfonic acid) and cationic quencher (DPX: p-xylene-bis-pyridinium bromide)(11). As the LUVs permeabilize, ANTS and DPX diffuse apart, and a gain in fluorescence is detected. Here, commonly used recombinant BCL-2 family protein combinations and controls using the LUVs containing ANTS/DPX are described. PMID:23070252

Asciolla, James J; Renault, Thibaud T; Chipuk, Jerry E

2012-01-01

76

Identification of a novel ZNF469 mutation in a large family with Ehlers-Danlos phenotype.  

PubMed

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. PMID:23010198

Al-Owain, Mohammed; Al-Dosari, Mohammed S; Sunker, Asma; Shuaib, Taghreed; Alkuraya, Fowzan S

2012-12-15

77

Measuring Family Outcomes Early Intervention: Findings from a Large-Scale Assessment  

ERIC Educational Resources Information Center

This article reports data from a large-scale assessment using the Family Outcomes Survey with families participating in early intervention. The study was designed to determine how families describe themselves with regard to outcomes achieved, the extent to which outcomes are interrelated, and the extent to which child, family, and program factors…

Raspa, Melissa; Bailey, Donald B., Jr.; Olmsted, Murrey G.; Nelson, Robin; Robinson, Nyle; Simpson, Mary Ellen; Guillen, Chelsea; Houts, Renate

2010-01-01

78

A family of dynamic models for large-eddy simulation  

NASA Technical Reports Server (NTRS)

Since its first application, the dynamic procedure has been recognized as an effective means to compute rather than prescribe the unknown coefficients that appear in a subgrid-scale model for Large-Eddy Simulation (LES). The dynamic procedure is usually used to determine the nondimensional coefficient in the Smagorinsky (1963) model. In reality the procedure is quite general and it is not limited to the Smagorinsky model by any theoretical or practical constraints. The purpose of this note is to consider a generalized family of dynamic eddy viscosity models that do not necessarily rely on the local equilibrium assumption built into the Smagorinsky model. By invoking an inertial range assumption, it will be shown that the coefficients in the new models need not be nondimensional. This additional degree of freedom allows the use of models that are scaled on traditionally unknown quantities such as the dissipation rate. In certain cases, the dynamic models with dimensional coefficients are simpler to implement, and allow for a 30% reduction in the number of required filtering operations.

Carati, D.; Jansen, K.; Lund, T.

1995-01-01

79

Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population  

PubMed Central

Mucopolysaccharidosis type I (MPS I) was a group of rare autosomal recessive disorder caused by the deficiency of the lysosomal enzyme, alpha -L -iduronidase, and the resulting accumulation of undergraded dematan sulfate and heparan sulfate. MPS I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counseling and also impedes the selection and evaluation of patients undergoing therapy bone marrow transplantation. Aim of the study consanguinity rates have been determined among 14 families with mucopolysaccharidosis type I, seen in the pediatric departments of different geographic areas of Tunisia (Central and Southern areas) for the period August 2004 - August 2011 in order to investigate the relation between consanguinity and this disorder. Patients and methods Clinical and molecular analyses confirmed the diagnosis for MPS type I in the studied families. Results Most of the Tunisian MPS I patients have been identified at the homozygous status: p.P533R mutation (7 homozygous and one double heterozygous p.L578Q/p.P533R patients; 41.66% of all the investigated MPSI patients), p.F177S (1 homozygous patient; 5.55%), p.L530fs (1 patient; 5.55%), p.Y581X (2 patients; 11.11%), p.F602X (3 patients; 16.66%), p.R628X (1 patient; 5.55%). Another mutation: p.L578Q has been identified at the heterozygous status in the only double heterozygous p.L578Q/p.P533R case. Part of the mutations was the result of a founder effect. These described points are the consequences of the high rate of consanguinity. Conclusion The high frequency of p.P533R mutation could be explained by the high degree of inbreeding. This is due to the richness of the genetic background of the studied population. A multidisciplinary approach is essential to develop adequate preventive program adapted to the social, cultural, and economic context.

2011-01-01

80

Diagnosis of Bardet-Biedl Syndrome in Consecutive Pregnancies Affected with Echogenic Kidneys and Polydactyly in a Consanguineous Couple  

PubMed Central

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathic human genetic disorder with variable expression that is difficult to diagnose in pregnancy without known risk factors. Homozygosity testing has been shown to be a useful tool in identifying BBS mutations and candidate genes in affected individuals. We present the first case of prenatal diagnosis of BBS in consecutive pregnancies aided by homozygosity testing via SNP microarray analysis. This case demonstrates a novel approach to the evaluation of recurrent echogenic kidneys in consanguineous couple with no significant family history.

Baker, Tieneka M.; Sturm, Erica L.; Turner, Clesson E.; Petersen, Scott M.

2013-01-01

81

Papillon-Lefevre syndrome: Reporting consanguinity as a risk factor  

PubMed Central

Papillon–Lefevre syndrome (PLS) is an autosomal recessive genetic disorder characterized by palmoplantar hyperkeratosis associated with severe early-onset periodontitis and premature loss of primary and permanent teeth. This report describes two cases of PLS in 28-year-old female and 16-year-old male siblings with consanguineously married parents. The patients presented to the Department of Public Health Dentistry of a dental education and research institute in India with thickening, flaking, and scaling of the skin on the palms and soles of the feet. On oral examination, the female patient presented completely resorbed maxillary and mandibular alveolar ridges with retention of only the third molars. The male patient retained only teeth 18, 13, 28, 38, and 45. Based on complete histories and clinical examination findings, a final diagnosis of PLS was made and treatment was initiated using an interdisciplinary dental approach in both cases.

Shah, Aasim Farooq; Tangade, Pradeep; Agarwal, Swatantra

2014-01-01

82

Genomic Runs of Homozygosity Record Population History and Consanguinity  

PubMed Central

The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (Ne), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental Ne (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.

Kirin, Mirna; McQuillan, Ruth; Franklin, Christopher S.; Campbell, Harry; McKeigue, Paul M.; Wilson, James F.

2010-01-01

83

Effects of consanguineous marriages on fertility among three endogamous groups of Andhra Pradesh.  

PubMed

To assess interrelationships between consanguineous marriage and fertility, 3 caste groups in Andhra Pradesh--the Desuri Kapu, an affluent agricultural caste; the Devanga, an artisan caste in the middle range of the hierarchy; and the Mala, a scheduled caste at the bottom--were selected for field study. Consanguineous marriages are an essential part of the social structure in this area of southern India. A total of 2524 marriages were analyzed, of which 46% were consanguineous. 19% of consanguineous marriages were between uncle and niece, 22% were between 1st cousins, and 5% were between more distant cousins. The Devanga had the highest rate of related marriages (48%), followed by the Desuri Kapu (47%) and the Mala (41%). Higher caste individuals, and wealthier persons within each caste, are more likely to marry relatives so they can avoid splitting their properties through dowry of bride price. The consanguineous unions as a whole were significantly more fertile than nonconsanguineous unions. The mean number of pregnancies, live births, and surviving offspring was 4.85, 4.44, and 2.99, respectively, among consanguineous couples compared with 3.41, 3.32, and 2.87, respectively, among nonconsanguineous couples. Although the number of pregnancies and live births was significantly higher among consanguineous couples in all 3 castes compared with nonconsanguineous couples, the difference in the number of surviving children between consanguineous and nonconsanguineous unions was not significant among the wealthier castes. This suggests that child mortality is higher among the offspring of consanguineous unions, despite their greater wealth. PMID:3686072

Reddy, P G

1987-01-01

84

Conserved water molecules in a large family of microbial ribonucleases.  

PubMed

We systematically analyzed the crystallographically determined water molecules of all known structures of RNase T1 and compared them to the ordered solvent in a large number of related microbial nucleases. To assess the crystallographers' impact on the interpretation of the solvent structure, we independently refined five validation structures from diffraction data derived from five isomorphous crystals of RNase T1. We also compared the positions of water molecules found in 11 published isomorphous RNase T1 inhibitor complexes. These data suggest that the positions of most of the waters located on the surface of a protein and that are well-determined in the experimental electron density maps are determined primarily by crystal packing forces. Water molecules with less well-defined electron density are in general unique to one or a small number of crystal structures. Only a small number of the well-defined waters are found to be independent of the crystal environment. These waters have a low accessible surface area and B-factor, and tend to be conserved in the crystal structures of a number of evolutionary related ribonucleases as well. A single water molecule is found conserved in all known microbial ribonucleases. PMID:10373011

Loris, R; Langhorst, U; De Vos, S; Decanniere, K; Bouckaert, J; Maes, D; Transue, T R; Steyaert, J

1999-07-01

85

An efficient algorithm for large-scale detection of protein families.  

PubMed

Detection of protein families in large databases is one of the principal research objectives in structural and functional genomics. Protein family classification can significantly contribute to the delineation of functional diversity of homologous proteins, the prediction of function based on domain architecture or the presence of sequence motifs as well as comparative genomics, providing valuable evolutionary insights. We present a novel approach called TRIBE-MCL for rapid and accurate clustering of protein sequences into families. The method relies on the Markov cluster (MCL) algorithm for the assignment of proteins into families based on precomputed sequence similarity information. This novel approach does not suffer from the problems that normally hinder other protein sequence clustering algorithms, such as the presence of multi-domain proteins, promiscuous domains and fragmented proteins. The method has been rigorously tested and validated on a number of very large databases, including SwissProt, InterPro, SCOP and the draft human genome. Our results indicate that the method is ideally suited to the rapid and accurate detection of protein families on a large scale. The method has been used to detect and categorise protein families within the draft human genome and the resulting families have been used to annotate a large proportion of human proteins. PMID:11917018

Enright, A J; Van Dongen, S; Ouzounis, C A

2002-04-01

86

Association of cerebral palsy with consanguineous parents and other risk factors in a Palestinian population.  

PubMed

This case-control study investigated risk factors for cerebral palsy in a Palestinian population. Cases were 107 children aged 1-15 years at a cerebral palsy referral centre in Jerusalem; controls were 233 children without cerebral palsy from West Bank outpatient clinics. Data were collected from medical records and a structured questionnaire to parents. In stepwise logistical regression, consanguinity and birth deficits in other family members were positively associated with cerebral palsy (OR = 4.62; 95% CI: 2.07-10.3 and OR = 12.7; 95% CI: 3.13-51.7 respectively), suggesting a possible genetic link. Other risk factors were: perinatal hypoxia (OR = 92.5; 95% CI: 24.5-350), low birth weight (OR = 4.98; 95% CI: 2.01-12.3), twin births (OR = 9.25; 95% CI: 1.29-66.8) and no prenatal medical care (OR = 5.22; 95% CI: 1.18-23.1). This first stepwise model of significant and modifiable risk factors in our population provides useful evidence for policy-makers. PMID:25023773

Daher, S; El-Khairy, L

2014-01-01

87

Consanguineous marriage in PR China: a study in rural Man (Manchu) communities.  

PubMed

Although there is a long history of consanguineous marriage in China, information on its prevalence is very limited. The Man (Qing) dynasty ruled China for over 250 years, but no consanguinity studies have been reported on this important population. The objective of the present investigation was to determine the present-day level of consanguineous marriage in the Man community, and to compare the data with existing consanguinity information on other Chinese populations. The study was conducted in a group of 11 rural Man communities in the north-eastern Chinese province of Liaoning. Household-based interviews were conducted by local staff on 513 couples, 418 of whom were Man with another 95 Man-Han inter-ethnic marriages. Basic pedigrees were constructed to determine the biological relationship between each set of spouses. Thirty of the 418 couples were in a consanguineous union, with a mean coefficient of inbreeding alpha = 0.0012. The small population sizes of the study may have contributed to the spatial variation in the patterns of inbreeding. Across generations there was a reduction in consanguineous marriages and an increase in inter-ethnic unions, which paralleled changes in civil marriage regulations. PMID:12573085

Wang, W; Qian, Cong; Bittles, A H

2002-01-01

88

Consanguinity in Qatar: knowledge, attitude and practice in a population born between 1946 and 1991.  

PubMed

From March 2007 to March 2008 a cross-sectional study was conducted in Qatar to estimate the prevalence of consanguinity among Qataris and to assess their knowledge of the risks and their attitudes towards the practice. A secondary objective was to test the acceptability of sixteen Likert-style questions within the Qatari population. Face-to-face interviews using a 70-item structured questionnaire were conducted by three native Arabic-speaking medical students with 362 Qatari employees. Where consanguinity existed between the employee's parents, a diagram of the consanguinal relationship (phylogram) was completed. The response rate was 93%. By phylogram, 22% of participants reported a cousin relationship between their parents (consanguinal relationship) and another 15% reported that their parents were from the same tribe (affinal relationship). With respect to their own marital decision, 68% of the respondents had been married at least once. By phylogram, 35% of these reported a consanguineous relationship (first marriage), 9% reported only an affinal relationship and 56% reported that they were not married to a blood relative. Results on the sixteen Likert-style attitude questions were stratified by consanguinity status of parents and of self. In the stratification by consanguinity status of parents the top five attitudes differed by group but there appeared to be more similarity between the consanguinal and only tribal groups. Attitudinal results were stratified by sex. Results showed that the males had a stronger belief in several of the attitudes than females with the exception of causation of genetic abnormalities and health problems. The phylogram was shown to collect more detailed and explicit data than hard-coding. With respect to knowledge, the results showed that knowledge was imperfect with high proportions of participants not knowing that consanguinity has been implicated in autosomal recessive diseases such as thalassaemia, inborn errors of metabolism, deafness, anomalies of the extremities and specific congenital heart defects. Additionally, a sizeable proportion of the participants did not know that a more distant cousin marriage (e.g. third cousin) theoretically could be a less genetically risky choice to potential offspring than a closer cousin marriage (half-first cousin). These results indicate that more effort needs to be made in developing public health strategies to improve the population's understanding of the cost-benefit analysis involved in contracting consanguineous marriages given the goal of healthy offspring. PMID:19895726

Sandridge, A L; Takeddin, J; Al-Kaabi, E; Frances, Y

2010-01-01

89

The fragile X syndrome in a large family. II. Psychological investigations  

Microsoft Academic Search

Intelligence levels and intelligence profiles were investigated in 52 members of a large family with the fragile X syndrome. The mental abilities were evaluated by the three Wechsler intelligence tests (WAIS, WISC-R, and WPPSI). Chromosomal and psychological data were then compared. In 22 non-retarded fra(X) negative family members, a mean IQ of 102 was found (males 97, females 106). Eleven

H Veenema; T Veenema; J P Geraedts

1987-01-01

90

Segregation Analysis of A Large t(21q22q) Family  

PubMed Central

A large family in which a t(21q22q) chromosome is segregating is described. Segregation analysis using data from this family and previously published families shows the risk to a female carrier of having a child with translocation Down's syndrome to be 0·0684±0·0270. The risk to a male carrier is probably much smaller with an upper limit of 0·0286. The segregation ratio for phenotypically normal offspring of carrier parents of both sexes is 0·5053±0·0524.

Chapman, C. J.; Gardner, R. J. M.; Veale, A. M. O.

1973-01-01

91

The roles of segmental and tandem gene duplication in the evolution of large gene families in Arabidopsis thaliana  

Microsoft Academic Search

BACKGROUND: Most genes in Arabidopsis thaliana are members of gene families. How do the members of gene families arise, and how are gene family copy numbers maintained? Some gene families may evolve primarily through tandem duplication and high rates of birth and death in clusters, and others through infrequent polyploidy or large-scale segmental duplications and subsequent losses. RESULTS: Our approach

Steven B Cannon; Arvind Mitra; Andrew Baumgarten; Nevin D Young; Georgiana May

2004-01-01

92

X-linked lymphoproliferative syndrome. Identification of a large family in Switzerland.  

PubMed

Observation of a patient with acquired hypogammaglobulinemia associated with a mononucleosis syndrome led to the identification of one of the largest families affected by the X-linked lymphoproliferative (XLP) syndrome in the world. It is the first such family identified in Switzerland and the largest in Europe. At least nine male subjects over two generations presented phenotypic expressions consistent with the XLP syndrome. Study of the pedigree extending over seven generations suggests that the mutation occurred in the proband's great-grandmother. In the next generation, a second mutation of the X chromosome in one branch of the family resulted in expression of hemophilia A in the children. This remarkably large family, comprising six living obligate female carriers, displays a wide spectrum of the XLP syndrome and offers valuable information for future genetic linkage studies and for genetic counseling. PMID:3348254

Hayoz, D; Lenoir, G M; Nicole, A; Pugin, P; Regamey, C

1988-03-01

93

Challenges in the care for consanguineous couples: an exploratory interview study among general practitioners and midwives  

PubMed Central

Background It is often suggested that an effort must be made to increase awareness among consanguineous couples of their reproductive risk, and to refer them for genetic counseling if needed. Primary care professionals are considered most appropriate for addressing the subject and identifying couples at risk during consultations in their practice. This Dutch study aims to explore the experiences, attitudes and beliefs of such professionals regarding their care for consanguineous couples. Methods Sixteen semi-structured interviews were conducted with midwives and general practitioners. Results Although most primary care professionals considered it their task to inform couples about the risks of consanguinity, during consultations the topic was generally only briefly touched upon and quickly abandoned. Important reasons for this were professionals’ beliefs about religious and social values of couples, their low perception of the couples’ reproductive risk and expected limited feasibility of referral. Feelings of embarrassment regarding addressing consanguinity did not seem to play a significant role. Conclusions Primary care professional beliefs about their clients’ religious and social values, their attitudes toward the risk, and perceived limited options for referral seem to conflict with the professional norm to address the topic of consanguinity.

2012-01-01

94

Polar Localization of the Autotransporter Family of Large Bacterial Virulence Proteins  

Microsoft Academic Search

Autotransporters are an extensive family of large secreted virulence-associated proteins of gram-negative bacteria. Secretion of such large proteins poses unique challenges to bacteria. We demonstrate that autotrans- porters from a wide variety of rod-shaped pathogens, including IcsA and SepA of Shigella flexneri, AIDA-I of diffusely adherent Escherichia coli, and BrkA of Bordetella pertussis, are localized to the bacterial pole. The

Sumita Jain; Peter van Ulsen; Inga Benz; M. Alexander Schmidt; Rachel Fernandez; Jan Tommassen; Marcia B. Goldberg

2006-01-01

95

Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1  

Microsoft Academic Search

Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBN1, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span;

M. J. Edwards; J. Roberts; M. W. Partington; P. W. Colley; G. E. Hollway; H. M. Kozman; J. C. Mulley

1994-01-01

96

A Large Family with Spinocerebellar Ataxia Type 6 in Iran: A Clinical and Genetic Study  

Microsoft Academic Search

The authors describe a large Iranian family with autosomal dominant cerebellar ataxia, which included 14 patients in four generations. We examined seven patients who had expanded CAG repeats in the CACNA1A gene with repeat instability (24 and 25 repeats). Although all patients showed cerebellar ataxia, each patient exhibited peripheral neuropathy or spasticity indicating intrafamilial phenotypic variability.

Haruo Shimazaki; Reza Vazifehmand; Mohhamad-Hassan Heidari; Hamid-Reza Khorram-Khorshid; Sassan Saber; Fatemeh Aghakhani-Moghadam; Yi Ouyang; Junko Honda; Imaharu Nakano; Yoshihisa Takiyama

97

Familial Occurrence of Letterer-Siwe Disease  

PubMed Central

Letterer-Siwe disease occurred in 4 infant sibs from two consanguineous families. An identical clinical course and pathological picture was observed in all 4 infants. The occurrence of families with multiple cases supports the hypothesis of genetic causation in Letterer-Siwe disease. The family patterns are in accord with an autosomal recessive inheritance.

Freundlich, Emil; Amit, Sarah; Montag, Yohan; Suprun, Harry; Nevo, Sarah

1972-01-01

98

An empirical analysis of the effects of consanguineous marriages on economic development.  

PubMed

In this study, development experiences toward economic development are investigated to provide an alternative analysis of economic development, human capital, and genetic inheritance in the light of consanguineous marriages. The countries analyzed in the study are discussed in accordance with consanguineous marriage practices and classified by their per capita gross domestic product (GDP) growth. A broad range of countries are analyzed in the study. Arab countries that experienced high rates of growth in their gross national income during the twentieth century but failed to fulfill adequate development measures as reflected in the growth in national income, countries undergoing transition from tight government regulation to free market democracy, and African nations that have experienced complications in the process of development show important differences in the process of economic development. It is shown that the countries that have reached high average development within the context of per capita GDP have overcome problems integral to consanguineous marriage. PMID:21105495

Bildirici, Melike; Kökdener, Meltem; Ersin, Oezgür ömer

2010-01-01

99

Common Origin of Four Diverse Families of Large Eukaryotic DNA Viruses  

PubMed Central

Comparative analysis of the protein sequences encoded in the genomes of three families of large DNA viruses that replicate, completely or partly, in the cytoplasm of eukaryotic cells (poxviruses, asfarviruses, and iridoviruses) and phycodnaviruses that replicate in the nucleus reveals 9 genes that are shared by all of these viruses and 22 more genes that are present in at least three of the four compared viral families. Although orthologous proteins from different viral families typically show weak sequence similarity, because of which some of them have not been identified previously, at least five of the conserved genes appear to be synapomorphies (shared derived characters) that unite these four viral families, to the exclusion of all other known viruses and cellular life forms. Cladistic analysis with the genes shared by at least two viral families as evolutionary characters supports the monophyly of poxviruses, asfarviruses, iridoviruses, and phycodnaviruses. The results of genome comparison allow a tentative reconstruction of the ancestral viral genome and suggest that the common ancestor of all of these viral families was a nucleocytoplasmic virus with an icosahedral capsid, which encoded complex systems for DNA replication and transcription, a redox protein involved in disulfide bond formation in virion membrane proteins, and probably inhibitors of apoptosis. The conservation of the disulfide-oxidoreductase, a major capsid protein, and two virion membrane proteins indicates that the odd-shaped virions of poxviruses have evolved from the more common icosahedral virion seen in asfarviruses, iridoviruses, and phycodnaviruses.

Iyer, Lakshminarayan M.; Aravind, L.; Koonin, Eugene V.

2001-01-01

100

Identification of a novel FBN1 gene mutation in a large Pakistani family with Marfan syndrome  

PubMed Central

Purpose To describe a novel mutation in the fibrillin-1 (FBN1) gene in a large Pakistani family with autosomal dominant Marfan syndrome (MFS). Methods Blood samples were collected of 11 family members affected with Marfan syndrome, and DNA was isolated by phenol-extraction. The coding exons of FBN1 were analyzed by polymerase chain reaction (PCR) and direct sequencing. One hundred-thirty controls were screened for a mutation in the FBN1 gene that was identified in this family by restriction fragment length polymorphism (RFLP) analysis. Results A novel heterozygous missense mutation c.2368T>A; p.Cys790Ser was observed in exon 19. This mutation substitutes a highly conserved cysteine residue by serine in a calcium binding epidermal growth factor-like domain (cbEGF) of FBN1. This mutation was present in all affected members and absent from unaffected individuals of the family in addition to 130 healthy Pakistani controls. Interestingly all affected family members presented with ectopia lentis, myopia and glaucoma, but lacked the cardinal cardiovascular features of MFS. Conclusions This is a first report of a mutation in FBN1 in MFS patients of Pakistani origin. The identification of a FBN1 mutation in this family confirms the diagnosis of MFS patients and expands the worldwide spectrum of FBN1 mutations.

Micheal, Shazia; Khan, Muhammad Imran; Akhtar, Farah; Weiss, Marjan M.; Islam, Farah; Ali, Mehmood; Qamar, Raheel; Maugeri, Alessandra

2012-01-01

101

Genetic heterogeneity in psoriasis vulgaris based on linkage analyses of a large family material  

SciTech Connect

Information on psoriasis among parents and siblings in 14,008 families has been collected. On the basis of this material, evidence for monogenetic autosomal recessive inheritance of psoriasis has recently been presented. Indications from more than one type of non-pustular psoriasis has been obtained from the population genetic data. Molecular genetic linkage analysis of psoriasis to a number of polymorphic genetic markers for a large number of families has been made. It is apparent that there is genetic heterogeneity in a psoriasis population with regard to psoriasis genes. Using the computer program Linkage 5.0 and a formula for heterogeneity, a lodscore over 3.0 for one locus has been obtained. This locus has further been confirmed by several other markers in the vicinity. The locus found is linked to slightly over half of the families, indicating that there are more genetically independent types of psoriasis. The age at onset of those families that are apparently linked to this locus have a slightly higher age at onset than those not linked to that locus but with a considerable overlap. In spite of close coverage of the whole chromosomes number 6 and 17, no linkage has been found in this regions. This indicates that neither the HLA region nor the region earlier found to be involved in one family with psoriasis are primarily involved in our families.

Wahlstroem, J.; Swanbeck, G.; Inerot, A. [ Univ. of Goeteborg (Sweden)] [and others

1994-09-01

102

Large family with both parents affected by distinct BRCA1 mutations: implications for genetic testing  

PubMed Central

Although the probability of both parents being affected by BRCA1 mutations is not negligible, such families have not been systematically described in the literature. Here we present a large breast-ovarian cancer family, where 3 sisters and 1 half-sister inherited maternal BRCA1 5382insC mutation while the remaining 2 sisters carried paternal BRCA1 1629delC allele. No BRCA1 homozygous mutations has been detected, that is consistent with the data on lethality of BRCA1 knockout mice. This report exemplifies that the identification of a single cancer-predisposing mutation within the index patient may not be sufficient in some circumstances. Ideally, all family members affected by breast or ovarian tumor disease have to be subjected to the DNA testing, and failure to detect the mutation in any of them calls for the search of the second cancer-associated allele.

Sokolenko, Anna P; Voskresenskiy, Dmitry A; Iyevleva, Aglaya G; Bit-Sava, Elena M; Gutkina, Nadezhda I; Anisimenko, Maxim S; Yu Sherina, Nathalia; Mitiushkina, Nathalia V; Ulibina, Yulia M; Yatsuk, Olga S; Zaitseva, Olga A; Suspitsin, Evgeny N; Togo, Alexandr V; Pospelov, Valery A; Kovalenko, Sergey P; Semiglazov, Vladimir F; Imyanitov, Evgeny N

2009-01-01

103

Deletion of the TWIST gene in a large five-generation family.  

PubMed

In this article, we describe a large five-generation family with characteristics of the Saethre-Chotzen syndrome as well as of the blepharophimosis ptosis epicanthus inversus syndrome. Segregating with their phenotype is a deletion of the chromosome 7p21 TWIST gene locus. The TWIST gene indeed is involved in Saethre-Chotzen syndrome, a craniosynostosis syndrome further characterized by specific facial and limb abnormalities. However, only two members of our family exhibited craniosynostosis. This report demonstrates that the genetics of craniofacial anomalies are less straightforward than they sometimes appear to be. Not only craniosynostosis, but also subtle facial deformities could be indicative of an abnormality of the TWIST gene. In conclusion, the clinical spectrum of genetic abnormalities of the TWIST gene is highly variable. We therefore recommend that genetic analysis of the TWIST gene locus, including fluorescence in situ hybridization, should be considered in familial cases of facial and eyelid abnormalities without the presence of craniosynostosis. PMID:15099347

De Heer, I M; Hoogeboom, A J M; Eussen, H J; Vaandrager, J M; De Klein, A

2004-05-01

104

Large French-Canadian family with Lewy body parkinsonism: exclusion of known loci.  

PubMed

The identification of rare, large families with Parkinson's disease (PD) has provided important clues that have contributed to our understanding of this complex disorder. We have identified a large French-Canadian kindred that spans five generations consisting of more than 90 individuals. A total of 65 individuals now have been examined, had venous blood drawn, and DNA extracted. Two-point and multipoint linkage analysis was performed to assess linkage to known PD genes or loci. Within the third and fourth generations of this family there are 10 living, plus 3 deceased members with well-documented levodopa responsive parkinsonism. Autopsy results on 1 member demonstrated the loss of pigmented neurons in the substantia nigra and the presence of alpha-synuclein positive Lewy bodies. Four of the PD patients have prominent postural and kinetic tremors that preceded their parkinsonism by up to 10 years. Two other individuals within the family have prominent isolated postural and kinetic tremors without parkinsonism. The alpha-synuclein(4q21.3-23), Parkin(6q25.2-27), PARK3 (2p13), PARK4, and ubiquitin carboxy terminal hydrolase-L1 (4p14-16.3) and PARK6 and PARK7 (1p35-36) loci were excluded in this kindred using closely linked markers. The clinical and pathological features of this family are consistent with the diagnosis of PD. This family further demonstrates the known genetic heterogeneity in PD and is large enough that a genome-wide screen has been undertaken in an effort to identify a novel PD gene. PMID:12465058

Grimes, David A; Grimes, J David; Racacho, Lem; Scoggan, Kylie A; Han, Fabin; Schwarz, Betty Anne; Woulfe, John; Bulman, Dennise

2002-11-01

105

Family history of various cancers and pancreatic cancer mortality in a large cohort.  

PubMed

A family history of pancreatic cancer is associated with increased risk of pancreatic cancer, but uncertainty remains about the magnitude of this association, whether it varies by age or smoking and whether a family history of other cancers may also be associated with increased risk. We examined family history of 14 cancers and pancreatic cancer mortality among ~1.1 million men and women in Cancer Prevention Study-II (CPS-II). CPS-II participants completed a questionnaire at enrollment in 1982. During follow-up through 2006, there were 7,306 pancreatic cancer deaths. A family history of pancreatic cancer in a parent or sibling was associated with pancreatic cancer mortality [multivariable adjusted rate ratio (RR) = 1.66, 95% confidence interval (CI) 1.43-1.94]. This association was stronger among participants aged under 60 (RR = 2.89, 95% CI 1.67-5.02) than among participants aged 60 or older (RR = 1.61, 95% CI 1.37-1.88). Weaker associations were observed for family history of stomach cancer (RR = 1.23, 95% CI 1.11-1.37), liver cancer (RR = 1.25, 95% CI 1.10-1.43), and colorectal cancer (RR = 1.12, 95% CI 1.01-1.23). Results from this large prospective study indicate family history of pancreatic cancer is associated with a moderate increase in risk of pancreatic cancer, and also identify associations with the family history of certain other cancers which may be useful in generating hypotheses about shared risk factors. PMID:19396555

Jacobs, Eric J; Rodriguez, Carmen; Newton, Christina C; Bain, Elizabeth B; Patel, Alpa V; Feigelson, Heather Spencer; Thun, Michael J; Calle, Eugenia E

2009-10-01

106

Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1  

SciTech Connect

Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBN1, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uninformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible. 25 refs., 6 figs., 2 tabs.

Edwards, M.J.; Roberts, J.; Partington, M.W. [Newcastle and Northern New South Wales Genetics Service (Australia); Colley, P.W. [John Hunter Hospital, Newcastle (Australia); Hollway, G.E.; Kozman, H.M.; Mulley, J.C. [Adelaide Children`s Hospital, North Adelaide (Australia)

1994-10-15

107

Consanguinity: a risk factor for preterm birth at less than 33 weeks' gestation.  

PubMed

Consanguinity promotes homozygosity of recessive susceptibility gene variants and can be used to investigate a recessive component in diseases whose inheritance is uncertain. The objective of this study was to assess the association between consanguinity and preterm birth (PTB), stratified by gestational age and clinical presentation (spontaneous vs. medically indicated). Data were collected on 39,745 singleton livebirths without major birth defects, admitted to 19 hospitals in Lebanon, from September 2003 to December 2007. Deliveries before completed 33 weeks' gestation and deliveries at 33-36 weeks' gestation were compared, with respect to cousin marriage, with those after completed 36 weeks' gestation by using multinomial multiple logistic regression. Overall, infants of consanguineous parents had a statistically significant 1.6-fold net increased risk of being born at less than 33 weeks' gestation compared with infants of unrelated parents. This association was statistically significant only with spontaneous PTB. There was no increased risk of being born at 33-36 weeks' gestation associated with consanguinity for both clinical presentations of PTB. Our findings support a genetic contribution to early onset PTB and suggest that early PTB should be targeted in future genetic studies rather than the classic lumping of all births less than 37 weeks' gestation. PMID:20978088

Mumtaz, Ghina; Nassar, Anwar H; Mahfoud, Ziyad; El-Khamra, Akaber; Al-Choueiri, Nathalie; Adra, Abdallah; Murray, Jeffrey C; Zalloua, Pierre; Yunis, Khalid A

2010-12-15

108

Molecular mechanism of angelman syndrome in two large families involves an imprinting mutation.  

PubMed Central

Patients with Angelman syndrome (AS) and Prader-Willi syndrome with mutations in the imprinting process have biparental inheritance but uniparental DNA methylation and gene expression throughout band 15q11-q13. In several of these patients, microdeletions upstream of the SNRPN gene have been identified, defining an imprinting center (IC) that has been hypothesized to control the imprint switch process in the female and male germlines. We have now identified two large families (AS-O and AS-F) segregating an AS imprinting mutation, including one family originally described in the first genetic linkage of AS to 15q11-q13. This demonstrates that this original linkage is for the 15q11-q13 IC. Affected patients in the AS families have either a 5.5- or a 15-kb microdeletion, one of which narrowed the shortest region of deletion overlap to 1.15 kb in all eight cases. This small region defines a component of the IC involved in AS (ie., the paternal-to-maternal switch element). The presence of an inherited imprinting mutation in multiple unaffected members of these two families, who are at risk for transmitting the mutation to affected children or children of their daughters, raises important genetic counseling issues.

Ohta, T; Buiting, K; Kokkonen, H; McCandless, S; Heeger, S; Leisti, H; Driscoll, D J; Cassidy, S B; Horsthemke, B; Nicholls, R D

1999-01-01

109

Towards identification of an epilepsy gene in a large family with idiopathic generalized epilepsy  

SciTech Connect

To identify the disease gene in a large, multiplex family segregating an autosomal dominant form of idiopathic generalized epilepsy (IGE). The IGEs have been recognized for several decades as being genetically determined. However, large pedigrees with a clear Mendelian inheritance are not commonly available. This, and the presence of locus heterogeneity have been obstacles to the identification of linkage in several IGE syndromes. We have identified a large IGE kindred with fifty-eight living individuals, including 26 affecteds, showing a clear autosomal dominant inheritance with incomplete penetrance. Forty-fur informative individuals, including 23 affecteds, were selected for the linkage studies. We have chosen 200 polymorphic microsatellite markers, about 20 cM apart, throughout the human autosomes as a genome-search linkage strategy. To date, 47 markers, representing 30% of the human genome, have been excluded for linkage in the Australian kindred. As our study progresses, we will report up-to-date results.

Roussear, M.; Lopes-Cendes, I. [Montreal General Hospital, Quebec (Canada); Berkovic, S.F. [Austin Hospital, Melbourne (Australia)] [and others

1994-09-01

110

Frequent detection of parental consanguinity in children with developmental disorders by a combined CGH and SNP microarray  

PubMed Central

Background Genomic microarrays have been used as the first-tier cytogenetic diagnostic test for patients with developmental delay/intellectual disability, autism spectrum disorders and/or multiple congenital anomalies. The use of SNP arrays has revealed regions of homozygosity in the genome which can lead to identification of uniparental disomy and parental consanguinity in addition to copy number variations. Consanguinity is associated with an increased risk of birth defects and autosomal recessive disorders. However, the frequency of parental consanguinity in children with developmental disabilities is unknown, and consanguineous couples may not be identified during doctor’s visit or genetic counseling without microarray. Results We studied 607 proband pediatric patients referred for developmental disorders using a 4?×?180 K array containing both CGH and SNP probes. Using 720, 360, 180, and 90 Mb as the expected sizes of homozygosity for an estimated coefficient of inbreeding (F) 1/4, 1/8, 1/16, 1/32, parental consanguinity was detected in 21cases (3.46%). Conclusion Parental consanguinity is not uncommon in children with developmental problems in our study population, and can be identified by use of a combined CGH and SNP chromosome microarray. Identification of parental consanguinity in such cases can be important for further diagnostic testing.

2013-01-01

111

No association of candidate genes with cannabis use in a large sample of Australian twin families  

PubMed Central

While there is solid evidence that cannabis use is heritable, attempts to identify genetic influences at the molecular level have yielded mixed results. Here, a large twin family sample (N=7452) was used to test for association between ten previously reported candidate genes and lifetime frequency of cannabis use using a gene-based association test. None of the candidate genes reached even nominal significance (p<.05). The lack of replication may point to our limited understanding of the neurobiology of cannabis involvement and also to potential publication bias and false-positive findings in previous studies.

Verweij, Karin J.H.; Zietsch, Brendan P.; Liu, Jimmy Z.; Medland, Sarah E.; Lynskey, Michael T.; Madden, Pamela A.F.; Agrawal, Arpana; Montgomary, Grant W.; Heath, Andrew C.; Martin, Nicholas G.

2012-01-01

112

No association of candidate genes with cannabis use in a large sample of Australian twin families.  

PubMed

While there is solid evidence that cannabis use is heritable, attempts to identify genetic influences at the molecular level have yielded mixed results. Here, a large twin family sample (n = 7452) was used to test for association between 10 previously reported candidate genes and lifetime frequency of cannabis use using a gene-based association test. None of the candidate genes reached even nominal significance (P < 0.05). The lack of replication may point to our limited understanding of the neurobiology of cannabis involvement and also to potential publication bias and false-positive findings in previous studies. PMID:21507154

Verweij, Karin J H; Zietsch, Brendan P; Liu, Jimmy Z; Medland, Sarah E; Lynskey, Michael T; Madden, Pamela A F; Agrawal, Arpana; Montgomery, Grant W; Heath, Andrew C; Martin, Nicholas G

2012-05-01

113

Autosomal dominant brachyolmia in a large Swedish family: Phenotypic spectrum and natural course.  

PubMed

Autosomal dominant brachyolmia (Type 3, OMIM #113500) belongs to a group of skeletal dysplasias caused by mutations in the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) gene, encoding a Ca(++) -permeable, non-selective cation channel. The disorder is characterized by disproportionate short stature with short trunk, scoliosis and platyspondyly. The phenotypic variability and long-term natural course remain inadequately characterized. The purpose of this study was to describe a large Swedish family with brachyolmia type 3 due to a heterozygous TRPV4 mutation c.1847G>A (p.R616Q) in 11 individuals. The mutation has previously been detected in another family with autosomal dominant brachyolmia [Rock et al., 2008]. Review of hospital records and patient assessments indicated that clinical symptoms of brachyolmia became evident by school age with chronic pain in the spine and hips; radiographic changes were evident earlier. Growth was not affected during early childhood but deteriorated with age in some patients due to increasing spinal involvement. Affected individuals had a wide range of subjective symptoms with chronic pain in the extremities and the spine, and paresthesias. Our findings indicate that autosomal dominant brachyolmia may be associated with significant long-term morbidity, as seen in this family. © 2014 Wiley Periodicals, Inc. PMID:24677493

Grigelioniene, Giedre; Geiberger, Stefan; Horemuzova, Eva; Moström, Eva; Jäntti, Nina; Neumeyer, Lo; Aström, Eva; Nordenskjöld, Magnus; Nordgren, Ann; Mäkitie, Outi

2014-07-01

114

Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA  

Microsoft Academic Search

BackgroundLeber's congenital amaurosis (LCA) is an inherited retinal dystrophy, which causes severe visual impairment in early childhood. Recent molecular genetic studies have linked 11 loci (AIPL1, CRB1, CRX, GUCY2D, RPE65, RDH12, RPGRIP1, TULP1, LCA3, LCA5, and LCA9) to LCA. LCA5 is a new locus, which maps to the 6q11–q16 chromosomal region and was found to be associated with macular coloboma-type

R K Özgül; B Bozkurt; H K?ratl?; A Ö?ü?

2006-01-01

115

Evolutionary mechanisms driving the evolution of a large polydnavirus gene family coding for protein tyrosine phosphatases  

PubMed Central

Background Gene duplications have been proposed to be the main mechanism involved in genome evolution and in acquisition of new functions. Polydnaviruses (PDVs), symbiotic viruses associated with parasitoid wasps, are ideal model systems to study mechanisms of gene duplications given that PDV genomes consist of virulence genes organized into multigene families. In these systems the viral genome is integrated in a wasp chromosome as a provirus and virus particles containing circular double-stranded DNA are injected into the parasitoids’ hosts and are essential for parasitism success. The viral virulence factors, organized in gene families, are required collectively to induce host immune suppression and developmental arrest. The gene family which encodes protein tyrosine phosphatases (PTPs) has undergone spectacular expansion in several PDV genomes with up to 42 genes. Results Here, we present strong indications that PTP gene family expansion occurred via classical mechanisms: by duplication of large segments of the chromosomally integrated form of the virus sequences (segmental duplication), by tandem duplications within this form and by dispersed duplications. We also propose a novel duplication mechanism specific to PDVs that involves viral circle reintegration into the wasp genome. The PTP copies produced were shown to undergo conservative evolution along with episodes of adaptive evolution. In particular recently produced copies have undergone positive selection in sites most likely involved in defining substrate selectivity. Conclusion The results provide evidence about the dynamic nature of polydnavirus proviral genomes. Classical and PDV-specific duplication mechanisms have been involved in the production of new gene copies. Selection pressures associated with antagonistic interactions with parasitized hosts have shaped these genes used to manipulate lepidopteran physiology with evidence for positive selection involved in adaptation to host targets.

2012-01-01

116

Consanguinity in Saudi Arabia: a unique opportunity for pediatric kidney research.  

PubMed

Identification of disease-related genes is a critical step in understanding the molecular basis of disease and developing targeted therapies. The genetic study of diseases occurring in the offspring of consanguineous unions is a powerful way to discover new disease genes. Pediatric nephrology provides an excellent example because ?70% of cases of kidney disease in childhood are congenital with a likely genetic basis. This percentage is likely to be even higher in countries with a high consanguinity rate, such as the Kingdom of Saudi Arabia. However, there are a number of challenges, such as cultural, legal, and religious restrictions, that should be appreciated before carrying out genetic research in a tradition-bound country. In this article, we discuss the background, opportunities, and challenges involved with this unique opportunity to conduct studies of such genetic disorders. Keys to success include collaboration and an understanding of local traditions and laws. PMID:24239020

Kari, Jameela A; Bockenhauer, Detlef; Stanescu, Horia; Gari, Mamdooh; Kleta, Robert; Singh, Ajay K

2014-02-01

117

Moxidectin and the avermectins: Consanguinity but not identity  

PubMed Central

The avermectins and milbemycins contain a common macrocyclic lactone (ML) ring, but are fermentation products of different organisms. The principal structural difference is that avermectins have sugar groups at C13 of the macrocyclic ring, whereas the milbemycins are protonated at C13. Moxidectin (MOX), belonging to the milbemycin family, has other differences, including a methoxime at C23. The avermectins and MOX have broad-spectrum activity against nematodes and arthropods. They have similar but not identical, spectral ranges of activity and some avermectins and MOX have diverse formulations for great user flexibility. The longer half-life of MOX and its safety profile, allow MOX to be used in long-acting formulations. Some important differences between MOX and avermectins in interaction with various invertebrate ligand-gated ion channels are known and could be the basis of different efficacy and safety profiles. Modelling of IVM interaction with glutamate-gated ion channels suggest different interactions will occur with MOX. Similarly, profound differences between MOX and the avermectins are seen in interactions with ABC transporters in mammals and nematodes. These differences are important for pharmacokinetics, toxicity in animals with defective transporter expression, and probable mechanisms of resistance. Resistance to the avermectins has become widespread in parasites of some hosts and MOX resistance also exists and is increasing. There is some degree of cross-resistance between the avermectins and MOX, but avermectin resistance and MOX resistance are not identical. In many cases when resistance to avermectins is noticed, MOX produces a higher efficacy and quite often is fully effective at recommended dose rates. These similarities and differences should be appreciated for optimal decisions about parasite control, delaying, managing or reversing resistances, and also for appropriate anthelmintic combination.

Prichard, Roger; Menez, Cecile; Lespine, Anne

2012-01-01

118

[Information should be given on consanguinity as a risk factor for congenital malformations].  

PubMed

In the Born in Bradford study, an increased risk for congenital anomalies was found in the Pakistani subpopulation of Bradford, where cousin marriage is relatively frequent. While consanguinity may be associated with a risk for congenital malformations, it does not prove a causal relationship. Whatever the case, high perinatal mortality as well as the high prevalence of congenital anomalies are good reasons for implementing the knowledge on reproductive risks that has been available for many years. Well-known risk factors include higher maternal age, that was associated with congenital anomalies in the British mothers. Further research in an intervention study may provide more data on whether the associations found are causal. Implementing preconception care should involve primary care physicians, who need both facilities and training. In the Netherlands, the high perinatal mortality, especially in some big cities, could profit from similar interventions. Dutch primary care physicians consider it their responsibility to discuss consanguinity with patients, although there is some reluctance because of anticipated religious and social value conflicts. Without information reaching the target populations, they may lack awareness and will not ask for information themselves. People from Dutch migrant groups would prefer to be informed about reproductive risks of consanguinity by their primary care physicians. PMID:24397975

Cornel, Martina C; Houwink, Elisa J F; Houwink, Pieter E F

2014-01-01

119

A large and functionally diverse family of Fad2 genes in safflower (Carthamus tinctorius L.)  

PubMed Central

Background The application and nutritional value of vegetable oil is highly dependent on its fatty acid composition, especially the relative proportion of its two major fatty acids, i.e oleic acid and linoleic acid. Microsomal oleoyl phosphatidylcholine desaturase encoded by FAD2 gene is known to introduce a double bond at the ?12 position of an oleic acid on phosphatidylcholine and convert it to linoleic acid. The known plant FAD2 enzymes are encoded by small gene families consisting of 1-4 members. In addition to the classic oleate ?12-desaturation activity, functional variants of FAD2 that are capable of undertaking additional or alternative acyl modifications have also been reported in a limited number of plant species. In this study, our objective was to identify FAD2 genes from safflower and analyse their differential expression profile and potentially diversified functionality. Results We report here the characterization and functional expression of an exceptionally large FAD2 gene family from safflower, and the temporal and spatial expression profiles of these genes as revealed through Real-Time quantitative PCR. The diversified functionalities of some of the safflower FAD2 gene family members were demonstrated by ectopic expression in yeast and transient expression in Nicotiana benthamiana leaves. CtFAD2-1 and CtFAD2-10 were demonstrated to be oleate desaturases specifically expressed in developing seeds and flower head, respectively, while CtFAD2-2 appears to have relatively low oleate desaturation activity throughout the plant. CtFAD2-5 and CtFAD2-8 are specifically expressed in root tissues, while CtFAD2-3, 4, 6, 7 are mostly expressed in the cotyledons and hypocotyls in young safflower seedlings. CtFAD2-9 was found to encode a novel desaturase operating on C16:1 substrate. CtFAD2-11 is a tri-functional enzyme able to introduce a carbon double bond in either cis or trans configuration, or a carbon triple (acetylenic) bond at the ?12 position. Conclusions In this study, we isolated an unusually large FAD2 gene family with 11 members from safflower. The seed expressed FAD2 oleate ?12 desaturase genes identified in this study will provide candidate targets to manipulate the oleic acid level in safflower seed oil. Further, the divergent FAD2 enzymes with novel functionality could be used to produce rare fatty acids, such as crepenynic acid, in genetically engineered crop plants that are precursors for economically important phytoalexins and oleochemical products.

2013-01-01

120

Splice-site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families  

PubMed Central

Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. To date, 67 autosomal recessive nonsyndromic hearing impairment (ARNSHI) loci have been mapped, and 24 genes have been identified. This report describes three large consanguineous ARNSHI Pakistani families, all of which display linkage to marker loci located in the genetic interval of DFNB49 locus on chromosome 5q13. Recently, Riazuddin et al. (Am J Hum Genet 2006; 79:1040–1051) reported that variants within the TRIC gene, which encodes tricellulin, are responsible for HI due to DFNB49. TRIC gene sequencing in these three families led to the identification of a novel mutation (IVS4 + 1G > A) in one family and the discovery of a previously described mutation (IVS4 + 2T > C) in two families. It is estimated that 1.06% (95% confidence interval 0.02–3.06%) of families with ARNSHI in Pakistan manifest HI due to mutations in the TRIC gene.

Chishti, Muhammad S.; Bhatti, Attya; Tamim, Sana; Lee, Kwanghyuk; McDonald, Merry-Lynn; Leal, Suzanne M.

2009-01-01

121

Estimating the degree of identity by descent in consanguineous couples.  

PubMed

In some clinical and research settings, it is often necessary to identify the true level of "identity by descent" (IBD) between two individuals. However, as the individuals become more distantly related, it is increasingly difficult to accurately calculate this value. Consequently, we have developed a computer program that uses genome-wide SNP genotype data from related individuals to estimate the size and extent of IBD in their genomes. In addition, the software can compare a couple's IBD regions with either the autozygous regions of a relative affected by an autosomal recessive disease of unknown cause, or the IBD regions in the parents of the affected relative. It is then possible to calculate the probability of one of the couple's children suffering from the same disease. The software works by finding SNPs that exclude any possible IBD and then identifies regions that lack these SNPs, while exceeding a minimum size and number of SNPs. The accuracy of the algorithm was established by estimating the pairwise IBD between different members of a large pedigree with varying known coefficients of genetic relationship (CGR). PMID:21901788

Carr, Ian M; Markham, Sir Alexander F; Pena, Sérgio D J

2011-12-01

122

Genetic and environmental factors affecting bone mineral density in large families.  

PubMed Central

This study assessed whether relatives with low bone mineral density (BMD) could be identified in five large families using historical, biochemical, and genetic markers for osteoporosis. Fifty of 65 relatives had their bone density and bone turnover markers measured, together with an assessment of their risk factors for osteoporosis. Only 33% (5/15) of siblings, 50% (6/12) of children and 43% (10/23) of nephews and nieces had entirely normal BMD. There was no difference in life-style risk factors for osteoporosis, history of previous fractures or body mass index between normal subjects and those with osteopenia or osteoporosis. Osteopenic individuals had a significantly higher than normal osteocalcin value. Within families, there was no clear association between BMD and any of the genetic markers (vitamin D receptor gene polymorphisms, COL 1A1 and COL 1A2 polymorphisms of the collagen gene), either alone or in combination. The addition of genetic markers to the other risk factors for low BMD did not improve the prediction of BMD. In conclusion, we suggest that the presence of osteoporosis in a first degree relative should be one of the clinical indications for bone density measurement as the individuals at risk would not be picked up by other methods.

Yeap, S. S.; Beaumont, M.; Bennett, A.; Keating, N. A.; White, D. A.; Hosking, D. J.

1998-01-01

123

Segregation of FRAXE in a large family: Clinical, psychometric, cytogenetic, and molecular data  

SciTech Connect

During an ongoing study on X-linked mental retardation, we ascertained a large family in which mild mental retardation was cosegregating with a fragile site at Xq27-28. Clinical, psychometric, cytogenetic, and molecular studies were performed. Apart from mild mental retardation, affected males and females did not show a specific clinical phenotype. Psychometric assessment of four representative affected individuals revealed low academic achievements, with verbal and performance IQs of 61-75 and 70-82, respectively. Cytogenetically the fragile site was always present in affected males and was not always present in affected females. With FISH the fragile site was located within the FRAXE region. The expanded GCC repeat of FRAXE was seen in affected males and females either as a discrete band or as a broad smear. No expansion was seen in unaffected males, whereas three unaffected females did have an enlarged GCC repeat. Maternal transmission of FRAXE may lead to expansion or contraction of the GCC repeat length, whereas in all cases of paternal transmission contraction was seen. In striking contrast to the situation in fragile X syndrome, affected males may have affected daughters. In addition, there appears to be no premutation of the FRAXE GCC repeat, since in the family studied here all males lacking the normal allele were found to be affected. 41 refs., 4 figs., 5 tabs.

Hamel, B.C.J.; Smits, A.P.T.; Smeets, F.C.M.; Schoute, F.; Assman-Hulsmans, C.F.C.H. [Univ. Hospital, Nijmegen (Netherlands); Graaff, E. de; Eussen, B.H.J.; Oostra, B.A. [Erasmus Univ., Rotterdam (Netherlands); Knight, S.J.L. [John Radcliffe Hospital, Headington, Oxford (Canada)

1994-11-01

124

Family replicated gauge groups and large mixing angle solar neutrino solution  

NASA Astrophysics Data System (ADS)

We present a modification of our previous family replicated gauge group model, which now generates the Large Mixing Angle MSW solution rather than the experimentally disfavoured Small Mixing Angle MSW solution to the solar neutrino oscillation problem. The model is based on each family of quarks and leptons having its own set of gauge fields, each containing a replica of the Standard Model gauge fields plus a ( B- L)-coupled gauge field. By a careful choice of the Higgs field gauge quantum numbers, we avoid our previous prediction that the solar neutrino mixing angle is equal order of magnitudewise to the Cabibbo angle, replacing it and the well-known Fritzsch relation with the relation ? c˜(? ?) -1/3 (m d/m s) 2/3. At the same time we retain a phenomenologically successful structure for the charged quark and lepton mass matrices. A fit of all the seventeen quark-lepton mass and mixing angle observables, using just six new Higgs field vacuum expectation values, agrees with the experimental data within the theoretically expected uncertainty of about 64%, i.e., it fits perfectly order of magnitudewise.

Froggatt, C. D.; Nielsen, H. B.; Takanishi, Y.

2002-06-01

125

Segregation of FRAXE in a large family: clinical, psychometric, cytogenetic, and molecular data.  

PubMed Central

During an ongoing study on X-linked mental retardation, we ascertained a large family in which mild mental retardation was cosegregating with a fragile site at Xq27-28. Clinical, psychometric, cytogenetic, and molecular studies were performed. Apart from mild mental retardation, affected males and females did not show a specific clinical phenotype. Psychometric assessment of four representative affected individuals revealed low academic achievements, with verbal and performance IQs of 61-75 and 70-82, respectively. Cytogenetically the fragile site was always present in affected males and was not always present in affected females. With FISH the fragile site was located within the FRAXE region. The expanded GCC repeat of FRAXE was seen in affected males and females either as a discrete band or as a broad smear. No expansion was seen in unaffected males, whereas three unaffected females did have an enlarged GCC repeat. Maternal transmission of FRAXE may lead to expansion or contraction of the GCC repeat length, whereas in all cases of paternal transmission contraction was seen. In striking contrast to the situation in fragile X syndrome, affected males may have affected daughters. In addition, there appears to be no premutation of the FRAXE GCC repeat, since in the family studied here all males lacking the normal allele were found to be affected. Images Figure 2 Figure 3 Figure 4

Hamel, B. C.; Smits, A. P.; de Graaff, E.; Smeets, D. F.; Schoute, F.; Eussen, B. H.; Knight, S. J.; Davies, K. E.; Assman-Hulsmans, C. F.; Oostra, B. A.

1994-01-01

126

Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa  

PubMed Central

Purpose Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. Methods DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Results Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T). Conclusions This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are available from more than one affected individual.

Paterson, Rachel L.; McLaren, Terri L.; Hewitt, Alex W.; Hoffmann, Ling; Lamey, Tina M.

2012-01-01

127

Family Strengthening Writ Large: On becoming a Nation that Promotes Strong Families and Successful Youth. Policy Brief No. 24  

ERIC Educational Resources Information Center

Culture and systemic change are paramount to achieving significant and long-lasting gains in child and youth wellbeing and, in time, securing the future of our nation. This brief, based on a high-level synthesis of eight years of experience and research in place-based family strengthening, makes the case for a national transformation to a society…

Online Submission, 2007

2007-01-01

128

THE EVALUATION OF THREE TEACHING STRATEGIES FOR A LARGE UNDERGRADUATE COURSE IN HUMAN DEVELOPMENT AND FAMILY STUDIES  

Microsoft Academic Search

Research suggests that effective teaching includes actively engaging students and connecting concepts and research to application. This is often difficult to do in large undergraduate courses of over 100 students. The present study evaluated three teaching strategies adapted for a large undergraduate course in a Human Development and Family Studies program. Using data collected over four years in an adolescence

Megan M. McClelland; Lizbeth Gray

129

Genetic heterogeneity and consanguinity lead to a "double hit": Homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa  

PubMed Central

Purpose Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. Methods The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. Results The family was found to segregate novel mutations of two different genes: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. Conclusions This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.

Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina

2013-01-01

130

Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families.  

PubMed

Early studies of genetic predisposition due to the BRCA1 and BRCA2 genes have focused largely on sequence alterations, but it has now emerged that 4-28% of inherited mutations in the BRCA genes may be due to large genomic rearrangements of these genes. However, to date, there have been relatively few studies of large genomic rearrangements in Asian populations. We have conducted a full sequencing and large genomic rearrangement analysis (using Multiplex Ligation-dependent Probe Amplification, MLPA) of 324 breast cancer patients who were selected from a multi-ethnic hospital-based cohort on the basis of age of onset of breast cancer and/or family history. Three unrelated individuals were found to have large genomic rearrangements: 2 in BRCA1 and 1 in BRCA2, which accounts for 2/24 (8%) of the total mutations detected in BRCA1 and 1/23 (4%) of the mutations in BRCA2 detected in this cohort. Notably, the family history of the individuals with these mutations is largely unremarkable suggesting that family history alone is a poor predictor of mutation status in Asian families. In conclusion, this study in a multi-ethnic (Malay, Chinese, Indian) cohort suggests that large genomic rearrangements are present at a low frequency but should nonetheless be included in the routine testing for BRCA1 and BRCA2. PMID:20617377

Kang, Peter; Mariapun, Shivaani; Phuah, Sze Yee; Lim, Linda Shushan; Liu, Jianjun; Yoon, Sook-Yee; Thong, Meow Keong; Mohd Taib, Nur Aishah; Yip, Cheng Har; Teo, Soo-Hwang

2010-11-01

131

Multicentric Castleman Disease in an HHV8-Infected Child Born to Consanguineous Parents With Systematic Review  

PubMed Central

Childhood multicentric Castleman disease (MCD) is a rare and unexplained lymphoproliferative disorder. We report a human herpesvirus-8 (HHV-8)-infected child, born to consanguineous Comorian parents, who displayed isolated MCD in the absence of any known immunodeficiency. We also systematically review the clinical features of the 32 children previously reported with isolated and unexplained MCD. The characteristics of this patient and the geographic areas of origin of most previous cases suggest that pediatric MCD is associated with HHV-8 infection. Moreover, as previously suggested for Kaposi sarcoma, MCD in childhood may result from inborn errors of immunity to HHV-8 infection.

Moshous, Despina; Cassar, Olivier; Reguerre, Yves; Byun, Minji; Pedergnana, Vincent; Canioni, Danielle; Gessain, Antoine; Oksenhendler, Eric; Fieschi, Claire; Mahlaoui, Nizar; Riviere, Jean-Pierre; Herbigneaux, Rose-Marie; Muszlak, Matthias; Arnaud, Jean-Pierre; Fischer, Alain; Picard, Capucine; Blanche, Stephane; Plancoulaine, Sabine

2012-01-01

132

Large genomic rearrangement of BRCA1 and BRCA2 genes in familial breast cancer patients in Korea.  

PubMed

We screened large genomic rearrangements of the BRCA1 and BRCA2 genes in Korean, familial breast cancer patients. Multiplex ligation-dependent probe amplification assay was used to identify BRCA1 and BRCA2 genomic rearrangements in 226 Korean familial breast cancer patients with risk factors for BRCA1 and BRCA2 mutations, who previously tested negative for point mutations in the two genes. We identified only one large deletion (c.4186-1593_4676-1465del) in BRCA1. No large rearrangements were found in BRCA2. Our result indicates that large genomic rearrangement in the BRCA1 and BRCA2 genes does not seem like a major determinant of breast cancer susceptibility in the Korean population. A large-scale study needs to validate our result in Korea. PMID:24566764

Cho, Ja Young; Cho, Dae-Yeon; Ahn, Sei Hyun; Choi, Su-Youn; Shin, Inkyung; Park, Hyun Gyu; Lee, Jong Won; Kim, Hee Jeong; Yu, Jong Han; Ko, Beom Seok; Ku, Bo Kyung; Son, Byung Ho

2014-06-01

133

Emergence of Switch-Like Behavior in a Large Family of Simple Biochemical Networks  

PubMed Central

Bistability plays a central role in the gene regulatory networks (GRNs) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of GRNs that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in ?90% of these GRN models, including several circuits that do not contain any of the TF cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in GRNs arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of CRNT to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, protein-DNA interaction, and gene expression data from Saccharomyces cerevisiae, and identified several GRNs predicted to behave in a bistable fashion.

Siegal-Gaskins, Dan; Mejia-Guerra, Maria Katherine; Smith, Gregory D.; Grotewold, Erich

2011-01-01

134

Scoliosis, blindness and arachnodactyly in a large Turkish family: is it a new syndrome?  

PubMed

In this report we have described an affected sib in a large Turkish family who appears to have a new distinct dominantly-inherited blindness, scoliosis and arachnodactyly syndrome. The combination of clinical abnormalities in these patients did not initially suggest Marfan syndrome or other connective tissue disorders associated with ectopia lentis. The proband was a 16-year-old boy who was referred to our clinics for scoliosis. He had arachnodactyly of both fingers and toes. He had been suffering from progressive visual loss and strabismus since he was eight-years-old. His 20-year-old brother had severe kyphoscoliosis, and arachnodactyly of fingers and toes. He was 130 cm tall and was bilaterally blind. His 23-year-old sister had only eye findings but no arachnodactyly or scoliosis. His 60-year-old father had mild scoliosis, blindness and arachnodactyly and mother was normal. We performed routine mutation analyses in the genes FBN1, TGFBR1 and TGFBR2, but no mutation has been detected. Our Turkish patients are most likely affected by a hitherto unrecorded condition which is caused by an autosomal dominant gene defect with variable expression but we can not exclude multigenic inheritance. Further studies are needed to assess the contribution of sex influence to the syndrome because the female relative is less affected. PMID:18990988

Dundar, M; Erkilic, K; Argun, M; Caglayan, A O; Comeglio, P; Koseoglu, E; Matyas, G; Child, A H

2008-01-01

135

Wiskott-Aldrich syndrome: review and report of a large family  

PubMed Central

Wiskott–Aldrich syndrome is a sex-linked recessive antibody-deficiency syndrome characterized by thrombocytopenia, eczema and increased susceptibility to infection. All forms of therapy are notably unsuccessful and these patients succumb in the first decade. Three cases of this syndrome are presented from a large family in which nine male infants have succumbed with manifestations of this disease. Two of the infants died at ages 10 months and 4 years respectively. A third child is alive at age 2. Serial quantitative immune globulin studies performed in two cases demonstrated markedly elevated ?A, decreased ?M and normal ?G; levels of ?M were initially normal but fell progressively as ?A levels increased. The low levels of ?M are probably a factor in their low or absent isoagglutinins, poor response to injected antigens, and increased susceptibility to infection; elevated ?A levels may indicate immunologic unresponsiveness and/or a compensatory mechanism for the defect in ?M synthesis. In two of these patients prolonged trials (17 and 23 months) of periodic plasma infusions (15 ml/kg at 6-week intervals), accompanied by ?-globulin injections (0·1 ml/kg) were undertaken. Although no remarkable effects on the platelets or their resistance to infection was noted, we feel that some benefit might have accrued and that further trails are indicated.

Stiehm, E. R.; McIntosh, R. M.

1967-01-01

136

Functional heterogeneity of a large family of human LTR-like promoters and enhancers.  

PubMed

The human genome contains a variety of elements similar in structure to retroviruses and retrotransposons. We have shown that the long terminal repeat (LTR) sequences of a large family of human retrovirus-like elements, RTVL-H, are heterogeneous in their ability to regulate the expression of linked genes. Although all of five LTRs tested could promote expression of the chloramphenicol acetyltransferase (CAT) gene, their relative promoter activities as well as range of activities varied widely. Several of the LTRs tested also exhibited bidirectional promoter activity either alone or when activated by an SV40 early enhancer. One LTR, H6, displayed strong promoter activity in human (NTera2D1, 293, Hep2), monkey (COS-1), and mouse (3T3) cells. In fact, the activity of this LTR was similar to that of the SV40 early promoter/enhancer in 293, COS-1, and 3T3 cells. RNA mapping studies have localized the transcription start site to the expected location in the H6 LTR. RTVL-H LTRs were also shown to contain sequences which could increase transcription from the human beta-globin promoter and be influenced by SV40 enhancer sequences. As the human genome contains several hundred related RTVL-H sequences and a similar number of solitary LTRs, these findings raise the possibility that RTVL-H LTRs could have diverse effects on the expression of adjacent cellular genes. PMID:1690875

Feuchter, A; Mager, D

1990-03-11

137

Functional heterogeneity of a large family of human LTR-like promoters and enhancers.  

PubMed Central

The human genome contains a variety of elements similar in structure to retroviruses and retrotransposons. We have shown that the long terminal repeat (LTR) sequences of a large family of human retrovirus-like elements, RTVL-H, are heterogeneous in their ability to regulate the expression of linked genes. Although all of five LTRs tested could promote expression of the chloramphenicol acetyltransferase (CAT) gene, their relative promoter activities as well as range of activities varied widely. Several of the LTRs tested also exhibited bidirectional promoter activity either alone or when activated by an SV40 early enhancer. One LTR, H6, displayed strong promoter activity in human (NTera2D1, 293, Hep2), monkey (COS-1), and mouse (3T3) cells. In fact, the activity of this LTR was similar to that of the SV40 early promoter/enhancer in 293, COS-1, and 3T3 cells. RNA mapping studies have localized the transcription start site to the expected location in the H6 LTR. RTVL-H LTRs were also shown to contain sequences which could increase transcription from the human beta-globin promoter and be influenced by SV40 enhancer sequences. As the human genome contains several hundred related RTVL-H sequences and a similar number of solitary LTRs, these findings raise the possibility that RTVL-H LTRs could have diverse effects on the expression of adjacent cellular genes. Images

Feuchter, A; Mager, D

1990-01-01

138

Patient perception and knowledge of acetaminophen in a large family medicine service.  

PubMed

ABSTRACT The use of acetaminophen is currently under increased scrutiny by the US Food and Drug Administration (FDA) due to the risk of intentional and more concerning, unintentional overdose-related hepatotoxicity. Acetaminophen is responsible for an estimated 48% of all acute liver failure diagnoses. The purpose of this study is to evaluate patient perception and knowledge of the safe use and potential toxicity of acetaminophen-containing products. The authors conducted a descriptive, 2-week study using a convenience sample from a large family medicine clinic waiting room. Survey questions assessed ability to identify acetaminophen, knowledge of the current recommended maximum daily dose, respondent acetaminophen use patterns, common adverse effects associated with acetaminophen, and respondent self-reported alcohol consumption. Acetaminophen safety information was provided to all persons regardless of participation in the study. Of the 102 patients who chose to participate, 79% recognized acetaminophen as a synonym of Tylenol, whereas only 9% identified APAP as a frequently used abbreviation. One third of respondents thought acetaminophen was synonymous with ibuprofen and naproxen. Approximately one fourth of patients correctly identified the then maximum recommended daily acetaminophen dose of 4 g. Seventy-eight percent of patients correctly identified hepatotoxicity as the most common serious adverse effect. We conclude that patient deficiencies in knowledge of acetaminophen recognition, dosing, and toxicity warrant public education by health professionals at all levels of interaction. Current initiatives are promising; however, further efforts are required. PMID:24813653

Herndon, Christopher M; Dankenbring, Dawn M

2014-06-01

139

Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry  

PubMed Central

Introduction Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1. Methods We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification. Results Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively. Conclusions Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations.

2011-01-01

140

Clinical, electrophysiological and genetic features of a large Australian family with paramyotonia congenita.  

PubMed

A 32-year-old woman with a 4-year history of multiple sclerosis presented with persistent clawing of the right hand. History revealed that she and five family members had lifelong symptoms of paradoxical myotonia (impaired relaxation of muscles following muscle contraction), exacerbated by cold. The family was diagnosed with paramyotonia congenita, based on neurophysiological and genetic studies. To our knowledge, this is the first report of an Australian family with paramyotonia congenita. PMID:19296818

Parasivam, Sharavanan; Krupa, Malgorzata; Slee, Mark; Thyagarajan, Dominic E; Dominic, Thyagarajan E

2009-03-16

141

A Consanguinity Related Autosomal Translocation which Leads to Premature Ovarian Failure  

PubMed Central

The premature ovarian failures with underlying chromosomal abnormalities are normally X-linked, although their associations with the autosomal and the Robertsonian translocations are also possible. Here, we are reporting a case of premature ovarian failure which was associated with a translocation between the long arm of chromosome 7 at q11.23 and the short arm of chromosome 5 at p15.3. The proband was a 26-year-old Malay woman who presented with premature ovarian failure, who was referred for cytogenetic testing due to the suspicion of a chromosomal anomaly. Her physical examination revealed that she had no abdominal or pelvic masses and that she had normal secondary sexual characteristics. Her medical history as well, revealed no points for concern. However, a consanguineous relationship existed, as the patient’s paternal grandmother and maternal grandfather were biological cousins. Our present case indicated that region p15.3 of chromosome 5 and region q11.23 of chromosome 7 possibly carried essential genes for the ovarian function and that they postulated a link between the consanguinity and the chromosomal abnormalities.

Yik, Mot Yee; Zain, Murizah Mohd; Zakaria, Zubaidah; Yusoff, Narazah Mohd

2013-01-01

142

The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of plasmodium falciparum-infected erythrocytes  

Microsoft Academic Search

The human malaria parasite Plasmodium falciparum evades host immunity by varying the antigenic and adhesive character of infected erythrocytes. We describe a large and extremely diverse family of P. falciparum genes (var) that encode 200–350 kDa proteins having the expected properties of antigenically variant adhesion molecules. Predicted amino acid sequences of var genes show a variable extracellular segment with domains

Xin-zhuan Su; Virginia M. Heatwole; Samuel P. Wertheimer; Frangoise Guinet; Jacqueline A. Herrfeldt; David S. Peterson; Jeffrey A. Ravetch; Thomas E. Wellems

1995-01-01

143

Identification of MYOC gene mutation and polymorphism in a large Malay family with juvenile-onset open angle glaucoma  

PubMed Central

Purpose To screen for mutations in the coding region of the myocilin (MYOC) gene in a large Malay family with juvenile-onset open angle glaucoma (JOAG). Methods A total of 122 family members were thoroughly examined and screened for JOAG. Venipuncture was conducted. Genomic DNA was extracted from peripheral blood leukocytes. The presence of a mutation and a polymorphism was ascertained with PCR amplification followed by the direct sequencing technique. Results Thirty-two of the 122 screened family members were identified to have JOAG (11 new cases and 21 known cases). An autosomal dominant inheritance pattern with incomplete penetrance was observed. A C?A substitution at position 1440 in exon 3 that changes asparagine (AAC) to lysine (AAA) was identified in affected family members except two probands (III:5 and IV:6). Six probands were identified as having the Asn480Lys mutation but have not developed the disease yet. An intronic polymorphism IVS2 730 +35 G>A was also identified. There was a significant association between Asn480Lys (p<0.001) and IVS2 730+35G>A (p<0.001) in the affected and unaffected probands in this family. Conclusions The Asn480Lys mutation and the IVS2 730+35 G>A polymorphism increased susceptibility to JOAG in this large Malay pedigree. Identifying the MYOC mutations and polymorphisms is important for providing presymptomatic molecular diagnosis.

Mimivati, Z; Nurliza, K; Marini, M; Liza-Sharmini, AT

2014-01-01

144

Tumor mapping in two large multigeneration families with CYLD mutations: Implications for patient management and tumor induction  

PubMed Central

Objective To comprehensively ascertain the extent and severity of clinical features in multiple affected individuals from two large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the three appendageal tumor predisposition syndromes, familial cylindromatosis (FC), Brooke-Spiegler syndrome (BSS), and multiple familial trichoepitheliomas (MFT) known to be associated with such germline mutations. Design Inter- and intra-familial observational study. Setting Tertiary genetic and dermatology referral centre. Participants 32 individuals were recruited from two large multigenerational families with CYLD mutations. Clinical details, history and tumor maps were obtained from all participants whilst 18 were further corroborated with detailed clinical examination. Main outcome measures Severity of tumor density, distribution and histology, associated medical conditions, patient symptoms and impact of disease on quality of life. Results We demonstrate a wide variation in clinical presentation seen in individuals from the same family. In addition, we provide clinical evidence that correlates with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction. Conclusion In view of our findings, we propose that the burden of disease at sites other than the head and neck is underreported in the literature, but impacts greatly on quality of life. The differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counselling even within individuals from the same family. Thus, we suggest an encompassing diagnosis of “CYLD cutaneous syndrome”. Finally, our results relating to the clinical distribution of tumors suggest hormonal factors may play an important role in tumor induction in these patients.

Rajan, N; Langtry, J A A; Ashworth, A; Roberts, C; Chapman, P; Burn, J; Trainer, A H

2010-01-01

145

Structural, Functional, and Evolutionary Analysis of the Unusually Large Stilbene Synthase Gene Family in Grapevine1[W  

PubMed Central

Stilbenes are a small family of phenylpropanoids produced in a number of unrelated plant species, including grapevine (Vitis vinifera). In addition to their participation in defense mechanisms in plants, stilbenes, such as resveratrol, display important pharmacological properties and are postulated to be involved in the health benefits associated with a moderate consumption of red wine. Stilbene synthases (STSs), which catalyze the biosynthesis of the stilbene backbone, seem to have evolved from chalcone synthases (CHSs) several times independently in stilbene-producing plants. STS genes usually form small families of two to five closely related paralogs. By contrast, the sequence of grapevine reference genome (cv PN40024) has revealed an unusually large STS gene family. Here, we combine molecular evolution and structural and functional analyses to investigate further the high number of STS genes in grapevine. Our reannotation of the STS and CHS gene families yielded 48 STS genes, including at least 32 potentially functional ones. Functional characterization of nine genes representing most of the STS gene family diversity clearly indicated that these genes do encode for proteins with STS activity. Evolutionary analysis of the STS gene family revealed that both STS and CHS evolution are dominated by purifying selection, with no evidence for strong selection for new functions among STS genes. However, we found a few sites under different selection pressures in CHS and STS sequences, whose potential functional consequences are discussed using a structural model of a typical STS from grapevine that we developed.

Parage, Claire; Tavares, Raquel; Rety, Stephane; Baltenweck-Guyot, Raymonde; Poutaraud, Anne; Renault, Lauriane; Heintz, Dimitri; Lugan, Raphael; Marais, Gabriel A.B.; Aubourg, Sebastien; Hugueney, Philippe

2012-01-01

146

Large BRCA1 gene deletions are found in 3% of German high-risk breast cancer families.  

PubMed

We have tested for large BRCA1 gene rearrangements in German high-risk breast and ovarian cancer families previously screened negative for point mutations by dHPLC and sequencing. Using the novel MLPA method, two deletions of exons 1A, 1B and 2 and exon 17, respectively, were detected in four out of 75 families investigated in Southern Germany. An identical exon 17 deletion with the same breakpoints and a deletion of exons 1A, 1B and 2 were found by fluorescent multiplex PCR in two out of 30 families investigated in Northern Germany. Combining both populations, genomic rearrangements were found in 6% of the mutation-negative families and 3% of all high-risk families and account for 8% of all BRCA1 mutations. Our data indicate that the exon 17 deletion may be a founder mutation in the German population. The prevalence of BRCA1 gene deletions or duplications in our patients is similar to previous reports from Germany and France. Genomic quantification by MLPA is a useful method for molecular diagnostics in high-risk breast cancer families. PMID:15532023

Hartmann, Carolin; John, Anika L; Klaes, Rüdiger; Hofmann, Wera; Bielen, Rainer; Koehler, Rolf; Janssen, Bart; Bartram, Claus R; Arnold, Norbert; Zschocke, Johannes

2004-12-01

147

Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family  

PubMed Central

Summary Bromodomains (BRDs) are protein interaction modules that specifically recognize ?-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.

Filippakopoulos, Panagis; Picaud, Sarah; Mangos, Maria; Keates, Tracy; Lambert, Jean-Philippe; Barsyte-Lovejoy, Dalia; Felletar, Ildiko; Volkmer, Rudolf; Muller, Susanne; Pawson, Tony; Gingras, Anne-Claude; Arrowsmith, Cheryl H.; Knapp, Stefan

2012-01-01

148

Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons  

PubMed Central

41 breast cancer or breast-ovarian cancer families, including 12 families with at least one affected first-degree male relative, were screened for mutations in the BRCA2 gene. Mutations had not been found in the BRCA1 gene of these families. Chemical cleavage of Mismatch was used to identify nucleotide changes within large PCR products (average size 1.2?kb) that carried strand-specific fluorescent end-labels. 15 amplicons were sufficient to scan 18 exons, including the large exon 11. The remaining 9 small exons were examined by Denaturing Gradient Gel Electrophoresis. The high sensitivity of this approach was documented by the detection, in these 41 patients, of all 9 exonic single nucleotide polymorphisms reported with heterozygosity >0.1. Truncating BRCA2 mutations were found in 7 of the 41 families. 3 of them were in the group of 12 families comprising cases of male breast cancer. Since the methods used here have no bias for particular types of mutations, these data confirm the high proportion of frameshifts among mutations in BRCA2. However, relevant single nucleotide substitutions were also found: one resulting in a stop codon and another one, present in a male patient, was the previously reported change Asp2723His, that affects a highly conserved region of the BRCA2 protein. This study indicates a BRCA2 contribution of 10% (95% CI 2.5–17.5) to our original cohort of 59 breast-ovarian cancer families, whereas the contribution of BRCA1 had been estimated at 46% (95% CI 33–59). © 2001 Cancer Research Campaign http://www.bjcancer.com

Pages, S; Caux, V; Stoppa-Lyonnet, D; Tosi, M

2001-01-01

149

Extraordinary diversity among members of the large gene family, 185/333, from the purple sea urchin, Strongylocentrotus purpuratus  

PubMed Central

Background Recent analysis of immune-related genes within the sea urchin genome revealed a number of large gene families with vertebrate homologues, such as the Toll-like and NOD/NALP-like receptor families and C-type lectins in addition to a rudimentary complement system. Therefore, the immune response of the purple sea urchin appears to be more complex than previously believed. Another component of the sea urchin immune response is an unusual family of mRNAs, known as 185/333, which is strongly upregulated in response to pathogen challenge. The work presented here indicates that this family of transcripts is derived from an unexpectedly diverse gene family. Results The 185/333 genes are small (< 2 kb) with only two exons. Their extraordinary diversity was exemplified by 121 unique sequences identified from 171 cloned genes. Sequences from the second exons were aligned optimally by introducing large gaps, which defined blocks of sequence known as elements. Genes were defined by the presence or absence of elements. Phylogenetic analysis defined five intron types which, when combined with the exon element patterns resulted in 31 gene patterns, 14 of which were not described previously. Sequence diversity was present in all elements, and was higher in the intron than the exons. Repeats within the sequence facilitated multiple alignments, of which two were analyzed in detail. Although the two alignments differed in length, number of elements, and number of patterns, both were about equally accurate at describing the 185/333 sequences. The genes were closely linked and flanked by short repeats. The repeats within and between the genes may promote their diversification through gene conversion, recombination, and meiotic mispairing. Conclusion The diversity of the 185/333 gene family represents an intriguing addition to what is known about the S. purpuratus immune response, and provides further evidence that invertebrate immune systems are neither simple nor static.

Buckley, Katherine M; Smith, L Courtney

2007-01-01

150

bZIPs and WRKYs: two large transcription factor families executing two different functional strategies  

PubMed Central

bZIPs and WRKYs are two important plant transcription factor (TF) families regulating diverse developmental and stress-related processes. Since a partial overlap in these biological processes is obvious, it can be speculated that they fulfill non-redundant functions in a complex regulatory network. Here, we focus on the regulatory mechanisms that are so far described for bZIPs and WRKYs. bZIP factors need to heterodimerize for DNA-binding and regulation of transcription, and based on a bioinformatics approach, bZIPs can build up more than the double of protein interactions than WRKYs. In contrast, an enrichment of the WRKY DNA-binding motifs can be found in WRKY promoters, a phenomenon which is not observed for the bZIP family. Thus, the two TF families follow two different functional strategies in which WRKYs regulate each other’s transcription in a transcriptional network whereas bZIP action relies on intensive heterodimerization.

Llorca, Carles M.; Potschin, Maren; Zentgraf, Ulrike

2014-01-01

151

Coincident neuraminidase and aspartoacylase deficiency associated with chromosome 9Q paracentric inversion in a Saudi family.  

PubMed

A large, consanguineous Saudi family with three members with sialidosis type 1 and five members with infantile central nervous system spongy degeneration of the brain (ICNSSD, or Canavan-Bertrand-van Bogaert disease) is described. The patients with sialidosis had normal aspartoacylase activity, while neuraminidase activity in the patients with ICNSSD was reduced. All patients had normal carboxypeptidase activity in their fibroblasts. In an additional member there was photic-induced epilepsy, but he had normal enzymes. Two of the patients and one normal brother, but not the parents, had pericentric inversion of chromosome 9q. We postulate that an unidentified gene function is responsible for varied expression of these neurodegenerative diseases in this family. PMID:1588018

Gascon, G G; Youssef, N G; Subramanyam, S B; Ozand, P T

1992-04-01

152

Autosomal recessive hypercholesterolaemia in a Morrocan family due to a mutation of the G266C LDL receptor.  

PubMed

Familial hypercholesterolaemia (FH) is quite common genetic disorder resulting in high low-density lipoprotein (LDL) cholesterol levels, but homozygous FH is rare. The authors describe a Moroccan family where a 24-year-old man and his 13-year-old brother, born from a consanguineous union, showed characteristics of FH with large tendon, tuberous and planar xanthomas. They had already five deaths in the sibship before the age of 15 years. Blood analysis found high LDL cholesterol levels. Arterial assessment showed diffuse atherosis. Genetic study found that patients are homozygous for the mutation of G266C LDL receptor. Treatment with high doses of statins and ezetimibe was introduced reducing cholesterol up to 70%. Large xanthomas were removed surgically. The G266C mutation has been previously identified in Morocco. Early identification and adequate treatment of individuals with hypercholesterolaemia and their relatives are essential for prevention of early death in these populations. PMID:22669020

El Aziz, Siham; Chadli, Asma; El Ghomari, Hassan; Farouqi, Ahmed

2012-01-01

153

Autosomal recessive hypercholesterolaemia in a Morrocan family due to a mutation of the G266C LDL receptor  

PubMed Central

Familial hypercholesterolaemia (FH) is quite common genetic disorder resulting in high low-density lipoprotein (LDL) cholesterol levels, but homozygous FH is rare. The authors describe a Moroccan family where a 24-year-old man and his 13-year-old brother, born from a consanguineous union, showed characteristics of FH with large tendon, tuberous and planar xanthomas. They had already five deaths in the sibship before the age of 15 years. Blood analysis found high LDL cholesterol levels. Arterial assessment showed diffuse atherosis. Genetic study found that patients are homozygous for the mutation of G266C LDL receptor. Treatment with high doses of statins and ezetimibe was introduced reducing cholesterol up to 70%. Large xanthomas were removed surgically. The G266C mutation has been previously identified in Morocco. Early identification and adequate treatment of individuals with hypercholesterolaemia and their relatives are essential for prevention of early death in these populations.

El Aziz, Siham; Chadli, Asma; El Ghomari, Hassan; Farouqi, Ahmed

2012-01-01

154

Aquaporins Constitute a Large and Highly Divergent Protein Family in Maize  

Microsoft Academic Search

Aquaporins (AQPs) are an ancient family of channel proteins that transport water and neutral solutes through a pore and are found in all eukaryotes and most prokaryotes. A comparison of the amino acid sequences and phylogenetic analysis of 31 full-length cDNAs of maize (Zea mays) AQPs shows that they comprise four different groups of highly divergent proteins. We have classified

Francois Chaumont; Francois Barrieu; Eva Wojcik; Maarten J. Chrispeels; Rudolf Jung

2001-01-01

155

Homozygosity mapping of depressive disorder in a large family from Pakistan: significant linkage on chromosome 6 and 9.  

PubMed

A large family with a high prevalence of recurrent major depression and high average inbreeding coefficient was ascertained from rural Pakistan. Subjects were interviewed and diagnosed by a trained psychiatrist, 370 microsatellite markers were genotyped and the program FEstim was used for homozygosity mapping. Significant linkage was found on Chromosome 9 and Chromosome 6 after fine mapping. These regions on Chromosome 6 and 9 may harbor genes which predispose to depression. PMID:23281311

Ayub, Muhammad; Irfan, Muhammad; Maclean, Alan; Naeem, Farooq; Blackwood, Douglas

2013-03-01

156

Ovarian dysfunction and FMR1 alleles in a large Italian family with POF and FRAXA disorders: case report  

Microsoft Academic Search

BACKGROUND: The association between premature ovarian failure (POF) and the FMR1 repeat number (41> CGGnFMR1 alleles. CASE PRESENTATION: We describe the coexistence in a large Italian kindred of Fragile X syndrome and familial POF in females with ovarian dysfunctions who carried normal or expanded FMR1 alleles. Genetic analysis of the FMR1 gene in over three generations of females revealed that

Maria Giuseppina Miano; Carmela Laperuta; Pietro Chiurazzi; Michele D'Urso; Matilde Valeria Ursini

2007-01-01

157

Fine mapping of Noonan\\/cardio-facio cutaneous syndrome in a large family  

Microsoft Academic Search

Noonan syndrome (NS) is an autosomal dominant condition with facial dysmorphy, congenital cardiac defects and short stature. A gene for NS has previously been linked to a 14 cM region in 12q24. We performed linkage analysis in a four generation Belgian family with NS in some individuals and cardio-facio-cutaneous (CFC) syndrome in others. Clinical data and linkage data in this

Eric Legius; Els Schollen; Gert Matthijs; Jean-Pierre Fryns

1998-01-01

158

Evolution of a Large, Conserved, and Syntenic Gene Family in Insects  

PubMed Central

The Osiris gene family, first described in Drosophila melanogaster, is clustered in the genomes of all Drosophila species sequenced to date. In D. melanogaster, it explains the enigmatic phenomenon of the triplo-lethal and haploinsufficient locus Tpl. The synteny of Osiris genes in flies is well conserved, and it is one of the largest syntenic blocks in the Drosophila group. By examining the genome sequences of other insects in a wide range of taxonomic orders, we show here that the gene family is well-conserved and syntenic not only in the diptera but across the holometabolous and hemimetabolous insects. Osiris gene homologs have also been found in the expressed sequence tag sequences of various other insects but are absent from all groups that are not insects, including crustacea and arachnids. It is clear that the gene family evolved by gene duplication and neofunctionalization very soon after the divergence of the insects from other arthropods but before the divergence of the insects from one another and that the sequences and synteny have been maintained by selection ever since.

Shah, Neethu; Dorer, Douglas R.; Moriyama, Etsuko N.; Christensen, Alan C.

2012-01-01

159

Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy  

PubMed Central

Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (?8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of second- through fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1–3 repeats or 4–8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4–8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4–8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family’s genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families.

Scionti, Isabella; Sera, Francesco; Govi, Monica; D'Amico, Roberto; Frambolli, Ilaria; Mele, Fabiano; Filosto, Massimiliano; Vercelli, Liliana; Ruggiero, Lucia; Berardinelli, Angela; Angelini, Corrado; Antonini, Giovanni; Bucci, Elisabetta; Cao, Michelangelo; Daolio, Jessica; Di Muzio, Antonio; Di Leo, Rita; Galluzzi, Giuliana; Iannaccone, Elisabetta; Maggi, Lorenzo; Maruotti, Valerio; Moggio, Maurizio; Mongini, Tiziana; Morandi, Lucia; Nikolic, Ana; Pastorello, Ebe; Ricci, Enzo; Rodolico, Carmelo; Santoro, Lucio; Servida, Maura; Siciliano, Gabriele; Tomelleri, Giuliano

2013-01-01

160

Myotonia congenita with strabismus in a large family with a mutation in the SCN4A gene  

PubMed Central

Background/Aims To determine the genetic basis of myotonia congenita (MC) and strabismus in a large Caucasian family. Methods Seven patients making up four generations of a family with MC and strabismus were recruited. All patients had at least one standard ophthalmic examination, including best-corrected visual acuity, refraction, and ocular motility measurements. CLCN1 and SCN4A genes were sequenced and analysed for mutations. Results Five out of the seven family members were diagnosed with MC by clinical history and electromyography. Ophthalmic history and exam revealed eyelid myotonia and strabismus. All patients with MC were diagnosed with strabismus between the ages of 3 and 6 and required surgical restoration of ocular alignment. Sequencing results revealed a c. 1333G>A; p. Val445Met mutation in the SCN4A gene. Conclusion There are few reports describing eyelid myotonia and strabismus in patients diagnosed with MC. We found significant ocular involvement in a family with a mutation in SCN4A. Future studies may confirm that MC with significant ocular involvement can be used to direct genetic analysis.

Du, H; Grob, S R; Zhao, L; Lee, J; El-Sahn, M; Hughes, G; Luo, J; Schaf, K; Duan, Y; Quach, J; Wei, X; Shaw, P; Granet, D; Zhang, K

2012-01-01

161

A Novel PRPF31 Mutation in a Large Chinese Family with Autosomal Dominant Retinitis Pigmentosa and Macular Degeneration  

PubMed Central

Purpose This study was intended to identify the disease causing genes in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration. Methods A genome scan analysis was conducted in this family for disease gene preliminary mapping. Snapshot analysis of selected SNPs for two-point LOD score analysis for candidate gene filter. Candidate gene PRPF31 whole exons' sequencing was executed to identify mutations. Results A novel nonsense mutation caused by an insertion was found in PRPF31 gene. All the 19 RP patients in 1085 family are carrying this heterozygous nonsense mutation. The nonsense mutation is in PRPF31 gene exon9 at chr19:54629961-54629961, inserting nucleotide “A” that generates the coding protein frame shift from p.307 and early termination at p.322 in the snoRNA binding domain (NOP domain). Conclusion This report is the first to associate PRPF31 gene's nonsense mutation and adRP and JMD. Our findings revealed that PRPF31 can lead to different clinical phenotypes in the same family, resulting either in adRP or syndrome of adRP and JMD. We believe our identification of the novel “A” insertion mutation in exon9 at chr19:54629961-54629961 in PRPF31 can provide further genetic evidence for clinical test for adRP and JMD.

Zheng, Hong; Liu, Xiaoqi; Yang, Jiyun; Shi, Yi; Lin, Ying; Gong, Bo; Zhu, Xianjun; Ma, Shi; Qiao, Lifeng; Lin, He; Cheng, Jing; Yang, Zhenglin

2013-01-01

162

Common Functions or Only Phylogenetically Related? The Large Family of PLAC8 Motif-Containing/PCR Genes  

PubMed Central

PLAC8 motif-containing proteins form a large family and members can be found in fungi, algae, higher plants and animals. They include the PCR proteins of plants. The name giving PLAC8 domain was originally found in a protein residing in the spongiotrophoblast layer of the placenta of mammals. A further motif found in a large number of these proteins including several PCR proteins is the CCXXXXCPC or CLXXXXCPC motif. Despite their wide distribution our knowledge about the function of these proteins is very limited. For most of them two membranespanning ?-helices are predicted, indicating that they are membrane associated or membrane intrinsic proteins. In plants PLAC8 motif-containing proteins have been described to be implicated in two very different functions. On one hand, it has been shown that they are involved in the determination of fruit size and cell number. On the other hand, two members of this family, AtPCR1 and AtPCR2 play an important role in transport of heavy metals such as cadmium or zinc. Transport experiments and approaches to model the 3_D structure of these proteins indicate that they could act as transporters for these divalent cations by forming homomultimers. In this minireview we discuss the present knowledge about this protein family and try to give an outlook on how to integrate the different proposed functions into a common picture about the role of PLAC8 motif-containing proteins.

Song, Won-Yong; Hortensteiner, Stefan; Tomioka, Rie; Lee, Youngsook; Martinoia, Enrico

2011-01-01

163

SLE like syndrome and functional deficiency of C1q in members of a large family.  

PubMed Central

Two sisters and a brother from one family are described whose sera were deficient in haemolytic complement function. This defect was restored by addition of purified C1q. In their sera, C1q like material was found, whereas C1r and C1s were normal or increased in concentration, as were the other complement components tested. All three had suffered from glomerulonephritis during childhood. A renal biopsy in the brother recently disclosed a membranous glomerulopathy stage 1; otherwise, he is apparently healthy. In both sisters, a systemic lupus erythematosus like disease became manifest at the age of 20 and 23, respectively, resulting in the death of one of them. In the serum of these three family members, the C1q like material was antigenically deficient compared with normal C1q and had, on sucrose gradient analysis, a molecular weight of approximately 65,000 daltons. It did not bind to C1r and C1s. Binding of the dysfunctional C1q to aggregated human gammaglobulin could be demonstrated. On double immunodiffusion analysis, the abnormal C1q was identical with reduced and alkylated C1q. The possible structure of the abnormal C1q molecule is discussed. Images Fig. 1 Fig. 2

Hannema, A J; Kluin-Nelemans, J C; Hack, C E; Eerenberg-Belmer, A J; Mallee, C; van Helden, H P

1984-01-01

164

Localization and functional analysis of the LARGE family of glycosyltransferases: significance for muscular dystrophy.  

PubMed

The dystroglycanopathies are a novel group of human muscular dystrophies due to mutations in known or putative glycosyltransferase enzymes. They share the common pathological feature of a hypoglycosylated form of alpha-dystroglycan, diminishing its ability to bind extracellular matrix ligands. The LARGE glycosyltransferase is mutated in both the myodystrophy mouse and congenital muscular dystrophy type 1D (MDC1D). We have transfected various cell lines with a variety of LARGE expression constructs in order to characterize their subcellular localization and effect on alpha-dystroglycan glycosylation. Wild-type LARGE co-localized with the Golgi marker GM130 and stimulated the production of highly glycosylated alpha-dystroglycan (hyperglycosylation). MDC1D mutants had no effect on alpha-dystroglycan glycosylation and failed to localize correctly, confirming their pathogenicity. The two predicted catalytic domains of LARGE contain three conserved DxD motifs. Systematically mutating each of these motifs to NNN resulted in the mislocalization of one construct, while all failed to have any effect on alpha-dystroglycan glycosylation. A construct lacking the transmembrane domain also failed to localize at the Golgi apparatus. These results indicate that LARGE needs to both physically interact with alpha-dystroglycan and function as a glycosyltransferase in order to stimulate alpha-dystroglycan hyperglycosylation. We have also cloned and overexpressed a homologue of LARGE, glycosyltransferase-like 1B (GYLTL1B). Like LARGE it localized to the Golgi apparatus and stimulated alpha-dystroglycan hyperglycosylation. These results suggest that GYLTL1B may be a candidate gene for muscular dystrophy and that its overexpression could compensate for the deficiency of both LARGE and other glycosyltransferases. PMID:15661757

Brockington, Martin; Torelli, Silvia; Prandini, Paola; Boito, Chiara; Dolatshad, Nazanin F; Longman, Cheryl; Brown, Susan C; Muntoni, Francesco

2005-03-01

165

Evaluating the feasibility of using candidate DNA barcodes in discriminating species of the large Asteraceae family  

Microsoft Academic Search

BACKGROUND: Five DNA regions, namely, rbcL, matK, ITS, ITS2, and psbA-trnH, have been recommended as primary DNA barcodes for plants. Studies evaluating these regions for species identification in the large plant taxon, which includes a large number of closely related species, have rarely been reported. RESULTS: The feasibility of using the five proposed DNA regions was tested for discriminating plant

Ting Gao; Hui Yao; Jingyuan Song; Yingjie Zhu; Chang Liu; Shilin Chen

2010-01-01

166

SV40 large T antigen trans-activates the long terminal repeats of a large family of human endogenous retrovirus-like sequences.  

PubMed

The Simian Virus 40 (SV40) large T antigen (T) is required for the initiation of viral replication, the autoregulation of early gene expression, and the activation of late gene expression in productively infected cells. In addition to these roles, T has been implicated in the transcriptional activation of a variety of viral and cellular promoters. We have used the chloramphenicol acetyltransferase (CAT) reporter gene system to study the effect of T on the long terminal repeats (LTRs) of a large family of human endogenous retrovirus-like sequences, RTVL-H. Here we show that T can activate expression from certain RTVL-H LTRs 5- to 30-fold. Competition experiments in which an excess of plasmid containing only an RTVL-H LTR was cotransfected with an LTR-CAT reporter gene construct confirmed that this effect is specific for RTVL-H sequences. Restriction enzyme analysis using methylation-sensitive enzymes has shown that this activation is not due to plasmid replication. We have also observed this trans-activation effect in two CV-1 cells lines containing stably integrated LTR-CAT constructs. These results demonstrate that a known transforming protein can alter the transcriptional capabilities of RTVL-H LTRs. As there are approximately 3000 related LTRs in the genomes of humans and other primates, these findings suggest that a large number of these promoters and their associated transcripts may be transcriptionally stimulated by this and other oncogens. PMID:1310558

Feuchter, A E; Mager, D L

1992-03-01

167

Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion.  

PubMed Central

It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen only outside the inversion. A recent study in yeast has shown that telomeres, rather than centromeres, lead in chromosome movement just prior to meiosis and may be involved in promoting recombination. We studied by cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in a three-generation family with a large pericentric X chromosome inversion, inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating with the inversion. On DNA analysis there was no evidence of meiotic recombination between the inverted and normal X chromosomes in the inverted segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No deletion or point mutation was found on analysis of the DMD gene. On the basis of the FISH results, we believe that the X inversion is the mutation responsible for DMD in this family. Our results indicate that (1) pericentric X chromosome inversions result in reduction of recombination between the normal and inverted X chromosomes; (2) meiotic X chromosome pairing in these individuals is likely initiated at the telomeres; and (3) in this family DMD is caused by the pericentric inversion. Images Figure 2 Figure 5 Figure 6 Figure 7

Shashi, V.; Golden, W. L.; Allinson, P. S.; Blanton, S. H.; von Kap-Herr, C.; Kelly, T. E.

1996-01-01

168

Computational analysis of looping of a large family of highly bent DNA by LacI.  

PubMed

Sequence-dependent intrinsic curvature of DNA influences looping by regulatory proteins such as LacI and NtrC. Curvature can enhance stability and control shape, as observed in LacI loops formed with three designed sequences with operators bracketing an A-tract bend. We explore geometric, topological, and energetic effects of curvature with an analysis of a family of highly bent sequences, using the elastic rod model from previous work. A unifying straight-helical-straight representation uses two phasing parameters to describe sequences composed of two straight segments that flank a common helically supercoiled segment. We exercise the rod model over this two-dimensional space of phasing parameters to evaluate looping behaviors. This design space is found to comprise two subspaces that prefer parallel versus anti-parallel binding topologies. The energetic cost of looping varies from 4 to 12 kT. Molecules can be designed to yield distinct binding topologies as well as hyperstable or hypostable loops and potentially loops that can switch conformations. Loop switching could be a mechanism for control of gene expression. Model predictions for linking numbers and sizes of LacI-DNA loops can be tested using multiple experimental approaches, which coupled with theory could address whether proteins or DNA provide the observed flexibility of protein-DNA loops. PMID:18931251

Lillian, Todd D; Goyal, Sachin; Kahn, Jason D; Meyhöfer, Edgar; Perkins, N C

2008-12-15

169

Izumo is part of a multiprotein family whose members form large complexes on mammalian sperm  

PubMed Central

SUMMARY Izumo, a sperm membrane protein, is essential for gamete fusion in the mouse. It has an Ig (Immunoglobulin) domain and an N-terminal domain for which neither the functions nor homologous sequences are known. In the present work we identified three novel proteins showing an N-terminal domain with significant homology to the N-terminal domain of Izumo. We named this region "Izumo domain", and the novel proteins “Izumo 2”,”Izumo 3” and “Izumo 4”, retaining “Izumo 1” for the first described member of the family. Izumo 1, 2 and 3 are transmembrane proteins expressed specifically in the testis, and Izumo 4 is a soluble protein expressed in the testis and in other tissues. Electrophoresis under mildly denaturing conditions, followed by Western blot analysis, showed that Izumo 1, 3 and 4 formed protein complexes on sperm, Izumo 1 forming several larger complexes and Izumo 3 and 4 forming a single larger complex. Studies using different recombinant Izumo constructs suggested the Izumo domain possesses the ability to form dimers, whereas the transmembrane domain or the cytoplasmic domain or both of Izumo 1 are required for the formation of multimers of higher order. Co-immunoprecipitation studies showed the presence of other sperm proteins associated with Izumo-1, suggesting Izumo 1 forms a multi-protein membrane complex. Our results raise the possibility that Izumo 1 might be involved in organizing or stabilizing a multi-protein complex essential for the function of the membrane fusion machinery.

Ellerman, Diego A; Pei, Jimin; Gupta, Surabhi; Snell, William J; Myles, Diana; Primakoff, Paul

2013-01-01

170

Fragmentations of the large-subunit rRNA in the family Rhizobiaceae.  

PubMed Central

A 130-nucleotide-long rRNA species corresponding to the 5' end of the 23S rRNA gene was found in 96 strains belonging to different Rhizobium, Bradyrhizobium, and Agrobacterium species. Additional fragmentation in the central region of the large-subunit rRNA occurred in all agrobacteria, except Agrobacterium vitis, and in most Rhizobium leguminosarum and Rhizobium etli strains but did not occur in any of the other rhizobia and bradyrhizobia studied.

Selenska-Pobell, S; Evguenieva-Hackenberg, E

1995-01-01

171

High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.  

PubMed

Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2. PMID:23837913

Brea-Fernández, A J; Cameselle-Teijeiro, J M; Alenda, C; Fernández-Rozadilla, C; Cubiella, J; Clofent, J; Reñé, J M; Anido, U; Milá, M; Balaguer, F; Castells, A; Castellvi-Bel, S; Jover, R; Carracedo, A; Ruiz-Ponte, C

2014-06-01

172

Association of the M1V PRKAR1A Mutation with Primary Pigmented Nodular Adrenocortical Disease in Two Large Families  

PubMed Central

Background: Carney complex (CNC) is a familial multiple neoplasia syndrome frequently associated with primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular adrenal hyperplasia that leads to Cushing’s syndrome (CS). Germline PRKAR1A mutations cause CNC and only rarely isolated PPNAD. Patients and Methods: PRKAR1A mutation analysis in two large families with CS and no other CNC manifestations demonstrated a M1V germline mutation; a total of 21 asymptomatic individuals were screened, and mutation carriers were evaluated for CNC. The mutation was expressed in vitro and functionally tested for its effects on protein kinase A function. Results: Presymptomatic testing identified five first-degree relatives who were M1V carriers and who were all diagnosed with subclinical, mild CS at ages ranging from 20–56 yr. There were no other signs of CNC. In a cell-free system, we detected a shorter compared with the wild-type type 1? regulatory subunit of protein kinase A (PRKAR1A) protein (43 kDa). This was not identified in cell lines from the patients or in transfection experiments in HEK293 cells that showed no detectable PRKAR1A protein from the M1V-bearing constructs. In these cells, the mutant mRNA was expressed in a 1:1 ratio. Conclusion: In two large families, the M1V PRKAR1A mutation resulted in a PPNAD-only phenotype with significant variability both in terms of age of onset and clinical severity. Expression studies showed a unique effect of this sequence change. This study has implications for genetic counseling of carriers of this PRKAR1A mutation and patients with CNC and PPNAD and for the study of PRKAR1A-related tumorigenesis.

Pereira, Alberto M.; Hes, Frederik J.; Horvath, Anelia; Woortman, Sanne; Greene, Elizabeth; Bimpaki, Eirini; Alatsatianos, Anton; Boikos, Sosipatros; Smit, Johannes W.; Romijn, Johannes A.; Nesterova, Maria; Stratakis, Constantine A.

2010-01-01

173

Genome-Wide Linkage Analysis of Cardiovascular Disease Biomarkers in a Large, Multigenerational Family  

PubMed Central

Given the importance of cardiovascular disease (CVD) to public health and the demonstrated heritability of both disease status and its related risk factors, identifying the genetic variation underlying these susceptibilities is a critical step in understanding the pathogenesis of CVD and informing prevention and treatment strategies. Although one can look for genetic variation underlying susceptibility to CVD per se, it can be difficult to define the disease phenotype for such a qualitative analysis and CVD itself represents a convergence of diverse etiologic pathways. Alternatively, one can study the genetics of intermediate traits that are known risk factors for CVD, which can be measured quantitatively. Using the latter strategy, we have measured 21 cardiovascular-related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment). These biomarkers belong to inflammatory and immune, connective tissue, lipid, and hemostasis pathways. Of these, 18 met our quality control standards. Using the pedigree and biomarker data, we have estimated the broad sense heritability (H2) of each biomarker (ranging from 0.09–0.56). A genome-wide panel of 6,015 SNPs was used subsequently to map these biomarkers as quantitative traits. Four showed noteworthy evidence for linkage in multipoint analysis (LOD score ? 2.6): paraoxonase (chromosome 8p11, 21), the chemokine RANTES (22q13.33), matrix metalloproteinase 3 (MMP3, 17p13.3), and granulocyte colony stimulating factor (GCSF, 8q22.1). Identifying the causal variation underlying each linkage score will help to unravel the genetic architecture of these quantitative traits and, by extension, the genetic architecture of cardiovascular risk.

Hauser, Elizabeth; Li, Yi-Ju; Thompson, Dana K.; Johnson, Jessica; Chen, Hsiang-Cheng; Nelson, Sarah; Haynes, Carol; Gregory, Simon G.; Kraus, Virginia B.; Shah, Svati H.

2013-01-01

174

Family structure and phylogenetic analysis of odorant receptor genes in the large yellow croaker (Larimichthys crocea)  

PubMed Central

Background Chemosensory receptors, which are all G-protein-coupled receptors (GPCRs), come in four types: odorant receptors (ORs), vomeronasal receptors, trace-amine associated receptors and formyl peptide receptor-like proteins. The ORs are the most important receptors for detecting a wide range of environmental chemicals in daily life. Most fish OR genes have been identified from genome databases following the completion of the genome sequencing projects of many fishes. However, it remains unclear whether these OR genes from the genome databases are actually expressed in the fish olfactory epithelium. Thus, it is necessary to clone the OR mRNAs directly from the olfactory epithelium and to examine their expression status. Results Eighty-nine full-length and 22 partial OR cDNA sequences were isolated from the olfactory epithelium of the large yellow croaker, Larimichthys crocea. Bayesian phylogenetic analysis classified the vertebrate OR genes into two types, with several clades within each type, and showed that the L. crocea OR genes of each type are more closely related to those of fugu, pufferfish and stickleback than they are to those of medaka, zebrafish and frog. The reconciled tree showed 178 duplications and 129 losses. The evolutionary relationships among OR genes in these fishes accords with their evolutionary history. The fish OR genes have experienced functional divergence, and the different clades of OR genes have evolved different functions. The result of real-time PCR shows that different clades of ORs have distinct expression levels. Conclusion We have shown about 100 OR genes to be expressed in the olfactory epithelial tissues of L. crocea. The OR genes of modern fishes duplicated from their common ancestor, and were expanded over evolutionary time. The OR genes of L. crocea are closely related to those of fugu, pufferfish and stickleback, which is consistent with its evolutionary position. The different expression levels of OR genes of large yellow croaker may suggest varying roles of ORs in olfactory function.

2011-01-01

175

Screening of 38 genes identifies mutations in 62% of families with nonsyndromic deafness in Turkey.  

PubMed

More than 60% of prelingual deafness is genetic in origin, and of these up to 95% are monogenic autosomal recessive traits. Causal mutations have been identified in 1 of 38 different genes in a subset of patients with nonsyndromic autosomal recessive deafness. In this study, we screened 49 unrelated Turkish families with at least three affected children born to consanguineous parents. Probands from all families were negative for mutations in the GJB2 gene, two large deletions in the GJB6 gene, and the 1555A>G substitution in the mitochondrial DNA MTRNR1 gene. Each family was subsequently screened via autozygosity mapping with genomewide single-nucleotide polymorphism arrays. If the phenotype cosegregated with a haplotype flanking one of the 38 genes, mutation analysis of the gene was performed. We identified 22 different autozygous mutations in 11 genes, other than GJB2, in 26 of 49 families, which overall explains deafness in 62% of families. Relative frequencies of genes following GJB2 were MYO15A (9.9%), TMIE (6.6%), TMC1 (6.6%), OTOF (5.0%), CDH23 (3.3%), MYO7A (3.3%), SLC26A4 (1.7%), PCDH15 (1.7%), LRTOMT (1.7%), SERPINB6 (1.7%), and TMPRSS3 (1.7%). Nineteen of 22 mutations are reported for the first time in this study. Unknown rare genes for deafness appear to be present in the remaining 23 families. PMID:21117948

Duman, Duygu; Sirmaci, Asli; Cengiz, F Basak; Ozdag, Hilal; Tekin, Mustafa

2011-01-01

176

SCA15 due to large ITPR1 deletions in a cohort of 333 Caucasian families with dominant ataxia  

PubMed Central

Objectives to determine the frequency and the phenotypical spectrum of SCA15 patients. Methods in the index cases of 333 families with autosomal dominant cerebellar ataxia (ADCA) negative for CAG repeat expansions in coding exons (SCA1,2,3,6,7,17 and dentatorubropallidoluysian atrophy), we searched for heterozygous rearrangements in ITPR1. Taqman PCR (258 index cases) or SNP genome-wide genotyping (75 index cases) were used. Results a deletion of ITPR1 was found in 6/333 (1.8%) families, corresponding to 13 SCA15 patients. Age at onset ranged from 18 to 66 years with a mean of 35±16 years. The symptom at onset was mainly cerebellar gait ataxia, except for one patient presenting with isolated upper limb tremor. Although we tested a large cohort of families irrespective of their phenotype, the main clinical features of SCA15 patients were homogeneous and characterized by a very slowly progressive gait and limb cerebellar ataxia with dysarthria. However, pyramidal signs (two patients), and mild cognitive problems (two patients) were occasionally present. Ocular alterations consisted of nystagmus, mainly horizontal and gaze-evoked (ten patients), and saccadic pursuit (seven patients). Radiological findings showed global or predominant vermian cerebellar atrophy in all patients. Conclusions In this series ITPR1 deletions are rare and account for ~1% of all ADCA. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present in a minority of patients.

Marelli, Cecilia; van de Leemput, Joyce; Johnson, Janel O; Tison, Francois; Thauvin-Robinet, Christel; Picard, Fabienne; Tranchant, Christine; Hernandez, Dena G; Huttin, Bernard; Boulliat, Jacques; Sangla, Iban; Marescaux, Christian; Brique, Serge; Dollfus, Helene; Arepalli, Sampath; Benatru, Isabelle; Ollagnon, Elisabeth; Forlani, Sylvie; Hardy, John; Stevanin, Giovanni; Durr, Alexandra; Singleton, Andrew; Brice, Alexis

2011-01-01

177

Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families.  

PubMed

BRCA1/2 large rearrangement (LR) testing has been available to patients since 2006. Three existing models commonly used in cancer genetics clinical and research settings (BRCAPRO, Penn II and Myriad II) have not been assessed for their performance in predicting the presence of BRCA1/2 large genomic rearrangements in patients who do not have mutations detectable by the traditional Sanger sequencing approach. This study sought to determine if there is an optimal pre-test probability "cut off" value, calculated using these models, to optimize detection of large rearrangements (LRs). Our cohort consisted of 3,301 probands seen for genetic counseling and BRCA1/2 clinical testing from September 2006 to September 2011. A detailed personal and three-generation family history, including self-reported ethnicity, was taken as part of our standard clinical practice. We applied the BRCAPRO, Penn II, and Myriad II models to the probands with LRs. In our cohort of 3,301 probands, 150 carried a non-Ashkenazi mutation in BRCA1 or BRCA2. Seventeen unrelated probands carried a private BRCA1/2 LR (17/150, 11.3 % of all detectable non-AJ mutations). At a pre-test probability cutoff of 10 %, all three empiric risk models would have failed to identify almost 30 % of probands with LRs. Our study shows that BRCA1/2 LR testing should be offered to all women who meet criteria for BRCA1/2 sequence analysis. PMID:24825132

Arnold, Angela G; Otegbeye, Ebunoluwa; Fleischut, Megan Harlan; Glogowski, Emily A; Siegel, Beth; Boyar, Sherry R; Salo-Mullen, Erin; Amoroso, Kim; Sheehan, Margaret; Berliner, Janice L; Stadler, Zsofia K; Kauff, Noah D; Offit, Kenneth; Robson, Mark E; Zhang, Liying

2014-06-01

178

A large family of antivirulence regulators modulates the effects of transcriptional activators in Gram-negative pathogenic bacteria.  

PubMed

We have reported that transcription of a hypothetical small open reading frame (orf60) in enteroaggregative E. coli (EAEC) strain 042 is impaired after mutation of aggR, which encodes a global virulence activator. We have also reported that the cryptic orf60 locus was linked to protection against EAEC diarrhea in two epidemiologic studies. Here, we report that the orf60 product acts as a negative regulator of aggR itself. The orf60 protein product lacks homology to known repressors, but displays 44-100% similarity to at least fifty previously undescribed small (<10 kDa) hypothetical proteins found in many gram negative pathogen genomes. Expression of orf60 homologs from enterotoxigenic E. coli (ETEC) repressed the expression of the AraC-transcriptional ETEC regulator CfaD/Rns and its regulon in ETEC strain H10407. Complementation in trans of EAEC 042orf60 by orf60 homologs from ETEC and the mouse pathogen Citrobacter rodentium resulted in dramatic suppression of aggR. A C. rodentium orf60 homolog mutant showed increased levels of activator RegA and increased colonization of the adult mouse. We propose the name Aar (AggR-activated regulator) for the clinically and epidemiologically important orf60 product in EAEC, and postulate the existence of a large family of homologs among pathogenic Enterobacteriaceae and Pasteurellaceae. We propose the name ANR (AraC Negative Regulators) for this family. PMID:24875828

Santiago, Araceli E; Ruiz-Perez, Fernando; Jo, Noah Y; Vijayakumar, Vidhya; Gong, Mei Q; Nataro, James P

2014-05-01

179

A Large Family of Antivirulence Regulators Modulates the Effects of Transcriptional Activators in Gram-negative Pathogenic Bacteria  

PubMed Central

We have reported that transcription of a hypothetical small open reading frame (orf60) in enteroaggregative E. coli (EAEC) strain 042 is impaired after mutation of aggR, which encodes a global virulence activator. We have also reported that the cryptic orf60 locus was linked to protection against EAEC diarrhea in two epidemiologic studies. Here, we report that the orf60 product acts as a negative regulator of aggR itself. The orf60 protein product lacks homology to known repressors, but displays 44–100% similarity to at least fifty previously undescribed small (<10 kDa) hypothetical proteins found in many gram negative pathogen genomes. Expression of orf60 homologs from enterotoxigenic E. coli (ETEC) repressed the expression of the AraC-transcriptional ETEC regulator CfaD/Rns and its regulon in ETEC strain H10407. Complementation in trans of EAEC 042orf60 by orf60 homologs from ETEC and the mouse pathogen Citrobacter rodentium resulted in dramatic suppression of aggR. A C. rodentium orf60 homolog mutant showed increased levels of activator RegA and increased colonization of the adult mouse. We propose the name Aar (AggR-activated regulator) for the clinically and epidemiologically important orf60 product in EAEC, and postulate the existence of a large family of homologs among pathogenic Enterobacteriaceae and Pasteurellaceae. We propose the name ANR (AraC Negative Regulators) for this family.

Santiago, Araceli E.; Ruiz-Perez, Fernando; Jo, Noah Y.; Vijayakumar, Vidhya; Gong, Mei Q.; Nataro, James P.

2014-01-01

180

The Crystal Structure of Bacteriophage HK97 gp6: Defining a Large Family of Head?Tail Connector Proteins  

SciTech Connect

The final step in the morphogenesis of long-tailed double-stranded DNA bacteriophages is the joining of the DNA-filled head to the tail. The connector is a specialized structure of the head that serves as the interface for tail attachment and the point of egress for DNA from the head during infection. Here, we report the determination of a 2.1 {angstrom} crystal structure of gp6 of bacteriophage HK97. Through structural comparisons, functional studies, and bioinformatic analysis, gp6 has been determined to be a component of the connector of phage HK97 that is evolutionarily related to gp15, a well-characterized connector component of bacteriophage SPP1. Whereas the structure of gp15 was solved in a monomeric form, gp6 crystallized as an oligomeric ring with the dimensions expected for a connector protein. Although this ring is composed of 13 subunits, which does not match the symmetry of the connector within the phage, sequence conservation and modeling of this structure into the cryo-electron microscopy density of the SPP1 connector indicate that this oligomeric structure represents the arrangement of gp6 subunits within the mature phage particle. Through sequence searches and genomic position analysis, we determined that gp6 is a member of a large family of connector proteins that are present in long-tailed phages. We have also identified gp7 of HK97 as a homologue of gp16 of phage SPP1, which is the second component of the connector of this phage. These proteins are members of another large protein family involved in connector assembly.

Cardarelli, Lia; Lam, Robert; Tuite, Ashleigh; Baker, Lindsay A.; Sadowski, Paul D.; Radford, Devon R.; Rubinstein, John L.; Battaile, Kevin P.; Chirgadze, Nickolay; Maxwell, Karen L.; Davidson, Alan R. (UHN); (Toronto); (Hauptman)

2010-08-17

181

Central areolar choroidal dystrophy associated with inherited drusen in a multigeneration Tunisian family: exclusion of the PRPH2 gene and the 17p13 locus.  

PubMed

Central areolar choroidal dystrophy (CACD) is a rare inherited disease, which causes progressive profound loss of vision in patients during their fourth decade. It is characterized by atrophy of retinal pigment epithelium, photoreceptors and choriocapillaris. The disease showed a genetic heterogeneity. Previously, mutations in the peripherin/RDS gene and a linkage to the CACD locus in the 17p13 region have been reported in CACD families. In this study, we report on a clinical and genetic investigation of CACD in a large Tunisian consanguineous family with 21 affected individuals in three living generations. CACD has been associated with drusen in some of them. Linkage analysis and mutational screening exclude linkage to the PRPH2/RDS gene and to the CACD locus. These data provide further evidence of the genetic heterogeneity of CACD. PMID:19696794

Ouechtati, Farah; Belhadj Tahar, Olfa; Mhenni, Amin; Chakroun, Sonia; Chouchene, Ibtissem; Oueslati, Souad; Rebai, Ahmed; Abdelhak, Sonia; Jeddi-Blouza, Amel

2009-10-01

182

A 27-bp deletion from one allele of the type III collagen gene (COL3A1) in a large family with Ehlers-Danlos syndrome type IV  

Microsoft Academic Search

A large family with Ehlers-Danlos syndrome type IV (EDS IV) has previously been described. Unlike most cases of EDS IV, fibroblasts from affected members secreted near normal amounts of type III collagen. We have localised the mutation in this family to the CB5 peptide of type III collagen, by using both protein and cDNA mapping techniques. Sequence analysis of cDNA

A. J. Richards; J. C. Lloyd; P. Narcisi; P. N. Ward; A. C. Nicholls; A. De Paepe; F. M. Pope

1992-01-01

183

Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families  

PubMed Central

In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250?K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23–p21.2/p13.3–q21.13 (DFNB83), 12q14.3–q21.2 (DFNB84; two families), 14q23.1–q31.1, and 17p12–q11.2 (DFNB85).

Shahin, Hashem; Walsh, Tom; Rayyan, Amal Abu; Lee, Ming K; Higgins, Jake; Dickel, Diane; Lewis, Kristen; Thompson, James; Baker, Carl; Nord, Alex S; Stray, Sunday; Gurwitz, David; Avraham, Karen B; King, Mary-Claire; Kanaan, Moien

2010-01-01

184

Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families.  

PubMed

In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250 K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23-p21.2/p13.3-q21.13 (DFNB83), 12q14.3-q21.2 (DFNB84; two families), 14q23.1-q31.1, and 17p12-q11.2 (DFNB85). PMID:19888295

Shahin, Hashem; Walsh, Tom; Rayyan, Amal Abu; Lee, Ming K; Higgins, Jake; Dickel, Diane; Lewis, Kristen; Thompson, James; Baker, Carl; Nord, Alex S; Stray, Sunday; Gurwitz, David; Avraham, Karen B; King, Mary-Claire; Kanaan, Moien

2010-04-01

185

Familial Life-Long Persistent Fever of Unknown Origin Responding to Dexamethasone and Uronic Acids.  

National Technical Information Service (NTIS)

A patient of Lebanese ethnic origin was found to have a persistent temperature of 102F with no diurnal variation. He gave a history of persistent life-long fever in himself and a twin brother. His family history was notable for multiple consanguineous mar...

R. H. Herman E. L. Overholt L. Hagler

1968-01-01

186

Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression.  

PubMed

Patient-specific induced pluripotent stem cells (iPSCs) represent a novel system for modeling human genetic disease and could provide a source of cells for large-scale drug-discovery screens. Here we demonstrate the feasibility of performing a primary screen in neural crest precursors derived from iPSCs that were generated from individuals with familial dysautonomia (FD), a rare, fatal genetic disorder affecting neural crest lineages. We tested 6,912 small-molecule compounds and characterized eight that rescued expression of IKBKAP, the gene responsible for FD. One of the hits, SKF-86466, was found to induce IKBKAP transcription through modulation of intracellular cAMP levels and PKA-dependent CREB phosphorylation. SKF-86466 also rescued IKAP protein expression and the disease-specific loss of autonomic neuronal marker expression. Our data implicate alpha-2 adrenergic receptor activity in regulating IKBKAP expression and demonstrate that small-molecule discovery using an iPSC-based disease model can identify candidate drugs for potential therapeutic intervention. PMID:23159879

Lee, Gabsang; Ramirez, Christina N; Kim, Hyesoo; Zeltner, Nadja; Liu, Becky; Radu, Constantin; Bhinder, Bhavneet; Kim, Yong Jun; Choi, In Young; Mukherjee-Clavin, Bipasha; Djaballah, Hakim; Studer, Lorenz

2012-12-01

187

Large repayments of premium subsidies may be owed to the IRS if family income changes are not promptly reported.  

PubMed

Subsidies for health insurance premiums under the Affordable Care Act are refundable tax credits. They can be taken when taxes are filed or in advance, as reductions in monthly premiums that must be reconciled at tax filing. Recipients who take subsidies in advance will receive tax refunds if their subsidies were too small but will have to make repayments if their subsidies were too high. We analyzed predicted repayments and refunds for people receiving subsidies, using California as a case study. We found that many families could owe large repayments to the Internal Revenue Service at their next tax filing. If income changes were reported and credits adjusted in a timely manner throughout the tax year, the number of filers owing repayments would be reduced by 7-41 percent and the median size of repayments reduced by as much as 61 percent (depending on the level of changes reported and the method used to adjust the subsidy amounts). We recommend that the health insurance exchanges mandated by the Affordable Care Act educate consumers about how the subsidies work and the need to promptly report income changes. We also recommend that they provide tools and assistance to determine the amount of subsidies that enrollees should take in advance. PMID:24019357

Jacobs, Ken; Graham-Squire, Dave; Gould, Elise; Roby, Dylan

2013-09-01

188

A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22.  

PubMed

Dentoleukoencephalopathies with autosomal recessive inheritance are very rare. Recently, a large inbred Syrian pedigree was reported with oligodontia in association with a degenerative neurologic condition characterized by progressive ataxia and pyramidal syndrome and abnormalities in the white matter and cortical atrophy. A whole-genome screening of this family using 382 microsatellite markers was completed, but no evidence was found of linkage to any chromosomal region. A genome-wide linkage analysis using the 260K single nucleotide polymorphism Affymetrix array was then undertaken and a maximum multipoint logarithm of the odds score of 5.66 (NPL score = 7.65) was detected on chromosome 10q22 region. This genomic interval contains 95 known genes including the Prosaposin gene (PSAP) responsible for metachromatic leukodystrophy, which was excluded. Seventeen additional candidate genes were tested and excluded. Sequencing of the whole candidate locus is in progress and should allow the identification of the causative gene in this rare disease, thereby improving the understanding of the physiopathology of this disease. PMID:20721593

Chouery, Eliane; Delague, Valérie; Jalkh, Nadine; Salem, Nabiha; Kfoury, Jessy; Rodriguez, Diana; Chabrol, Brigitte; Boespflug-Tanguy, Odile; Lévy, Nicolas; Serre, Jean Louis; Mégarbané, André

2011-02-01

189

Familial chondrocalcinosis in the Chiloe Islands, Chile.  

PubMed Central

Studies about chondrocalcinosis in the Chiloe Islands (Chile) showed the high frequency of the disease there and how most of it is aggregated in a few highly involved families. Pedigrees and the high degree of consanguinity among parents of index cases pointed to a recessive inheritance. The presence of common Caucasian anthropological features of genetic value in the patients and the lack of Indian mixture in three of the involved families, documented back to 1600, suggest a Caucasian origin of the mutation. Biochemical studies of the patients' synovial fluid showed a significant rise in pyrophosphate concentration. Calcium, phosphorus, and alkaline phosphatase concentrations were not different from a control group.

Reginato, A J; Hollander, J L; Martinez, V; Valenzuela, F; Schiapachasse, V; Covarrubias, E; Jacobelli, S; Arinoviche, R; Silcox, D; Ruiz, F

1975-01-01

190

Identification and analysis of large intergenic non-coding RNAs regulated by p53 family members through a genome-wide analysis of p53-binding sites.  

PubMed

p53 is one of the most important known tumor suppressor genes, and it is inactivated in approximately half of human cancers. p53 family members execute various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. Therefore, the direct transcriptional targets of the p53 family must be explored to elucidate the functional mechanisms of family members. To identify the direct transcriptional targets of p53 family members, we performed chromatin immunoprecipitation together with next-generation sequencing (ChIP-seq) and searched for p53-binding motifs across the entire human genome. Among the identified ChIP-seq peaks, approximately half were located in an intergenic region. Therefore, we assumed large intergenic non-coding RNAs (lincRNAs) to be major targets of the p53 family. Recent reports have revealed that lincRNAs play an important role in various biological and pathological processes, such as development, differentiation, stemness and carcinogenesis. Through a combination of ChIP-seq and in silico analyses, we found 23 lincRNAs that are upregulated by the p53 family. Additionally, knockdown of specific lincRNAs modulated p53-induced apoptosis and promoted the transcription of a gene cluster. Our results suggest that p53 family members, and lincRNAs constitute a complex transcriptional network involved in various biological functions and tumor suppression. PMID:24403050

Idogawa, Masashi; Ohashi, Tomoko; Sasaki, Yasushi; Maruyama, Reo; Kashima, Lisa; Suzuki, Hiromu; Tokino, Takashi

2014-06-01

191

Praxic and Nonverbal Cognitive Deficits in a Large Family with a Genetically Transmitted Speech and Language Disorder  

Microsoft Academic Search

A pronounced speech and language disorder affecting half of the 30 members of the four-generational KE family has been attributed by some researchers to a specific defect in the generation of morphosyntactic rules. The reported selectivity of the impairment has led to the view that the affected members suffer from a grammar-specific disorder. Our investigations of the same KE family

Faraneh Vargha-Khadem; Kate Watkins; Katie Alcock; Paul Fletcher; Richard Passingham

1995-01-01

192

The gustatory receptor family in the silkworm moth Bombyx mori is characterized by a large expansion of a single lineage of putative bitter receptors.  

PubMed

The gustatory receptor (Gr) family of insect chemoreceptors includes receptors for sugars and bitter compounds, as well as cuticular hydrocarbons and odorants such as carbon dioxide. We have annotated a total of 65 Gr genes from the silkworm Bombyx mori genome. The Gr family in the silkworm moth includes putative carbon dioxide receptors and sugar receptors, as well as duplicated orthologues of the orphan DmGr43a receptor. Most prominent in this 65-gene family, however, is a single large expansion of 55 Grs that we propose are predominantly 'bitter' receptors involved in perception of the large variety of secondary plant chemicals that caterpillars and moths encounter. These Grs might therefore mediate food choice and avoidance as well as oviposition site preference. PMID:19133074

Wanner, K W; Robertson, H M

2008-12-01

193

Living in a Large Family does Something for You: Influence of Family on the Achievement of African and Caribbean Women in Science  

NASA Astrophysics Data System (ADS)

This article examines the influence of the family on women's achievement in scientific careers in the sub-Saharan African and Caribbean regions. It is based on semistructured interviews with 20 doctoral-level African and Caribbean women scientists working in research and academic institutions in these societies. Given the diversity of structural conditions, and economic, geopolitical, and sociocultural experiences, it is argued that the road to success in the pursuance of a scientific career are not the same, although there are areas of common ground. The study shows that when compared with their North American and European counterparts, there are significant differences in the family experiences of African and Caribbean women scientists that must be made visible and pursued more rigorously in further studies.

Beoku-Betts, Josephine A.

194

A Familial Form of Congenital Hypopituitarism Due to a PROP1 Mutation in a Large Kindred: Phenotypic and in Vitro Functional Studies  

Microsoft Academic Search

We report the natural history of a hypopituitarism in a large Tunisian kindred including 29 subjects from the same con- sanguineous family. The index case was a 9-yr-old girl with severe growth retardation due to complete GH deficiency and partial corticotroph, lactotroph, and thyrotroph deficiencies. Magnetic resonance imaging showed a hyperplastic anterior pituitary. Thirteen of the 28 relatives examined (10

RACHEL REYNAUD; MOLKA CHADLI-CHAIEB; SOPHIE VALLETTE-KASIC; ANNE BARLIER; JACQUES SARLES; ISABELLE PELLEGRINI-BOUILLER; ALAIN ENJALBERT; LARBI CHAIEB; THIERRY BRUE

195

Mapping of a possible X-linked form of familial developmental dysphasia (FDD) in a single large pedigree  

SciTech Connect

Children diagnosed with developmental dysphasia develop speech very late without exhibiting sensory or motor dysfunction, and when they do begin to speak their grammar is abnormal. A large three-generation British pedigree was recently identified in which 16 out of 30 members were diagnosed as dysphasic. Assuming a dominant mode of inheritance with homogeneous phenotypic expression and complete penetrance among affected members, we showed by simulation analysis that this pedigree has the power to detect linkage to marker loci with an average maximum LOD score of 3.67 at {theta}=0.1. Given the absence of male-to-male transmission and a ratio of female to male affecteds (10/6) in this pedigree within the expected range for an X-linked dominant mode of inheritance, we decided to begin a genome-wide linkage analysis with microsatellite markers on the human X chromosome. Fifteen individuals (10 affected) from three generations were genotyped with 35 polymorphic STS`s (Research Genetics) which were approximately uniformly distributed along the X chromosome. Two-point linkage was assessed using the MLINK and ILINK programs from the LINKAGE package. Markers DXS1223, DXS987, DXS996 and DXS1060 on Xp22 showed consistent linkage to the disease locus with a maximum LOD score of 0.86 at a distance of 22 cM for DXS1060. If further analysis with additional markers and additional family members confirms X-linkage, such a localization would provide support for Lehrke`s hypothesis for X-linkage of major intellectual traits including verbal functioning.

Dunne, P.W.; Doody, R.S.; Epstein, H.F. [Baylor College of Medicine, Houston, TX (United States)] [and others

1994-09-01

196

Application of a sensitive collection heuristic for very large protein families: Evolutionary relationship between adipose triglyceride lipase (ATGL) and classic mammalian lipases  

PubMed Central

Background Manually finding subtle yet statistically significant links to distantly related homologues becomes practically impossible for very populated protein families due to the sheer number of similarity searches to be invoked and analyzed. The unclear evolutionary relationship between classical mammalian lipases and the recently discovered human adipose triglyceride lipase (ATGL; a patatin family member) is an exemplary case for such a problem. Results We describe an unsupervised, sensitive sequence segment collection heuristic suitable for assembling very large protein families. It is based on fan-like expanding, iterative database searches. To prevent inclusion of unrelated hits, additional criteria are introduced: minimal alignment length and overlap with starting sequence segments, finding starting sequences in reciprocal searches, automated filtering for compositional bias and repetitive patterns. This heuristic was implemented as FAMILYSEARCHER in the ANNIE sequence analysis environment and applied to search for protein links between the classical lipase family and the patatin-like group. Conclusion The FAMILYSEARCHER is an efficient tool for tracing distant evolutionary relationships involving large protein families. Although classical lipases and ATGL have no obvious sequence similarity and differ with regard to fold and catalytic mechanism, homology links detected with FAMILYSEARCHER show that they are evolutionarily related. The conserved sequence parts can be narrowed down to an ancestral core module consisting of three ?-strands, one ?-helix and a turn containing the typical nucleophilic serine. Moreover, this ancestral module also appears in numerous enzymes with various substrate specificities, but that critically rely on nucleophilic attack mechanisms.

Schneider, Georg; Neuberger, Georg; Wildpaner, Michael; Tian, Sun; Berezovsky, Igor; Eisenhaber, Frank

2006-01-01

197

Protein kinase C ? and ? are members of a large kinase family of high potential for novel anticancer targeted therapy  

Microsoft Academic Search

Protein kinase C (PKC) family enzymes participate in several cell-signaling pathways by controlling proliferation, differentiation,\\u000a senescence, invasion, and apoptosis both in normal and in cancer cells. The PKC family consists of serine\\/threonine kinases\\u000a including 12 isoforms, which could be divided in three groups based on their interactions with calcium and diacylglycerol.\\u000a Studies have suggested that PKCs play a role in

A. Ghoul; M. Serova; K. A. Benhadji; E. Cvitkovic; S. Faivre; E. Philips; F. Calvo; F. Lokiec; E. Raymond

2006-01-01

198

Familial hereditary progressive sensorineural hearing loss among Saudi population  

Microsoft Academic Search

Clinical and audiological studies of 234 Saudi patients from the central area of Saudi Arabia with progressive sensorineural hearing loss were carried out in Riyadh. One hundred and sixty-four came from 38 families, i.e. 70% of the total and 30% were sporadic cases. Consanguinity was found in 80.8%. Their hearing loss was characterized as being bilateral sensorineural, starting at 1

Siraj M. Zakzouk; Kawther Abul Fadle; Fatma H. Al Anazy

1995-01-01

199

Exome sequencing identifies MPL as a causative gene in familial aplastic anemia.  

PubMed

The primary cause of aplastic anemia remains unknown in many patients. The aim of this study was to clarify the genetic cause of familial aplastic anemia. Genomic DNA of an affected individual from a multiplex consanguineous family was hybridized to a Nimblegen exome library before being sequenced on a GAIIx genome analyzer. Once the disease causing homozygous mutation had been confirmed in the consanguineous family, this gene was then analyzed for mutation in 33 uncharacterized index cases of aplastic anemia (<13 years) using denaturing HPLC. Abnormal traces were confirmed by direct sequencing. Exome sequencing identified a novel homozygous nonsense mutation in the thrombopoietin receptor gene MPL. An additional novel homozygous MPL mutation was identified in the screen of 33 aplastic anemia patients. This study shows for the first time a link between homozygous MPL mutations and familial aplastic anemia. It also highlights the important role of MPL in trilineage hematopoiesis. PMID:22180433

Walne, Amanda J; Dokal, Arran; Plagnol, Vincent; Beswick, Richard; Kirwan, Michael; de la Fuente, Josu; Vulliamy, Tom; Dokal, Inderjeet

2012-04-01

200

Providing maternal and child health-family planning services to a large rural population: results of the Bohol Project, Philippines.  

PubMed Central

The Bohol Project (1975-1979) sought to improve maternal and child health and to increase the use of family planning among a rural Philippine population of 400,000. Research indicated that maternal and child health (MCH) services did become more available during the Project period and coverage of the priority populations improved. Family planning (FP) use, particularly of less effective methods, increased and fertility declined although some change could have been expected even without the Project. Deaths due to neonatal tetanus were almost eliminated by mortality rates did not decline for a number of reasons, including the fact that services were probably not tailored closely enough to local health problems, especially respiratory diseases. The Project showed that it was possible to increase health and family planning services by using low-cost strategies (such as setting up community drug stores) and by employing paramedical workers, in this case, midwives. Preventive MCH-FP services were not overwhelmed by curative services as had been feared. Perhaps the most significant contributions of the Project were the lessons learned about delivering health and family planning services and conducting evaluation research. In general, if developing countries could maintain well-evaluated field laboratories for working out health and family planning delivery approaches before going nationwide, it is likely that time and money would be saved in the long run.

Williamson, N E; Parado, J P; Maturan, E G

1983-01-01

201

Analysis of BRCA1and BRCA2 large genomic rearrangements in Sri Lankan familial breast cancer patients and at risk individuals  

PubMed Central

Background Majority of mutations found to date in the BRCA1/BRCA2 genes in breast and/or ovarian cancer families are point mutations or small insertions and deletions scattered over the coding sequence and splice junctions. Such mutations and sequence variants of BRCA1 and BRCA2 genes were previously identified in a group of Sri Lankan breast cancer patients. Large genomic rearrangements have been characterized in BRCA1 and BRCA2 genes in several populations but these have not been characterized in Sri Lankan breast cancer patients. Findings A cohort of familial breast cancer patients (N?=?57), at risk individuals (N?=?25) and healthy controls (N?=?23) were analyzed using multiplex ligation-dependent probe amplification method to detect BRCA1 and BRCA2 large genomic rearrangements. One familial breast cancer patient showed an ambiguous deletion in exon 6 of BRCA1 gene. Full sequencing of the ambiguous region was used to confirm MLPA results. Ambiguous deletion detected by MLPA was found to be a false positive result confirming that BRCA1 large genomic rearrangements were absent in the subjects studied. No BRCA2 rearrangement was also identified in the cohort. Conclusion Thus this study demonstrates that BRCA1 and BRCA2 large genomic rearrangements are unlikely to make a significant contribution to aetiology of breast cancer in Sri Lanka.

2014-01-01

202

Familial mitochondrial DNA depletion in liver: haplotype analysis of candidate genes  

Microsoft Academic Search

Two sons and one daughter of healthy consanguineous parents presented with fatal hepatic failure in association with severe\\u000a depletion of mitochondrial (mt)DNA in liver; a third son is healthy. Other published cases of mtDNA depletion concern single\\u000a members of a family, which excludes the use of haplotype analysis. In the family presented here, the inheritance of the genes\\u000a for mitochondrial

Johannes N. Spelbrink; Mieke J. M. Van Galen; R. Zwart; Henk D. Bakker; Anja Rovio; Howard T. Jacobs; Coby Van den Bogert

1998-01-01

203

Familial hypercholesterolemia and intracavernous venous spilling of cholesterol in a child with large suprasellar dermoid cyst. Case report  

Microsoft Academic Search

A unique case of suprasellar dermoid cyst and familial hypercholesterolemia in a child is reported. Such an association, which strengthens the congenital hypothesis of dermoid cysts, could be a manifestation of a complex dyslipidemic inherited syndrome, at least in children. Surgical removal of the dermoid cyst which spilled cholesterol into the cavernous and intercavernous sinuses, allowed reduction of cholesterol levels

Pierpaolo Lunardi; Paolo Missori

1995-01-01

204

Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families.  

PubMed Central

Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. We recently have demonstrated that AVED is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP). We now have identified a total of 13 mutations in 27 families. Four mutations were found in >=2 independent families: 744delA, which is the major mutation in North Africa, and 513insTT, 486delT, and R134X, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the alpha-TTP gene revealed differences from Friedreich ataxia: cardiomyopathy was found in only 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represents the largest group of patients and mutations reported for this often misdiagnosed disease and points to the need for an early differential diagnosis with Friedreich ataxia, in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops.

Cavalier, L; Ouahchi, K; Kayden, H J; Di Donato, S; Reutenauer, L; Mandel, J L; Koenig, M

1998-01-01

205

The fragile X syndrome in a large family. III. Investigations on linkage of flanking DNA markers with the fragile site Xq27  

Microsoft Academic Search

In a large family with the fragile X syndrome, we performed linkage investigations with six probes, detecting RFLPs at both sides of the fragile site Xq27. The nearest flanking markers were cX55.7 (DXS105) on the centromeric side (theta = 0.04, lod 5.0) and St14 (DXS52) on the telomeric side (theta = 0.08, lod 4.0). Non-penetrance could be shown by the

H Veenema; N J Carpenter; E Bakker; M H Hofker; A M Ward; P L Pearson

1987-01-01

206

Function Search in a Large Transcription Factor Gene Family in Arabidopsis: Assessing the Potential of Reverse Genetics to Identify Insertional Mutations in R2R3 MYB Genes  

Microsoft Academic Search

More than 92 genes encoding MYB transcription factors of the R2R3 class have been described in Arabidopsis. The functions of a few members of this large gene family have been described, indicating important roles for R2R3 MYB transcription factors in the regulation of secondary metabolism, cell shape, and disease resistance, and in responses to growth regulators and stresses. For the

Ruth C. Meissner; Hailing Jin; Eleonora Cominelli; Marten Denekamp; Antonio Fuertes; Raffaella Greco; Harald D. Kranz; Steven Penfield; Katia Petroni; Ana Urzainqui; Cathie Martin; Javier Paz-Ares; Sjef Smeekens; Chiara Tonelli; Bernd Weisshaar; Elvira Baumann; Victor Klimyuk; Sylvestre Marillonnet; Kanu Patel; Elly Speulman; Alain F. Tissier; David Bouchez; Jonathan J. D. Jones; Andy Pereira; Ellen Wisman; Michael Bevan

1999-01-01

207

Deletion of exons 1-3 of the MEN1 gene in a large Italian family causes the loss of menin expression.  

PubMed

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disease, characterized by parathyroid adenomas, endocrine gastroenteropancreatic tumors and pituitary adenomas, due to inactivating mutations of the MEN1 gene (chromosome 11q13). MEN1 mutations are mainly represented by nonsense, deletions/insertions, splice site or missense mutations that can be detected by direct sequencing of genomic DNA. However, MEN1 patients with large heterozygous deletions may escape classical genetic screening and may be misidentified as phenocopies, thereby hindering proper clinical surveillance. We employed a real-time polymerase chain reaction application, the TaqMan copy number variation assay, to evaluate a family in which we failed to identify an MEN1 mutation by direct sequencing, despite a clear clinical diagnosis of MEN1 syndrome. Using the TaqMan copy number variation assay we identified a large deletion of the MEN1 gene involving exons 1 and 2, in three affected family members, but not in the other nine family members that were to date clinically unaffected. The same genetic alteration was not found in a group of ten unaffected subjects, without family history of endocrine tumors. The MEN1 deletion was further confirmed by multiplex ligation-dependent probe amplification, which showed the deletion extended from exon 1 to exon 3. This new approach allowed us to correctly genetically diagnose three clinical MEN1 patients that were previously considered as MEN1 phenocopies. More importantly, we excluded the presence of genetic alterations in the unaffected family members. These results underline the importance of using a variety of available biotechnology approaches when pursuing a genetic diagnosis in a clinically suggestive setting of inherited endocrine cancer. PMID:24522746

Zatelli, Maria Chiara; Tagliati, Federico; Di Ruvo, Mauro; Castermans, Emilie; Cavazzini, Luigi; Daly, Adrian F; Ambrosio, Maria Rosaria; Beckers, Albert; degli Uberti, Ettore

2014-06-01

208

Age-related Macular Degeneration Clinical Features in a Large Family and Linkage to Chromosome 1q  

Microsoft Academic Search

Methods: An ARMD pedigree was identified, and the disease state of family members was documented by stereoscopic fundus photography and was classified us- ing a modified version of the Wisconsin Age-Related Maculopathy Grading System. A genome-wide screen at approximately 6-centimorgan spacing using a DNA- pooling strategy combined with shared-segment analy- sis was used to identify likely chromosomal regions. The entire

Michael L. Klein; Dennis W. Schultz; Al Edwards; Tara C. Matise; Kristal Rust; C. Blair Berselli; Karmen Trzupek; Richard G. Weleber; Jurg Ott; Mary K. Wirtz; Ted S. Acott; Arch Ophthalmol

1998-01-01

209

The relatively large beta-tubulin gene family of Arabidopsis contains a member with an unusual transcribed 5? noncoding sequence  

Microsoft Academic Search

We have characterized the beta-tubulin gene family of Arabidopsis thaliana. Five distinct genes were cloned and analyzed by restriction enzyme mapping and cross-hybridization studies. Three of the genes appear to be dispersed, whereas two others are linked within 1.5 kb of one another. The two linked genes are closely related and appear to have resulted from a fairly recent duplication.

M. David Marks; Joanne West

1987-01-01

210

Three new families with arterial tortuosity syndrome.  

PubMed

Arterial tortuosity syndrome (ATS) is a rare condition with autosomal recessive inheritance characterized by connective tissue abnormalities. The most specific clinical findings are cardiovascular anomalies including tortuosity, lengthening, aneurysm, and stenosis formation of major arteries. Also ventricular hypertrophy is frequently present. Other anomalies are skin hyperextensibility and cutis laxa, joint laxity or contractures of the joints, and inguinal herniae. Histology shows disruption of elastic fibers of the media. These features suggest that ATS is a connective tissue disorder. A biochemical or molecular defect has not yet been identified. We describe here nine additional ATS patients from three consanguineous Moroccan families and review a total of 35 patients with this uncommon condition. PMID:15529317

Wessels, Marja W; Catsman-Berrevoets, Coriene E; Mancini, Grazia M S; Breuning, Martijn H; Hoogeboom, Jeanette J M; Stroink, Hans; Frohn-Mulder, Ingrid; Coucke, Paul J; Paepe, Anne De; Niermeijer, Martinus F; Willems, Patrick J

2004-12-01

211

A family-wide RT-PCR assay for detection of paramyxoviruses and application to a large-scale surveillance study.  

PubMed

Family-wide molecular diagnostic assays are valuable tools for initial identification of viruses during outbreaks and to limit costs of surveillance studies. Recent discoveries of paramyxoviruses have called for such assay that is able to detect all known and unknown paramyxoviruses in one round of PCR amplification. We have developed a RT-PCR assay consisting of a single degenerate primer set, able to detect all members of the Paramyxoviridae family including all virus genera within the subfamilies Paramyxovirinae and Pneumovirinae. Primers anneal to domain III of the polymerase gene, with the 3' end of the reverse primer annealing to the conserved motif GDNQ, which is proposed to be the active site for nucleotide polymerization. The assay was fully optimized and was shown to indeed detect all available paramyxoviruses tested. Clinical specimens from hospitalized patients that tested positive for known paramyxoviruses in conventional assays were also detected with the novel family-wide test. A high-throughput fluorescence-based RT-PCR version of the assay was developed for screening large numbers of specimens. A large number of samples collected from wild birds was tested, resulting in the detection of avian paramyxoviruses type 1 in both barnacle and white-fronted geese, and type 8 in barnacle geese. Avian metapneumovirus type C was found for the first time in Europe in mallards, greylag geese and common gulls. The single round family-wide RT-PCR assay described here is a useful tool for the detection of known and unknown paramyxoviruses, and screening of large sample collections from humans and animals. PMID:22496880

van Boheemen, Sander; Bestebroer, Theo M; Verhagen, Josanne H; Osterhaus, Albert D M E; Pas, Suzan D; Herfst, Sander; Fouchier, Ron A M

2012-01-01

212

Consanguinity around the world: what do the genomic data of the HGDP-CEPH diversity panel tell us?  

PubMed

Inbreeding coefficients and consanguineous mating types are usually inferred from population surveys or pedigree studies. Here, we present a method to estimate them from dense genome-wide single-nucleotide polymorphism genotypes and apply it to 940 unrelated individuals from the Human Genome Diversity Panel (HGDP-CEPH). Inbreeding is observed in almost all populations of the panel, and the highest inbreeding levels and frequencies of inbred individuals are found in populations of the Middle East, Central South Asia and the Americas. In these regions, first cousin (1C) marriages are the most frequent, but we also observed marriages between double first cousins (2 × 1C) and between avuncular (AV) pairs. Interestingly, if 2 × 1C marriages are preferred to AV marriages in Central South Asia and the Middle East, the contrary is found in the Americas. There are thus some regional trends but there are also some important differences between populations within a region. Individual results can be found on the CEPH website at ftp://ftp.cephb.fr/hgdp_hbd/. PMID:21364699

Leutenegger, Anne-Louise; Sahbatou, Mourad; Gazal, Steven; Cann, Howard; Génin, Emmanuelle

2011-05-01

213

A clinical evaluation tool for SNP arrays, especially for autosomal recessive conditions in offspring of consanguineous parents  

PubMed Central

Purpose: This report describes a fast online tool to accelerate and improve clinical interpretation of single nucleotide polymorphism array results for diagnostic purposes, when consanguinity or inbreeding is identified. Methods: We developed a web-based program that permits entry of regions of homozygosity and, using OMIM, UCSC, and NCBI databases, retrieves genes within these regions as well as their associated autosomal recessive disorders. Relevant OMIM Clinical Synopses can be searched, using key clinical terms permitting further filtering for candidate genes and disorders. Results: The tool aids the clinician by arriving at a short list of relevant candidate disorders, guiding the continued diagnostic work-up. Its efficacy is illustrated by presenting seven patients who were diagnosed using this tool. Conclusion: The online single nucleotide polymorphism array evaluation tool rapidly and systematically identifies relevant genes and associated conditions mapping to identified regions of homozygosity. The built-in OMIM clinical feature search allows the user to further filter to reach a short list of candidate conditions relevant for the diagnosis, making it possible to strategize more focused diagnostic testing. The tabulated results can be downloaded and saved to the desktop in an Excel format. Its efficacy is illustrated by providing a few clinical examples.

Wierenga, Klaas J.; Jiang, Zhijie; Yang, Amy C.; Mulvihill, John J.; Tsinoremas, Nicholas F.

2013-01-01

214

Further evidence that pediatric-onset bipolar disorder comorbid with ADHD represents a distinct subtype: results from a large controlled family study.  

PubMed

We used familial risk analysis to clarify the diagnostic comorbidity between pediatric BP-I disorder and ADHD, testing the hypothesis that pediatric-BP-I disorder comorbid with ADHD represents a distinct subtype. Structured diagnostic interviews were used to obtain DSM-IV psychiatric diagnoses on first-degree relatives (n = 726) of referred children and adolescents satisfying diagnostic criteria for BP-I disorder (n = 239). For comparison, diagnostic information on the first-degree relatives (N = 511) of non-bipolar ADHD children (N = 162) and the first degree relatives (N = 411) of control children (N = 136) with neither ADHD nor BP-I disorder were examined. BP-I disorder and ADHD in probands bred true irrespective of the comorbidity with the other disorder. We also found that the comorbid condition of BP-I disorder plus ADHD also bred true in families, and the two disorders co-segregated among relatives. This large familial risk analysis provides compelling evidence that pediatric BP-I disorder comorbid with ADHD represents a distinct familial subtype. PMID:22979994

Biederman, Joseph; Faraone, Stephen V; Petty, Carter; Martelon, Marykate; Woodworth, K Yvonne; Wozniak, Janet

2013-01-01

215

Further Evidence that Pediatric-Onset Bipolar Disorder Comorbid with ADHD Represents a Distinct Subtype: Results from a Large Controlled Family Study  

PubMed Central

We used familial risk analysis to clarify the diagnostic comorbidity between pediatric BP-I disorder and ADHD, testing the hypothesis that pediatric BP-I disorder comorbid with ADHD represents a distinct subtype. Structured diagnostic interviews were used to obtain DSM-IV psychiatric diagnoses on first-degree relatives (n=726) of referred children and adolescents satisfying diagnostic criteria for BP-I disorder (n=239). For comparison, diagnostic information on the first-degree relatives (N=511) of non-bipolar ADHD children (N=162) and the first degree relatives (N=411) of control children (N=136) with neither ADHD nor BP-I disorder were examined. BP-I disorder and ADHD in probands bred true irrespective of the comorbidity with the other disorder. We also found that the comorbid condition of BP-I disorder plus ADHD also bred true in families, and the two disorders co-segregated among relatives. This large familial risk analysis provides compelling evidence that pediatric BP-I disorder comorbid with ADHD represents a distinct familial subtype.

Biederman, Joseph; Faraone, Stephen V.; Petty, Carter; Martelon, MaryKate; Woodworth, K. Yvonne; Wozniak, Janet

2012-01-01

216

Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree  

PubMed Central

BACKGROUND/AIMS—Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases. A large autosomal dominant FEVR family was studied, both clinically and by linkage analysis, to determine whether it differed from the known forms of FEVR.?METHODS—Affected members and obligate gene carriers from this family were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and in some cases fluorescein angiography. Patient DNAs were genotyped for markers at the EVR1 locus on chromosome 11q13.?RESULTS—The clinical evaluation in this family is consistent with previous descriptions of FEVR pedigrees, but linkage analysis proves that it has a form of FEVR genetically distinct from the EVR1 locus on 11q.?CONCLUSION—This proves that there are at least three different loci associated with comparable FEVR phenotypes, a situation similar to that existing for many forms of retinal degeneration.??

Bamashmus, M; Downey, L; Inglehearn, C; Gupta, S; Mansfield, D

2000-01-01

217

Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.  

PubMed

Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies. PMID:24375629

Soldovieri, Maria Virginia; Boutry-Kryza, Nadia; Milh, Mathieu; Doummar, Diane; Heron, Benedicte; Bourel, Emilie; Ambrosino, Paolo; Miceli, Francesco; De Maria, Michela; Dorison, Nathalie; Auvin, Stephane; Echenne, Bernard; Oertel, Julie; Riquet, Audrey; Lambert, Laetitia; Gerard, Marion; Roubergue, Anne; Calender, Alain; Mignot, Cyril; Taglialatela, Maurizio; Lesca, Gaetan

2014-03-01

218

A novel variation in the AVP gene resulting in familial neurohypophyseal diabetes insipidus in a large Italian kindred.  

PubMed

Familial neurohypophyseal diabetes insipidus (FNDI) is mostly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria typically in early childhood. To date, 69 different variations in the AVP gene encoding the AVP prohormone have been identified in autosomal dominant FNDI (adFNDI). In this study we present a family of seven generations, in which a novel variation in the AVP gene seems to cause adFNDI. Clinical assessment by 24 h urine collection, water deprivation test, desmopressin (dDAVP) challenge, and magnetic resonance imaging (MRI) of the posterior pituitary are presented. The diagnosis of adFNDI was confirmed by direct DNA sequence analysis of the AVP gene. Inheritance pattern and clinical history clearly pointed towards adFNDI. Inability of concentrating urine upon dehydration was demonstrated by a water deprivation test, and neurohypophyseal diabetes insipidus was strongly suspected after dDAVP administration, during which renal concentration ability quadrupled. MRI revealed a very weak pituitary "bright spot" in each of six subjects and a further reduction in the size of the neurohypophysis in a 7-year follow-up MRI scan in one subject. DNA sequence analysis revealed heterozygousity for a novel g.1785T > C gene variation predicting a p.Leu63Pro substitution in four affected subjects. Genetic testing in the diagnostic evaluation of families in which diabetes insipidus segregates is highly recommended in that interpretation of clinical assessments can be difficult. Furthermore, presymptomatic diagnosis can ease the parental concern of the carrier status of their offspring, and also avoid unnecessary surveillance of those being unaffected. PMID:22695750

Birkegaard, Camilla; Christensen, Jane H; Falorni, Alberto; Marzotti, Stefania; Minarelli, Viviana; Gregersen, Niels; Rittig, Søren

2013-06-01

219

The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family.  

PubMed

Inherited retinal diseases are a group of clinically and genetically heterogeneous disorders for which a significant number of cases remain genetically unresolved. Increasing knowledge on underlying pathogenic mechanisms with precise phenotype-genotype correlation is, however, critical for establishing novel therapeutic interventions for these yet incurable neurodegenerative conditions. We report phenotypic and genetic characterization of a large family presenting an unusual autosomal dominant retinal dystrophy. Phenotypic characterization revealed a retinopathy dominated by inner retinal dysfunction and ganglion cell abnormalities. Whole-exome sequencing identified a missense variant (c.782A>C, p.Glu261Ala) in ITM2B coding for Integral Membrane Protein 2B, which co-segregates with the disease in this large family and lies within the 24.6 Mb interval identified by microsatellite haplotyping. The physiological role of ITM2B remains unclear and has never been investigated in the retina. RNA in situ hybridization reveals Itm2b mRNA in inner nuclear and ganglion cell layers within the retina, with immunostaining demonstrating the presence of the corresponding protein in the same layers. Furthermore, ITM2B in the retina co-localizes with its known interacting partner in cerebral tissue, the amyloid ? precursor protein, critical in Alzheimer disease physiopathology. Interestingly, two distinct ITM2B mutations, both resulting in a longer protein product, had already been reported in two large autosomal dominant families with Alzheimer-like dementia but never in subjects with isolated retinal diseases. These findings should better define pathogenic mechanism(s) associated with ITM2B mutations underlying dementia or retinal disease and add a new candidate to the list of genes involved in inherited retinal dystrophies. PMID:24026677

Audo, Isabelle; Bujakowska, Kinga; Orhan, Elise; El Shamieh, Said; Sennlaub, Florian; Guillonneau, Xavier; Antonio, Aline; Michiels, Christelle; Lancelot, Marie-Elise; Letexier, Melanie; Saraiva, Jean-Paul; Nguyen, Hoan; Luu, Tien D; Léveillard, Thierry; Poch, Olivier; Dollfus, Hélène; Paques, Michel; Goureau, Olivier; Mohand-Saïd, Saddek; Bhattacharya, Shomi S; Sahel, José-Alain; Zeitz, Christina

2014-01-15

220

Intracellular positioning of isoforms explains an unusually large adenylate kinase gene family in the parasite Trypanosoma brucei.  

PubMed

Adenylate kinases occur classically as cytoplasmic and mitochondrial enzymes, but the expression of seven adenylate kinases in the flagellated protozoan parasite Trypanosoma brucei (order, Kinetoplastida; family, Trypanosomatidae) easily exceeds the number of isoforms previously observed within a single cell and raises questions as to their location and function. We show that a requirement to target adenylate kinase into glycosomes, which are unique kinetoplastid-specific microbodies of the peroxisome class in which many reactions of carbohydrate metabolism are compartmentalized, and two different flagellar structures as well as cytoplasm and mitochondrion explains the expansion of this gene family in trypanosomes. The three isoforms that are selectively built into either the flagellar axoneme or the extra-axonemal paraflagellar rod, which is essential for motility, all contain long N-terminal extensions. Biochemical analysis of the only short form trypanosome adenylate kinase revealed that this enzyme catalyzes phosphotransfer of gamma-phosphate from ATP to AMP, CMP, and UMP acceptors; its high activity and specificity toward CMP is likely to reflect an adaptation to very low intracellular cytidine nucleotide pools. Analysis of some of the phosphotransfer network using RNA interference suggests considerable complexity within the homeostasis of cellular energetics. The anchoring of specific adenylate kinases within two distinct flagellar structures provides a paradigm for metabolic organization and efficiency in other flagellates. PMID:15657034

Ginger, Michael L; Ngazoa, E Solange; Pereira, Claudio A; Pullen, Timothy J; Kabiri, Mostafa; Becker, Katja; Gull, Keith; Steverding, Dietmar

2005-03-25

221

First evidence of a large CHEK2 duplication involved in cancer predisposition in an Italian family with hereditary breast cancer  

PubMed Central

Background CHEK2 is a multi-cancer susceptibility gene whose common germline mutations are known to contribute to the risk of developing breast and prostate cancer. Case presentation Here, we describe an Italian family with a high number of cases of breast cancer and other types of tumour subjected to the MLPA test to verify the presence of BRCA1, BRCA2 and CHEK2 deletions and duplications. We identified a new 23-kb duplication in the CHEK2 gene extending from intron 5 to 13 that was associated with breast cancer in the family. The presence and localisation of the alteration was confirmed by a second analysis by Next-Generation Sequencing. Conclusions This finding suggests that CHEK2 mutations are heterogeneous and that techniques other than sequencing, such as MLPA, are needed to identify CHEK2 mutations. It also indicates that CHEK2 rare variants, such as duplications, can confer a high susceptibility to cancer development and should thus be studied in depth as most of our knowledge of CHEK2 concerns common mutations.

2014-01-01

222

Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome  

Microsoft Academic Search

We describe four Italian patients (aged 3, 4, 12, and 13 years ) affected by a novel autosomal form of recessive congenital muscular dystrophy. These patients were from three non-consanguineous families and presented an almost identical phenotype. This was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absent speech, inability to walk and almost no interest

Marcello Villanova; Eugenio Mercuri; Enrico Bertini; Patrizia Sabatelli; Lucia Morandi; Marina Mora; Caroline Sewry; Martin Brockington; Susan C Brown; Ana Ferreiro; Nadir M Maraldi; Tatsushi Toda; Pascale Guicheney; Luciano Merlini; Francesco Muntoni

2000-01-01

223

The Cryphonectria parasitica plasmid pUG1 contains a large ORF with motifs characteristic of family B DNA polymerases.  

PubMed Central

The isolation and characterization of the circular mitochondrial plasmid pUG1 from the ascomycete Cryphonectria parasitica is described. The entire sequence (4182 bp) was obtained and high similarities to DNA-dependent DNA polymerases were revealed. Strikingly common features with the DNA polymerases encoded by the Neurospora intermedia plasmids Fiji and LaBelle, such as matches to the conserved motifs A and B and the presence of TTD instead of DTD in motif C, were found, suggesting the existence of a distinct group of members of the B DNA family polymerases. These strong similarities between the plasmids might suggest a common origin of the C.parasitica and the Neurospora plasmids.

Gobbi, E; Carpanelli, A; Firrao, G; Locci, R

1997-01-01

224

X-linked Kallmann syndrome and renal agenesis occurring together and independently in a large Australian family  

Microsoft Academic Search

Males with X-linked Kallmann syndrome (XLKS) may have renal agenesis. We studied a large kindred with a history of eight males affected by XLKS born in five generations. Their XLKS was shown to be due to an in- tragenic mutation of the KAL-1 gene. We also documented three male neonatal deaths due to bilateral renal agenesis (BRA), five males with

James S. Colquhoun-Kerr; Wen-Xia Gu; J. Larry Jameson; Stephen Withers; Hans H. Bode

1999-01-01

225

Consanguinity and the sib-pair method: An approach using identity by descent between and within individuals  

SciTech Connect

To test for linkage between a trait and a marker, one can consider identical marker alleles in related individuals, for instance, sibs. For recessive diseases, it has been shown that some information may be gained from the identity by descent (IBD) of the two alleles of an affected inbred individual at the marker locus. The aim of this paper is to extend the sib-pair method of linkage analysis to the situation of sib pairs sampled from consanguineous populations. This extension takes maximum advantage of the information provided by both the IBD pattern between sibs and allelic identity within each sib of the pair. This is possible through the use of the condensed identity coefficients. Here, we propose a new test of linkage based on a {Chi}{sup 2}. We compare the performance of this test with that of the classical {Chi}{sup 2} test based on the distribution of sib pairs sharing 0, 1, or 2 alleles IBD. For sib pairs from first-cousin matings, the proposed test can better detect the role of a disease-susceptibility (DS) locus. Its power is shown to be greater than that of the classical test, especially for models where the DS allele may be common and incompletely penetrant; that is to say for situations that may be encountered in multifactorial diseases. A study of the impact of inbreeding on the expected proportions of sib pairs sharing 0, 1, or 2 alleles IBD is also performed here. Ignoring inbreeding, when in fact inbreeding exists, increases the rate of type I errors in tests of linkage. 21 refs., 8 figs., 9 tabs.

Genin, E.; Clerget-Darpoux, F. [Institut National d`Etudes Demographiques, Paris (France)

1996-11-01

226

Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus.  

PubMed

Spondylocostal dysotosis (SCD) is a rare developmental congenital abnormality of the axial skeleton. Mutation of genes in the Notch signaling pathway cause SCD types 1-5. Dextrocardia with situs inversus is a rare congenital malformation in which the thoracic and abdominal organs are mirror images of normal. Such laterality defects are associated with gene mutations in the Nodal signaling pathway or cilia assembly or function. We investigated two distantly related individuals with a rare combination of severe segmental defects of the vertebrae (SDV) and dextrocardia with situs inversus. We found that both individuals were homozygous for the same mutation in HES7, and that this mutation caused a significant reduction of HES7 protein function; HES7 mutation causes SCD4. Two other individuals with SDV from two unrelated families were found to be homozygous for the same mutation. Interestingly, although the penetrance of the vertebral defects was complete, only 3/7 had dextrocardia with situs inversus, suggesting randomization of left-right patterning. Two of the affected individuals presented with neural tube malformations including myelomeningocele, spina bifida occulta and/or Chiari II malformation. Such neural tube phenotypes are shared with the originally identified SCD4 patient, but have not been reported in the other forms of SCD. In conclusion, it appears that mutation of HES7 is uniquely associated with defects in vertebral, heart and neural tube formation, and this observation will help provide a discriminatory diagnostic guide in patients with SCD, as well as inform molecular genetic testing. PMID:23897666

Sparrow, Duncan B; Faqeih, Eissa Ali; Sallout, Bahauddin; Alswaid, Abdulrahman; Ababneh, Faroug; Al-Sayed, Moeenaldeen; Rukban, Hadeel; Eyaid, Wafaa M; Kageyama, Ryoichiro; Ellard, Sian; Turnpenny, Peter D; Dunwoodie, Sally L

2013-09-01

227

Transmission of an FMR1 premutation allele in a large family identified through newborn screening: the role of AGG interruptions  

PubMed Central

The CGG repeat within the premutation range in the FMR1 gene can lead to neurodegenerative disorders and intellectual disabilities. An increase in size upon transmission from parent to child is more likely to occur for larger alleles and without AGG interruptions. We describe the molecular structure and the transmission of an FMR1 premutation allele in a multigenerational family, identified through newborn screening for fragile X syndrome. Transmission of the premutation allele was traced through 5 generations in 14 of the 23 individuals who were genotyped through cascade testing. Allele size instability during transmission was observed but no expansions to a full mutation were detected. Clinical and molecular characterizations of the participants lead to the diagnosis of FXTAS in one subject identified as a premutation carrier. A gradual small increase in the size of the premutation allele was observed during transmission through five generations. The relative stability is likely due to the presence of two AGGs within the allele. The detection of AGG interruptions within the premutation alleles is important in genetic counseling to better predict the risk of expansion during transmission from a premutation to a full mutation allele.

Yrigollen, Carolyn M.; Mendoza-Morales, Guadalupe; Hagerman, Randi; Tassone, Flora

2014-01-01

228

Transmission of an FMR1 premutation allele in a large family identified through newborn screening: the role of AGG interruptions.  

PubMed

The CGG repeat within the premutation range in the fragile X mental retardation 1 (FMR1) gene can lead to neurodegenerative disorders and intellectual disabilities. An increase in size upon the transmission from parent to child is more likely to occur for larger alleles and without AGG interruptions. We describe the molecular structure and the transmission of an FMR1 premutation allele in a multigenerational family, identified through newborn screening for fragile X syndrome. Transmission of the premutation allele was traced through five generations in 14 of the 23 individuals who were genotyped through cascade testing. Allele size instability during transmission was observed, but no expansions to a full mutation were detected. Clinical and molecular characterizations of the participants lead to the diagnosis of fragile X-associated tremor ataxia syndrome in one subject identified as a premutation carrier. A gradual small increase in the size of the premutation allele was observed during transmission through five generations. The relative stability is likely due to the presence of two AGGs within the allele. The detection of AGG interruptions within the premutation alleles is important in genetic counseling, to better predict the risk of expansion during transmission from a premutation to a full-mutation allele. PMID:23739124

Yrigollen, Carolyn M; Mendoza-Morales, Guadalupe; Hagerman, Randi; Tassone, Flora

2013-08-01

229

Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast\\/ovarian cancer family  

Microsoft Academic Search

Background Alterations in BRCA1 gene are responsible for the majority of hereditary breast and\\/or ovarian cancers. However, the frequency of detected germline\\u000a mutations is lower than expected by linkage analysis. Standard PCR-based screening methods are mainly used for detecting mutations,\\u000a but the large genomic rearrangements are commonly overlooked. The purpose of this study was to confirm and characterize a\\u000a novel

Sarai Palanca Suela; Eva Esteban Cardeñosa; Eva Barragán González; Silvestre Oltra Soler; Inma de Juan Jiménez; Isabel Chirivella González; Ángel Segura Huerta; Carmen Guillén Ponce; Eduardo Martínez de Dueñas; Pascual Bolufer Gilabert

2008-01-01

230

NLRP3 E311K mutation in a large family with Muckle-Wells syndrome - description of a heterogeneous phenotype and response to treatment  

PubMed Central

Introduction Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment. Methods A total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab. Results All 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-?, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab. Conclusion The NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

2011-01-01

231

Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2  

PubMed Central

Background Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering?>?90% of cases, are KCNQ1, KCNH2 and SCN5A. Methods We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. Results Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 “unrelated” families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of?large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.

2014-01-01

232

A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families  

PubMed Central

Background: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. Methods: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. Results: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 3' untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3–5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. Conclusions: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits.

Gaukrodger, N; Mayosi, B; Imrie, H; Avery, P; Baker, M; Connell, J; Watkins, H; Farrall, M; Keavney, B

2005-01-01

233

Identification of three novel ECEL1 mutations in three families with distal arthrogryposis type 5D.  

PubMed

Arthrogryposis refers to congenital contracture in at least two different body parts. When distal joints are primarily involved, the term distal arthrogryposis (DA) is used. The recognition of clinically distinct subtypes of DA has proven very useful in mapping the disease genes for this genetically heterogeneous condition. DA5D is characterized by ocular involvement usually in the form of ptosis and incomitant strabismus, but extraocular manifestations have also been reported. In a multiplex consanguineous family with DA5D, we combined autozygosity mapping and exome sequencing to identify a novel mutation in ECEL1. This was followed by targeted sequencing of this gene in another two extended consanguineous family with the same phenotype, which revealed two additional novel homozygous mutations. Our results support the recent identification of mutations in ECEL1 as a disease gene in DA5D and expand the clinical and allelic spectrum of this condition. PMID:23829171

Shaheen, R; Al-Owain, M; Khan, A O; Zaki, M S; Hossni, H A A; Al-Tassan, R; Eyaid, W; Alkuraya, F S

2014-06-01

234

Whole Exome Sequencing Identifies New Causative Mutations in Tunisian Families with Non-Syndromic Deafness  

PubMed Central

Identification of the causative mutations in patients affected by autosomal recessive non syndromic deafness (DFNB forms), is demanding due to genetic heterogeneity. After the exclusion of GJB2 mutations and other mutations previously reported in Tunisian deaf patients, we performed whole exome sequencing in patients affected with severe to profound deafness, from four unrelated consanguineous Tunisian families. Four biallelic non previously reported mutations were identified in three different genes: a nonsense mutation, c.208C>T (p.R70X), in LRTOMT, a missense mutation, c.5417T>C (p.L1806P), in MYO15A and two splice site mutations, c.7395+3G>A, and c.2260+2T>A, in MYO15A and TMC1 respectively. We thereby provide evidence that whole exome sequencing is a powerful, cost-effective screening tool to identify mutations causing recessive deafness in consanguineous families.

Zainine, Rim; Louha, Malek; Bouyacoub, Yosra; Laroussi, Nadia; Chargui, Mariem; Kefi, Rym; Jonard, Laurence; Dorboz, Imen; Hardelin, Jean-Pierre; Salah, Sihem Belhaj; Levilliers, Jacqueline; Weil, Dominique; McElreavey, Kenneth; Boespflug, Odile Tanguy; Besbes, Ghazi; Abdelhak, Sonia; Petit, Christine

2014-01-01

235

Mutations in SLC29A3, Encoding an Equilibrative Nucleoside Transporter ENT3, Cause a Familial Histiocytosis Syndrome (Faisalabad Histiocytosis) and Familial Rosai-Dorfman Disease  

PubMed Central

The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder.

Morgan, Neil V.; Morris, Mark R.; Cangul, Hakan; Gleeson, Diane; Straatman-Iwanowska, Anna; Davies, Nicholas; Keenan, Stephen; Pasha, Shanaz; Rahman, Fatimah; Gentle, Dean; Vreeswijk, Maaike P. G.; Devilee, Peter; Knowles, Margaret A.; Ceylaner, Serdar; Trembath, Richard C.; Dalence, Carlos; Kismet, Erol; Koseoglu, Vedat; Rossbach, Hans-Christoph; Gissen, Paul; Tannahill, David; Maher, Eamonn R.

2010-01-01

236

A Large Family with Carney Complex Caused by the S147G PRKAR1A Mutation Shows a Unique Spectrum of Disease Including Adrenocortical Cancer  

PubMed Central

Context: Most tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-? (RI?) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC. Objective: We studied the genotype-phenotype correlation in CNC. Design and Setting: We reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center. Patients: Twenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations. Results: Cushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RI? defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RI? and increased protein kinase A activity in vitro. Conclusions: In a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD.

Anselmo, Joao; Medeiros, Sandra; Carneiro, Victor; Greene, Elizabeth; Levy, Isaac; Nesterova, Maria; Lyssikatos, Charalampos; Horvath, Anelia; Carney, J. Aidan

2012-01-01

237

Comparison of autoantibody specificities between traditional and bead-based assays in a large, diverse collection of SLE patients and family members  

PubMed Central

Objective The replacement of standard immunofluorescence anti-nuclear antibody (ANA) methods with bead-based assays is a new clinical option. A large, multi-racial cohort of SLE patients, blood relatives and unaffected control individuals was evaluated for familial aggregation and subset clustering of autoantibodies by high-throughput serum screening technology and traditional methods. Methods Serum samples (1,540 SLE patients, 1,127 unaffected relatives, and 906 healthy, population-based controls) were analyzed for SLE autoantibodies using a bead-based assay, immunofluorescence, and immunodiffusion. Autoantibody prevalence, disease sensitivity, clustering, and association with standard immunodiffusion results were evaluated. Results ANA frequency in SLE patient sera were 89%, 73%, and 67% by BioPlex 2200 and 94%, 84%, and 86% by immunofluorescence in African-American, Hispanic, and European-American patients respectively. 60kD Ro, La, Sm, nRNP A, and ribosomal P prevalence were compared across assays, with sensitivities ranging from 0.92 to 0.83 and specificities ranging from 0.90 to 0.79. Cluster autoantibody analysis showed association of three subsets: 1) 60kD Ro, 52kD Ro and La, 2) spliceosomal proteins, and 3) dsDNA, chromatin, and ribosomal P. Familial aggregation of Sm/RNP, ribosomal P, and 60kD Ro in SLE patient sibling pairs was observed (p ? 0.004). Simplex pedigree patients had a greater prevalence for dsDNA (p=0.0003) and chromatin (p=0.005) autoantibodies than multiplex patients. Conclusion ANA frequencies detected by a bead-based assay are lower in European-American SLE patients compared to immunofluorescence. These assays have strong positive predictive values across racial groups, provide useful information for clinical care, and provide unique insights to familial aggregation and autoantibody clustering.

Bruner, Benjamin F.; Guthridge, Joel M.; Lu, Rufei; Vidal, Gabriel; Kelly, Jennifer A.; Robertson, Julie M.; Kamen, Diane L.; Gilkeson, Gary S.; Neas, Barbara R.; Reichlin, Morris; Scofield, R. Hal; Harley, John B.; James, Judith A.

2012-01-01

238

A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly.  

PubMed Central

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically similar to but genetically distinct from Marfan syndrome. Genetic-linkage analysis has implicated the fibrillin-2 gene (FBN2) as the CCA locus. Mutation analysis of two isolated CCA patients revealed missense mutations, indicating that defects in FBN2 may be responsible for this disorder. However, cosegregation of a mutant allele with the disease phenotype has not yet been established. We have investigated the primary cause of CCA in a large well-characterized kindred with five generations comprising 18 affected individuals. Previous studies demonstrated linkage of this family's CCA phenotype to FBN2. Mutation analysis of cDNA derived from the proband and her affected brother, using a nonisotopic RNase cleavage assay, revealed the partial skipping of exon 31. Approximately 25% mutant transcript is produced, which is apparently sufficient to cause a CCA phenotype. Sequence analysis of genomic DNA revealed an unusual base composition for intron 30 and identified the mutation, a g-26t transversion, in the vicinity of the splicing branch-point site in intron 30. Genomic DNA from 30 additional family members, both affected and unaffected, then was analyzed for the mutation. The results clearly demonstrate cosegregation of the branch-point mutation with the CCA phenotype. This is the first report of a CCA mutation in a multiplex family, unequivocally establishing that mutation in FBN2 are responsible for the CCA phenotype. In addition, branch-point mutations only very rarely have been associated with human disease, suggesting that the unusual composition of this intron influences splicing stability. Images Figure 2ab Figure 2c Figure 3ab Figure 3c Figure 4 Figure 6 Figure 7

Maslen, C; Babcock, D; Raghunath, M; Steinmann, B

1997-01-01

239

A rare branch-point mutation is associated with missplicing of fibrillin-2 in a large family with congenital contractural arachnodactyly.  

PubMed

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically similar to but genetically distinct from Marfan syndrome. Genetic-linkage analysis has implicated the fibrillin-2 gene (FBN2) as the CCA locus. Mutation analysis of two isolated CCA patients revealed missense mutations, indicating that defects in FBN2 may be responsible for this disorder. However, cosegregation of a mutant allele with the disease phenotype has not yet been established. We have investigated the primary cause of CCA in a large well-characterized kindred with five generations comprising 18 affected individuals. Previous studies demonstrated linkage of this family's CCA phenotype to FBN2. Mutation analysis of cDNA derived from the proband and her affected brother, using a nonisotopic RNase cleavage assay, revealed the partial skipping of exon 31. Approximately 25% mutant transcript is produced, which is apparently sufficient to cause a CCA phenotype. Sequence analysis of genomic DNA revealed an unusual base composition for intron 30 and identified the mutation, a g-26t transversion, in the vicinity of the splicing branch-point site in intron 30. Genomic DNA from 30 additional family members, both affected and unaffected, then was analyzed for the mutation. The results clearly demonstrate cosegregation of the branch-point mutation with the CCA phenotype. This is the first report of a CCA mutation in a multiplex family, unequivocally establishing that mutation in FBN2 are responsible for the CCA phenotype. In addition, branch-point mutations only very rarely have been associated with human disease, suggesting that the unusual composition of this intron influences splicing stability. PMID:9199560

Maslen, C; Babcock, D; Raghunath, M; Steinmann, B

1997-06-01

240

Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p.Leu511Pro).  

PubMed

Wolfram syndrome, also named "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an inherited association of juvenile-onset diabetes mellitus and optic atrophy as key diagnostic criteria. Renal tract abnormalities and neurodegenerative disorder may occur in the third and fourth decade. The wolframin gene, WFS1, associated with this syndrome, is located on chromosome 4p16.1. Many mutations have been described since the identification of WFS1 as the cause of Wolfram syndrome. We identified a new homozygous WFS1 mutation (c.1532T>C; p.Leu511Pro) causing Wolfram syndrome in a large inbred Turkish family. The patients showed early onset of IDDM, diabetes insipidus, optic atrophy, sensorineural hearing impairment and very rapid progression to renal failure before age 12 in three females. Ectopic expression of the wolframin mutant in HEK cells results in greatly reduced levels of protein expression compared to wild-type wolframin, strongly supporting that this mutation is disease-causing. The mutation showed perfect segregation with disease in the family, characterized by early and severe clinical manifestations. PMID:21968327

Yuca, Sevil Ari; Rendtorff, Nanna Dahl; Boulahbel, Houda; Lodahl, Marianne; Tranebjærg, Lisbeth; Cesur, Yasar; Dogan, Murat; Yilmaz, Cahide; Akgun, Cihangir; Acikgoz, Mehmet

2012-01-01

241

Novel homozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes.  

PubMed

Desmoplakin is an important cytoskeletal linker for the function of the desmosomes. Linking desmoplakin to certain types of cardiocutaneous syndromes has been a hot topic recently. Skin fragility-woolly hair syndrome is a rare autosomal recessive disorder involving the desmosomes and is caused by mutation in the desmoplakin gene (DSP). We report five members from a large family with skin fragility-woolly hair syndrome. The index is a 14-year-old girl with palmoplantar keratoderma, woolly hair, variable alopecia, dystrophic nails, and excessive blistering to trivial mechanical trauma. No cardiac symptoms were reported. Although formal cardiac examination was not feasible, the echocardiographic evaluation of the other two affected younger siblings was normal. Homozygosity mapping and linkage analysis revealed a high LOD score region in the short arm of chromosome 6 that harbors the DSP. Full sequencing of the DSP showed a novel homozygous c.7097 G>A (p.R2366H) mutation in all affected members, and the parents were heterozygous. This is the report of the third case/family of the skin fragility-woolly hair syndrome in the literature. We also present a clinical and molecular review of various desmoplakin-related phenotypes, with emphasis on onset of cardiomyopathy. The complexity of the desmoplakin and its variable presentations warrant introducing the term 'desmoplakinopathies' to describe all the phenotypes related to defects in the desmoplakin. PMID:20738328

Al-Owain, M; Wakil, S; Shareef, F; Al-Fatani, A; Hamadah, E; Haider, M; Al-Hindi, H; Awaji, A; Khalifa, O; Baz, B; Ramadhan, R; Meyer, B

2011-07-01

242

The Community of Family Circles (CFC) algorithm: a new inversion approach to obtaining self-consitent 4D thermal histories from large, spatially distributed thermochronological data sets  

NASA Astrophysics Data System (ADS)

One of the most significant advances in interpreting thermochronological data is arguably our ability to extract information about the rate and trajectory of cooling over a range of temperatures, rather than having to rely on the veracity of the simplification of assuming a single closure temperature specified by a rate of monotonic cooling. Modern thermochronometry data, such as apatite fission track and (U-Th)/He analysis, are particularly good examples of data amenable to this treatment as acceptably well calibrated kinetic models now exist for both systems. With ever larger data sets of this type being generated over ever larger areas the prospect of inverting very large amounts of such data distributed spatially over large areas offers new possibilities for constraining the thermal and erosional histories over length scales approximating whole orogens and sub-continents. The challenge though is in how to properly deal with joint inversion of multiple samples in a self-consistent manner while also utilising all the available information contained in the data. We describe a new approach to this problem, called the Community of Family Circles (CFC) algorithm, which extracts information from spatially distributed apatite fission track ages (AFT) and track length distributions (TLD). The method is based on the rationale that the 3D geothermal field of the crust varies smoothly through space and time because of the efficiency of thermal diffusion. Our approach consists of seeking groups of spatially adjacent samples, or families, within a given circular radius for which a common thermal history is appropriate. The temperature offsets between individual time-temperature paths are determined relative to a low-pass filtered topographic surface, whose shape is assumed to mimic the shape of the isotherms in the partial annealing zone. This enables a single common thermal history to be shared, or interpolated, between the family members while still honouring the individual samples temperature offset requirements. The geothermal gradient can be either treated as a parameter in the inversion scheme or evaluated when local vertical profile or heat flow measurements are available. As data for each sample is inverted several times with different subsets, or as a member of different families, we then extract the subset with the lowest misfit and assign that sample to its respective ''family'' whose optimum time-temperature path is subsequently assigned to the sample. We thus obtain a set of thermal histories (one for each sample) which can then be interpolated to obtain exhumation rates or maximum temperature maps. We demonstrate our approach on a variety of synthetic datasets, generated for different geomorphologies and sampling densities, using the 3D thermal Pecube code in order to test the resolution and limits of the method. The approach is then applied to a 600 by 600 km area in northern Namibia where an extensive apatite fission track dataset including ages and track length distributions is available. We finally discuss extension of the technique to multiple thermochronometers. We also discuss possible future modifications and strategies for improving the flexibility and computational efficiency and effectiveness of the method.

Beucher, R.; Brown, R. W.

2013-12-01

243

Compound Heterozygosity for Two Novel SLC26A4 Mutations in a Large Iranian Pedigree with Pendred Syndrome  

PubMed Central

Objectives The aim of this study was to detect the genetic cause of deafness in a large Iranian family. Due to the importance of SLC26A4 in causing hearing loss, information about the gene mutations can be beneficial in molecular detection and management of deaf patients. Methods We investigated the genetic etiology in a large consanguineous family with 9 deaf patients from Fars province of Iran with no GJB2 mutations. Initially, linkage analysis was performed by four DFNB4 short tandem repeat markers. The result showed linkage to DFNB4 locus. Following that, DNA sequencing of all 21 exons, their adjacent intronic sequences and the promoter of SLC26A4 was carried out for mutation detection. Results Two novel mutations (c.863-864insT and c.881-882delAC) were identified in exon 7 of the gene, in both homozygous and compound heterozygous state in patients. Conclusion Our results supported the importance of the SLC26A4 mutations in the etiology of hearing loss among the Iranian patients and therefore its mutation screening should be considered after GJB2 in the molecular diagnostics of hearing loss, especially when enlarged vestibular aqueduct or goiter is detected.

Yazdanpanahi, Nasrin; Tabatabaiefar, Mohammad Amin; Farrokhi, Effat; Abdian, Narges; Bagheri, Nader; Shahbazi, Shirin; Noormohammadi, Zahra

2013-01-01

244

Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 EPH families using 15 polymorphic loci in the region 5q11. 2-q13. 3  

SciTech Connect

The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q.13.3 in 1990. Here, the authors present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q.13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at z[sub max] = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557. The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene. They localized a recently described polymorphic marker, D5S351, close to the SMA. Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, they developed a new reverse primer for the nearest centromeric locus D5S435, a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5s507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q.13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507-D5S6-D5S125-D5S680-D5S435-SMA-D5S557-D5S35 -15[prime]MAP1B-3[prime]MAP1B-JK53CA1/2-(D5S127-D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable. 25 refs., 4 figs., 5 tabs.

Wirth, B.; Pick, E.; Leutner, A.; Dadze, A.; Voosen, B.; Piechaczek-Wappenschmidt, B.; Rudnik-Schoeneborn, S.; Schoenling, J.; Zerres, K. (Institute of Human Genetics, Bonn (Germany)); Knapp, M. (Institute of Medical Statistics, Bonn (Germany)) (and others)

1994-03-01

245

Familial short fifth metacarpals and insulin resistance.  

PubMed

Very few reports on the phenotype of short fifth metacarpals have been published in the medical literature. We report a Jordanian family in which three sisters aged 15, 13 and 8 years revealed bilateral shortening of the fifth fingers and radiological shortening of the fifth metacarpals. The father had unilateral short fifth metacarpal. The elder two sisters, their father as well as their brother and another sister manifested insulin resistance. Spherocytosis was diagnosed in one of the girls and her father. The parents are non-consanguineous. This constellation of findings has not been previously reported and could point to the presence of two disorders segregating in the family or to a novel syndrome with autosomal dominant inheritance and variable expressivity. PMID:16132981

Hyari, Muwafag; Hamamy, Hanan; Barham, Muries; Al-Hadidy, Azmy; Ajlouni, Kamel

2006-09-01

246

Werner's syndrome: seven cases in one family.  

PubMed

7 cases of Werner's syndrome in one family of northern Sardinia (the female : male ratio being 4:3) are reported. A 9-year-old girl affected with Cooley's anemia is reported too. The typical complete pattern of the syndrome was observed in patients in the fourth decade of their lives, whereas in the two youngest ones, some features were missing. 1 patient died of gastric carcinoma, 1 of cachexia. Consanguinity was established in two generations. The genealogical tree suggests an autosomal recessive mode of inheritance. Genealogical, clinical, biochemical, and histopathological studies were performed. As far as we know, this is the largest number of patients with Werner's syndrome reported in one family. PMID:437224

Rabbiosi, G; Borroni, G

1979-01-01

247

Congenital myopathies in Israeli families.  

PubMed

The clinical features of 37 patients from 32 Israeli families with congenital myopathies evaluated between 1983 and 2004 are described: 13 children were diagnosed with congenital fiber type disproportion, 10 had myotubular myopathy, 7 had nemaline myopathy, 5 had central core disease, 1 had actin myopathy, and 1 had multi-minicore disease. There were 7 families (22%) that had parental consanguinity, and 4 families (12%) had more than 1 patient with congenital myopathy. Of the patients, 31 (84%) presented with clinical symptoms before 4 months of age, and 6 children (16%) presented after 1 year of age. Thirteen children (35%) had a severe phenotype with chronic ventilatory dependence or mortality before the age of 11 years. Facial weakness was associated with a severe phenotype. There was a high rate of a severe clinical phenotype in patients with myotubular myopathy (60%) and in patients with nemaline myopathy (57%), whereas in patients with congenital fiber type disproportion and in patients with central core disease, the proportion of a severe phenotype was lower (23% and 0%, respectively). PMID:17641259

Weiss, Karin; Shapira, Yehuda; Glick, Benjamin; Lerman-Sagie, Tally; Shahar, Eli; Goez, Helly; Kutai, Miriam; Nevo, Yoram

2007-06-01

248

Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment.  

PubMed

A homozygous reciprocal translocation, 46,XY,t(10;11),t(10;11), was detected in a boy with non-syndromic congenital sensorineural hearing impairment. Both parents and their four other children were heterozygous translocation carriers, 46,XX,t(10;11) and 46,XY,t(10;11), respectively. Fluorescence in situ hybridization of region-specific clones to patient chromosomes was used to localize the breakpoints within bacterial artificial chromosome (BAC) RP11-108L7 on chromosome 10q24.3 and within BAC CTD-2527F12 on chromosome 11q23.3. Junction fragments were cloned by vector ligation and sequenced. The chromosome 10 breakpoint was identified within the PDZ domain containing 7 (PDZD7) gene, disrupting the open reading frame of transcript PDZD7-C (without PDZ domain) and the 5'-untranslated region of transcript PDZD7-D (with one PDZ and two prolin-rich domains). The chromosome 11 breakpoint was localized in an intergenic segment. Reverse transcriptase-polymerase chain reaction analysis revealed PDZD7 expression in the human inner ear. A murine Pdzd7 transcript that is most similar in structure to human PDZD7-D is known to be expressed in the adult inner ear and retina. PDZD7 shares sequence homology with the PDZ domain-containing genes, USH1C (harmonin) and DFNB31 (whirlin). Allelic mutations in harmonin and whirlin can cause both Usher syndrome (USH1C and USH2D, respectively) and congenital hearing impairment (DFNB18 and DFNB31, respectively). Protein-protein interaction assays revealed the integration of PDZD7 in the protein network related to the human Usher syndrome. Collectively, our data provide strong evidence that PDZD7 is a new autosomal-recessive deafness-causing gene and also a prime candidate gene for Usher syndrome. PMID:19028668

Schneider, Eberhard; Märker, Tina; Daser, Angelika; Frey-Mahn, Gabriele; Beyer, Vera; Farcas, Ruxandra; Schneider-Rätzke, Brigitte; Kohlschmidt, Nicolai; Grossmann, Bärbel; Bauss, Katharina; Napiontek, Ulrike; Keilmann, Annerose; Bartsch, Oliver; Zechner, Ulrich; Wolfrum, Uwe; Haaf, Thomas

2009-02-15

249

Pitfalls of homozygosity mapping: an extended consanguineous Bardet–Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism  

Microsoft Academic Search

The extensive genetic heterogeneity of Bardet–Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1–9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping

Virginie Laurier; Corinne Stoetzel; Jean Muller; Christelle Thibault; Sandra Corbani; Nadine Jalkh; Nabiha Salem; Eliane Chouery; Olivier Poch; Serge Licaire; Jean-Marc Danse; Patricia Amati-Bonneau; Dominique Bonneau; André Mégarbané; Jean-Louis Mandel; Hélène Dollfus

2006-01-01

250

IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome.  

PubMed

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified genes cannot account for all the BBS cases. The genetic heterogeneity of this disease poses significant challenge to the identification of additional BBS genes. In this study, we coupled human genetics with functional validation in zebrafish and identified IFT27 as a novel BBS gene (BBS19). This is the first time an intraflagellar transport (IFT) gene is implicated in the pathogenesis of BBS, highlighting the genetic complexity of this disease. PMID:24488770

Aldahmesh, Mohammed A; Li, Yuanyuan; Alhashem, Amal; Anazi, Shams; Alkuraya, Hisham; Hashem, Mais; Awaji, Ali A; Sogaty, Sameera; Alkharashi, Abdullah; Alzahrani, Saeed; Al Hazzaa, Selwa A; Xiong, Yong; Kong, Shanshan; Sun, Zhaoxia; Alkuraya, Fowzan S

2014-06-15

251

Two female siblings with West syndrome: Familial idiopathic West syndrome with genetic susceptibility and variable phenotypic expression  

PubMed Central

The West syndrome (WS) is a characteristic form of epilepsy which usually begins in the first year of life. We describe two female siblings, aged 4 and 2 years, respectively, born from third degree consanguineous parents, with infantile spasms and developmental delay. Epileptic spasms had not a good outcome under antiepileptic drug treatment. Clinical and imaging features were of different severity in both siblings. Routine biochemical tests, metabolic investigations, and chromosomal analysis were normal. We analyzed CDKL5 gene by direct sequences and denaturing high-performance liquid chromatography using Transgenomic WAVE system. Analysis of the CDKL5 gene, which is responsible for female patient with WS, did not show any disease-causing mutation. WS has heterogeneous backgrounds, and may be more than one gene is responsible for its familial forms. In this family, consanguinity is observed in parents, which usually suggests that autosomal recessive inheritance is likely.

Caglayan, Ahmet Okay; Gumus, Hakan; Kato, Mitsuhiro

2010-01-01

252

Family Arguments  

MedlinePLUS

... Healthy Children > Family Life > Family Dynamics > Family Arguments Family Life Listen Family Arguments Article Body We seem to have a lot of arguments in our family. Is this normal? Disputes between you and your ...

253

Comparative Analysis of P450 Signature Motifs EXXR and CXG in the Large and Diverse Kingdom of Fungi: Identification of Evolutionarily Conserved Amino Acid Patterns Characteristic of P450 Family  

PubMed Central

Cytochrome P450 monooxygenases (P450s) are heme-thiolate proteins distributed across the biological kingdoms. P450s are catalytically versatile and play key roles in organisms primary and secondary metabolism. Identification of P450s across the biological kingdoms depends largely on the identification of two P450 signature motifs, EXXR and CXG, in the protein sequence. Once a putative protein has been identified as P450, it will be assigned to a family and subfamily based on the criteria that P450s within a family share more than 40% homology and members of subfamilies share more than 55% homology. However, to date, no evidence has been presented that can distinguish members of a P450 family. Here, for the first time we report the identification of EXXR- and CXG-motifs-based amino acid patterns that are characteristic of the P450 family. Analysis of P450 signature motifs in the under-explored fungal P450s from four different phyla, ascomycota, basidiomycota, zygomycota and chytridiomycota, indicated that the EXXR motif is highly variable and the CXG motif is somewhat variable. The amino acids threonine and leucine are preferred as second and third amino acids in the EXXR motif and proline and glycine are preferred as second and third amino acids in the CXG motif in fungal P450s. Analysis of 67 P450 families from biological kingdoms such as plants, animals, bacteria and fungi showed conservation of a set of amino acid patterns characteristic of a particular P450 family in EXXR and CXG motifs. This suggests that during the divergence of P450 families from a common ancestor these amino acids patterns evolve and are retained in each P450 family as a signature of that family. The role of amino acid patterns characteristic of a P450 family in the structural and/or functional aspects of members of the P450 family is a topic for future research.

Syed, Khajamohiddin; Mashele, Samson Sitheni

2014-01-01

254

Comparative analysis of P450 signature motifs EXXR and CXG in the large and diverse kingdom of fungi: identification of evolutionarily conserved amino acid patterns characteristic of P450 family.  

PubMed

Cytochrome P450 monooxygenases (P450s) are heme-thiolate proteins distributed across the biological kingdoms. P450s are catalytically versatile and play key roles in organisms primary and secondary metabolism. Identification of P450s across the biological kingdoms depends largely on the identification of two P450 signature motifs, EXXR and CXG, in the protein sequence. Once a putative protein has been identified as P450, it will be assigned to a family and subfamily based on the criteria that P450s within a family share more than 40% homology and members of subfamilies share more than 55% homology. However, to date, no evidence has been presented that can distinguish members of a P450 family. Here, for the first time we report the identification of EXXR- and CXG-motifs-based amino acid patterns that are characteristic of the P450 family. Analysis of P450 signature motifs in the under-explored fungal P450s from four different phyla, ascomycota, basidiomycota, zygomycota and chytridiomycota, indicated that the EXXR motif is highly variable and the CXG motif is somewhat variable. The amino acids threonine and leucine are preferred as second and third amino acids in the EXXR motif and proline and glycine are preferred as second and third amino acids in the CXG motif in fungal P450s. Analysis of 67 P450 families from biological kingdoms such as plants, animals, bacteria and fungi showed conservation of a set of amino acid patterns characteristic of a particular P450 family in EXXR and CXG motifs. This suggests that during the divergence of P450 families from a common ancestor these amino acids patterns evolve and are retained in each P450 family as a signature of that family. The role of amino acid patterns characteristic of a P450 family in the structural and/or functional aspects of members of the P450 family is a topic for future research. PMID:24743800

Syed, Khajamohiddin; Mashele, Samson Sitheni

2014-01-01

255

Assessment of clinical and laboratory presentations of familial hemophagocytic lymphohistiocytosis patients with homozygous W374X mutation  

Microsoft Academic Search

Homozygous W374X mutation was identified in unrelated 13 patients (6M\\/7F) from consanguineous families, 62% of which had history of deceased sibling. Haplotype analysis provided evidence for the probable existence of a founder effect. Age at disease onset ranged from 1 day to 5.5 months (median 2 months). Hepatic dysfunction was observed in 69%, ascite 62%, hypertriglyceridemia 77%, each hyperferritinemia and

Gunay Balta; Hamza Okur; Sule Unal; Nese Yaral?; Adalet Meral Gunes; Selma Unal; Meral Turker; Elif Guler; Mehmet Ertem; Meryem Albayrak; Turkan Patiroglu; Aytemiz Gurgey

2010-01-01

256

Large-scale Molecular Analysis of a 34 Mb Interval on Chromosome 6q: Major Refinement of the RP25 Interval  

PubMed Central

Summary A large scale bioinformatics and molecular analysis of a 34 Mb interval on chromosome 6q12 was undertaken as part of our ongoing study to identify the gene responsible for an autosomal recessive retinitis pigmentosa (arRP) locus, RP25. Extensive bioinformatics analysis indicated in excess of 110 genes within the region and we also noted unfinished sequence on chromosome 6q in the Human Genome Database, between 58 and 61.2 Mb. Forty three genes within the RP25 interval were considered as good candidates for mutation screening. Direct sequence analysis of the selected genes in 7 Spanish families with arRP revealed a total of 244 sequence variants, of which 67 were novel but none were pathogenic. This, together with previous reports, excludes 60 genes within the interval (~55%) as disease causing for RP. To investigate if copy number variation (CNV) exists within RP25, a comparative genomic hybridization (CGH) analysis was performed on a consanguineous family. A clone from the tiling path array, chr6tp-19C7, spanning ~100-Kb was found to be deleted in all affected members of the family, leading to a major refinement of the interval. This will eventually have a significant impact on cloning of the RP25 gene.

El-Aziz, M. M. Abd; Barragan, I.; O'Driscoll, C.; Borrego, S.; Abu-Safieh, L.; Pieras, J. I.; El-Ashry, M. F.; Prigmore, E.; Carter, N.; Antinolo, G.; Bhattacharya, S. S.

2009-01-01

257

A novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability.  

PubMed

Mutations in the KDM5C gene (lysine (K)-specific demethylase 5C gene; also known as JARID1C and SMCX; MIM 314690) were recently associated with X-linked intellectual disability (XLID). To date only two case reports and five studies that screen for mutations in the KDM5C gene have been published, with 21 mutations reported. Herein we present a large family with XLID caused by a novel mutation c.2T > C in the start codon of the KDM5C gene, presumably leading to loss of gene translation. Six sibs out of seven (two sons and four sisters) and their mother carry this mutation. Two affected males presented the distinctive clinical phenotype, characterized by moderate short stature, clumsy gait, ataxia, increased muscle tone and brisk tendon reflexes. They constantly bore a happy and smiling facial expression, with a protruding tongue. We hereby offer the first thorough description of five affected females with the KDM5C gene mutation. Most frequent clinical features were short stature, facial dysmorphism and developmental problems. X-chromosome inactivation study showed completely skewed inactivation pattern of mutation-carrying chromosome in all affected female patients. PMID:22326837

Ounap, Katrin; Puusepp-Benazzouz, Helen; Peters, Maire; Vaher, Ulvi; Rein, Reet; Proos, Anne; Field, Mike; Reimand, Tiia

2012-03-01

258

A Missense Mutation in the Alpha-Actinin 1 Gene (ACTN1) Is the Cause of Autosomal Dominant Macrothrombocytopenia in a Large French Family  

PubMed Central

Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.

Gueguen, Paul; Rouault, Karen; Chen, Jian-Min; Raguenes, Odile; Fichou, Yann; Hardy, Elisabeth; Gobin, Eric; Pan-petesch, Brigitte; Kerbiriou, Mathieu; Trouve, Pascal; Marcorelles, Pascale; Abgrall, Jean-francois; Le Marechal, Cedric; Ferec, Claude

2013-01-01

259

Lipid transfer particle from the silkworm, Bombyx mori, is a novel member of the apoB/large lipid transfer protein family.  

PubMed

Lipid transfer particle (LTP) is a high-molecular-weight, very high-density lipoprotein known to catalyze the transfer of lipids between a variety of lipoproteins, including both insects and vertebrates. Studying the biosynthesis and regulation pathways of LTP in detail has not been possible due to a lack of information regarding the apoproteins. Here, we sequenced the cDNA and deduced amino acid sequences for three apoproteins of LTP from the silkworm (Bombyx mori). The three subunit proteins of the LTP are coded by two genes, apoLTP-II/I and apoLTP-III. ApoLTP-I and apoLTP-II are predicted to be generated by posttranslational cleavage of the precursor protein, apoLTP-II/I. Clusters of amphipathic secondary structure within apoLTP-II/I are similar to Homo sapiens apolipoprotein B (apoB) and insect lipophorins. The apoLTP-II/I gene is a novel member of the apoB/large lipid transfer protein gene family. ApoLTP-III has a putative conserved juvenile hormone-binding protein superfamily domain. Expression of apoLTP-II/I and apoLTP-III genes was synchronized and both genes were primarily expressed in the fat body at the stage corresponding to increased lipid transport needs. We are now in a position to study in detail the physiological role of LTP and its biosynthesis and assembly. PMID:23812557

Yokoyama, Hiroshi; Yokoyama, Takeru; Yuasa, Masashi; Fujimoto, Hirofumi; Sakudoh, Takashi; Honda, Naoko; Fugo, Hajime; Tsuchida, Kozo

2013-09-01

260

Human KZNF Gene Catalog - A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors  

DOE Data Explorer

Kruppel-type zinc finger (ZNF) motifs are prevalent components of transcription factor proteins in all eukaryotes. KRAB-ZNF proteins, in which a potent repressor domain is attached to a tandem array of DNA-binding zinc-finger motifs, are specific to tetrapod vertebrates and represent the largest class of ZNF proteins in mammals. To define the full repertoire of human KRAB-ZNF proteins, we searched the genome sequence for key motifs and then constructed and manually curated gene models incorporating those sequences. The resulting gene catalog contains 423 KRAB-ZNF protein-coding loci, yielding alternative transcripts that altogether predict at least 742 structurally distinct proteins. Active rounds of segmental duplication, involving single genes or larger regions and including both tandem and distributed duplication events, have driven the expansion of this mammalian gene family. Comparisons between the human genes and ZNF loci mined from the draft mouse, dog, and chimpanzee genomes not only identified 103 KRAB-ZNF genes that are conserved in mammals but also highlighted a substantial level of lineage-specific change; at least 136 KRAB-ZNF coding genes are primate specific, including many recent duplicates. KRAB-ZNF genes are widely expressed and clustered genes are typically not coregulated, indicating that paralogs have evolved to fill roles in many different biological processes. To facilitate further study, we have developed a Web-based public resource with access to gene models, sequences, and other data, including visualization tools to provide genomic context and interaction with other public data sets. [This abstract was copied from: S Huntley, DM Baggott, AT Hamilton, M Tran-Gyamfi, S Yang, J Kim, L Gordon, E Branscomb, and L Stubbs. 2006. A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors, Genome Research 16(5):669 - 677] The website provides the ability to search the online catalog by genomic coordinates, name, locus type, and motifs, to utilize a graphical browser and to download data files.

Huntley, S; Baggott, D.M.; Hamilton, A.T.; Tran-Gyamfi, M.; Yang, S.; Kim, J.; Gordon, L.; Branscomb, E.; Stubbs, L.

261

Differential Expression of BCL-2 Family Proteins in ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma of T/Null-Cell Lineage  

PubMed Central

Anaplastic large-cell lymphoma (ALCL) of T- or null-cell lineage, as defined in the revised European-American lymphoma classification, includes a subset of tumors that carry the t(2;5)(p23;q35) resulting in overexpression of anaplastic lymphoma kinase (ALK). Patients with ALK+ ALCL are reported to have a better prognosis than patients with ALK? ALCL. Because the mechanisms for this survival difference are unknown, we investigated the hypothesis that apoptotic pathways may be involved. We therefore assessed expression levels of the anti-apoptotic proteins BCL-2 and BCL-XL and the pro-apoptotic proteins BAX and BCL-XS in T/null-cell ALCL using immunohistochemical methods and correlated the findings with ALK expression and apoptotic rate (AR), the latter assessed by a modified Tdt-mediated dUTP nick-end labeling assay. ALK was detected in 21 of 66 (31.8%) ALCLs. BCL-2 was not detected in 21 ALK+ ALCLs but was present in 26 of 45 (57.8%) ALK? ALCLs (P < 0.0001). ALK+ and ALK? ALCLs also showed significant differences in expression of BCL-XL, BAX, and BCL-XS. ALK+ tumors less commonly had a high level of BCL-XL (1 of 17 versus 14 of 35, P = 0.01), and more commonly had high levels of BAX (13 of 18 versus 15 of 36, P = 0.05), and BCL-XS (11 of 16 versus 12 of 31, P = 0.05) compared with ALK? tumors. ALK+ tumors also had a higher mean AR than ALK? tumors (3.4% versus 1.1%, P = 0.0002). Differential expression of BCL-2 family proteins may be responsible for the higher AR observed in ALK+ ALCL and provides a possible biological explanation for the better prognosis reported for patients with ALK+ ALCL.

Rassidakis, George Z.; Sarris, Andreas H.; Herling, Marco; Ford, Richard J.; Cabanillas, Fernando; McDonnell, Timothy J.; Medeiros, L. Jeffrey

2001-01-01

262

Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo  

PubMed Central

Apogossypolone (ApoG2) is a semi-synthesized derivative of gossypol. The principal objective of this study was to compare stability and toxicity between ApoG2 and gossypol, and to evaluate anti-lymphoma activity of ApoG2 in vitro and in vivo. ApoG2 shows better stability when compared with a racemic gossypol and can be better tolerated by mice compared to gossypol. ApoG2 showed significant inhibition of cell proliferation of WSU-DLCL2 and primary cells obtained from lymphoma patients, whereas it displayed no toxicity on normal peripheral blood lymphocytes. For a treatment of 72 h, the IC50 of ApoG2 was determined to be 350 nM against WSU-DLCL2 cells. Treatment with ApoG2 at 600 mg/kg resulted in significant growth inhibition of WSU-DLCL2 xenografts. When combined with CHOP, ApoG2 displayed even more complete inhibition of tumor growth. ApoG2 binds to purified recombinant Bcl-2, Mcl-1 and Bcl-XL proteins with high affinity and is shown to block the formation of heterodimers between Bcl-XL and Bim. For a treatment of 72 h, ApoG2 induced a maximum of 32% of apoptotic cell death. Western blot experiments showed that treatment with ApoG2 led to cleavage of caspase-3, caspase-9 and PARP. Moreover, pretreatment of DLCL2 cells with caspase-3, -9 and broad spectrum caspase inhibitors significantly blocked growth inhibition induced by ApoG2. In conclusion, ApoG2 effectively inhibits growth of DLCL2 cells at least partly by inducing apoptosis. It is an attractive small molecule inhibitor of the Bcl-2 family proteins to be developed further for the treatment of diffuse large cell lymphoma.

Sun, Yuan; Wu, Jack; Aboukameel, Amro; Banerjee, Sanjeev; Arnold, Alan A.; Chen, Jianyong; Nikolovska-Coleska, Zaneta; Lin, Yanqiong; Ling, Xiaolan; Yang, Dajun; Wang, Shaomeng; Al-Katib, Ayad; Mohammad, Ramzi M.

2014-01-01

263

Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family.  

PubMed

We describe 10 patients from a large family with early onset motor and sensory neuropathy. Six were still living at the time of the study. In all cases, early motor milestones had been achieved. Mean age at onset of symptoms was 34 months; these included progressive distal and proximal muscle weakness of lower limbs. Pes equinovarus developed in all patients during childhood. Slight facial weakness was present in four patients, and one of them also had bilateral facial synkinesia. Intellectual function was normal in all cases. There was no evidence of thickened peripheral nerves. All three adult patients (mean age, 27 years) were seriously handicapped and wheelchair-bound. Death occurred in the fourth to fifth decade of life and the duration of the illness varied from 27 to 39 years. Motor nerve conduction velocities ranged from 15 to 17 m/sec in the upper limbs of the youngest patients, and were undetectable in the adult patients. Sensitive action potentials were almost always absent. In all patients, auditory evoked potentials showed abnormally delayed interpeak I-III latencies. The most prominent pathologic finding was a highly unusual myelin abnormality consisting of irregular redundant loops and folding of the myelin sheath. The genealogic study gave strong evidence of autosomal-recessive inheritance. The molecular analysis failed to demonstrate either duplication in the chromosome 17p11.2-12, point mutations in the four exons of the PMP-22 (17p11.2) and the six exons of the Po (1q21-q25) genes, or linkage to chromosome 8q13-21.1. PMID:8628474

Quattrone, A; Gambardella, A; Bono, F; Aguglia, U; Bolino, A; Bruni, A C; Montesi, M P; Oliveri, R L; Sabatelli, M; Tamburrini, O; Valentino, P; Van Broeckhoven, C; Zappia, M

1996-05-01

264

Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo.  

PubMed

Apogossypolone (ApoG2) is a semi-synthesized derivative of gossypol. The principal objective of this study was to compare stability and toxicity between ApoG2 and gossypol, and to evaluate anti-lymphoma activity of ApoG2 in vitro and in vivo. ApoG2 shows better stability when compared with a racemic gossypol and can be better tolerated by mice compared to gossypol. ApoG2 showed significant inhibition of cell proliferation of WSU-DLCL(2) and primary cells obtained from lymphoma patients, whereas it displayed no toxicity on normal peripheral blood lymphocytes. For a treatment of 72 h, the IC(50) of ApoG2 was determined to be 350 nM against WSU-DLCL2 cells. Treatment with ApoG2 at 600 mg/kg resulted in significant growth inhibition of WSU-DLCL(2) xenografts. When combined with CHOP, ApoG2 displayed even more complete inhibition of tumor growth. ApoG2 binds to purified recombinant Bcl-2, Mcl-1 and Bcl-X(L) proteins with high affinity and is shown to block the formation of heterodimers between Bcl-X(L) and Bim. For a treatment of 72 h, ApoG2 induced a maximum of 32% of apoptotic cell death. Western blot experiments showed that treatment with ApoG2 led to cleavage of caspase-3, caspase-9 and PARP. Moreover, pretreatment of DLCL(2) cells with caspase-3, -9 and broad spectrum caspase inhibitors significantly blocked growth inhibition induced by ApoG2. In conclusion, ApoG2 effectively inhibits growth of DLCL(2) cells at least partly by inducing apoptosis. It is an attractive small molecule inhibitor of the Bcl-2 family proteins to be developed further for the treatment of diffuse large cell lymphoma. PMID:18769131

Sun, Yuan; Wu, Jack; Aboukameel, Amro; Banerjee, Sanjeev; Arnold, Alan A; Chen, Jianyong; Nikolovska-Coleska, Zaneta; Lin, Yanqiong; Ling, Xiaolan; Yang, Dajun; Wang, Shaomeng; Al-Katib, Ayad; Mohammad, Ramzi M

2008-09-01

265

An unusual case of familial hyperlipidaemia.  

PubMed

A 40 days old male baby born to a consanguineous couple was found to have highly viscous and milky serum with caking of chylomicrons on refrigeration of serum. Cholesterol was 889.5 mg/dl (23.04mmol/L) and Triglycerides 12881 mg/dl (141.69mmol/L). He was active and did not have any hepatospleenomegaly, xanthomas or dysmorphic features. Thyroid functions were normal. Lipid electrophoresis showed thick chylomicron band. There was positive family history of hypertriglyceridemia in a first cousin. Both siblings and both parents of the index case had normal lipid profiles. This child was referred to higher centre where he was put on Lipid lowering drugs (Gemfibrozil), Iron drops and special formula for feeding containing medium chain fatty acids. PMID:23105777

Nagar, Renu; Arora, Uma

2008-07-01

266

The Clinical Spectrum of Missense Mutations of the First Aspartic Acid of cbEGF-like Domains in Fibrillin-1 Including a Recessive Family  

PubMed Central

Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation. © 2010 Wiley-Liss, Inc.

Hilhorst-Hofstee, Yvonne; Rijlaarsdam, Marry EB; Scholte, Arthur JHA; Swart-van den Berg, Marietta; Versteegh, Michel IM; van der Schoot-van Velzen, Iris; Schabitz, Hans-Joachim; Bijlsma, Emilia K; Baars, Marieke J; Kerstjens-Frederikse, Wilhelmina S; Giltay, Jacques C; Hamel, Ben C; Breuning, Martijn H; Pals, Gerard

2010-01-01

267

Novel mutation in the SLC19A2 gene in an Iranian family with thiamine-responsive megaloblastic anemia: a series of three cases.  

PubMed

Thiamine-responsive megaloblastic anemia (TRMA) is a clinical triad characterized by megaloblastic anemia, non-autoimmune diabetes mellitus, and sensory-neural hearing loss. Mutations in the thiamine transporter gene, solute carrier family 19, member 2 (SLC19A2), have been associated with TRMA. Three pediatric patients from a large consanguineous Iranian family with hyperglycemia, anemia, and hearing loss were clinically diagnosed with TRMA. In all three patients, TRMA was confirmed by direct sequencing of the SLC19A2 gene that revealed a novel missense homozygous mutation c.382 G>A (p.E128K). This mutation results in the substitution of glutamic acid to lysine at position 128 in exon 2 and was not detected in 200 control chromosomes. Thiamine therapy reversed the anemia and alleviated the hyperglycemia in all three patients. We recommend sequence analysis of the SLC19A2 gene in individuals with a clinical triad of diabetes mellitus, hearing loss, and anemia. The administration of thiamine ameliorates the megaloblastic anemia and the hyperglycemia in patients with TRMA. PMID:24072090

Ghaemi, Nosrat; Ghahraman, Martha; Abbaszadegan, Mohammad Reza; Baradaran-Heravi, Alireza; Vakili, Rahim

2013-09-10

268

Novel Mutation in the SLC19A2 Gene in an Iranian Family with Thiamine-Responsive Megaloblastic Anemia: A Series of Three Cases  

PubMed Central

Thiamine-responsive megaloblastic anemia (TRMA) is a clinical triad characterized by megaloblastic anemia, non-autoimmune diabetes mellitus, and sensory-neural hearing loss. Mutations in the thiamine transporter gene, solute carrier family 19, member 2 (SLC19A2), have been associated with TRMA. Three pediatric patients from a large consanguineous Iranian family with hyperglycemia, anemia, and hearing loss were clinically diagnosed with TRMA. In all three patients, TRMA was confirmed by direct sequencing of the SLC19A2 gene that revealed a novel missense homozygous mutation c.382 G>A (p.E128K). This mutation results in the substitution of glutamic acid to lysine at position 128 in exon 2 and was not detected in 200 control chromosomes. Thiamine therapy reversed the anemia and alleviated the hyperglycemia in all three patients. We recommend sequence analysis of the SLC19A2 gene in individuals with a clinical triad of diabetes mellitus, hearing loss, and anemia. The administration of thiamine ameliorates the megaloblastic anemia and the hyperglycemia in patients with TRMA. Conflict of interest:None declared.

Ghaemi, Nosrat; Ghahraman, Martha; Abbaszadegan, Mohammad Reza; Baradaran-Heravi, Alireza; Vakili, Rahim

2013-01-01

269

Decreased High-Density Lipoprotein (HDL) Particle Size, Pre, and Large HDL Subspecies Concentration in Finnish Low-HDL Families Relationship With Intima-Media Thickness  

Microsoft Academic Search

Objective—High-density lipoprotein (HDL) cholesterol correlates inversely with the risk of coronary heart disease (CHD). The precise antiatherogenic mechanisms of HDL subspecies are not thoroughly elucidated. We studied the relationship between carotid intima-media thickness (IMT) and HDL subspecies distribution in Finnish families with low HDL cholesterol and premature CHD. Methods and Results—Altogether, 148 members of Finnish low-HDL families and 133 healthy

Hiroshi Watanabe; Sanni Soderlund; Aino Soro-Paavonen; Anne Hiukka; Eeva Leinonen; Corradina Alagona; Riitta Salonen; Tomi-Pekka Tuomainen; Christian Ehnholm; Matti Jauhiainen; Marja-Riitta Taskinen

2010-01-01

270

Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred  

SciTech Connect

Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantly inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies have been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.

Andermann, F.; Andermann, E.; Carpenter, S. [and others

1994-09-01

271

Further Evidence for Robust Familiality of Pediatric Bipolar-I Disorder: Results from a Very Large Controlled Family Study of Pediatric Bipolar-I Disorder and a Meta-Analysis  

PubMed Central

Objective To determine the risk for BP-I disorder in first-degree relatives of children with DSM-IV bipolar-I disorder (BP-I) via meta-analysis and expanded controlled study. Data Sources and Extraction Meta-Analysis We searched the Pubmed database for scientific articles published in the world literature in the English language through 2011. The key words searched were: bipolar disorder, first-degree relatives, family study, control. All online abstracts were reviewed and relevant full manuscripts were collected and reviewed. Citations were also examined for other potential relevant articles. We included only controlled family studies that examined rates of bipolar-I disorder in all first-degree relatives (parents and siblings) of pediatric bipolar-I probands and included only studies that had age and sex matched controls. Family history studies were excluded. Also excluded were studies that were not in English, did not report the rates of all first-degree relatives, and reported only bipolar spectrum rates. We also excluded family studies that included only adult probands. We conducted a meta-analysis of the five controlled family studies of pediatric BP-I probands that met our search criteria using the random effects model of DerSimonian and Laird. Method Family Study We greatly expanded our previous sample of DSM-IV BP-I probands using structured diagnostic interviews. Our new study included 239 children satisfying full with DSM-IV diagnostic criteria for BP-I (n=726 first-degree relatives), 162 ADHD (without BP-I) probands (n=511 first-degree relatives), and 136 healthy control (without ADHD or BP-I) probands (n=411 first-degree relatives). We used the Kaplan-Meier cumulative failure function to calculate survival curves and cumulative, lifetime risk in relatives. Cox proportional hazard models were used to calculate the risk of BP-I in relatives. Results The pooled odds ratio for BP-I disorder in relatives was estimated to be 6.96 (95% Confidence Interval (CI): 4.8 to 10.1). We also found first-degree relatives of BP-I probands to be significantly more likely than first-degree relatives of both ADHD (Hazards Ratio: 3.02; 95% CI: 1.85 to 4.93; p<0.001) and control probands (HR: 2.83; 1.65 to 4.84; p<0.001) to have bipolar-I disorder. Conclusion Our results document an increased familial risk for BP-I disorder in relatives of pediatric probands with DSM-IV BP-I.

Wozniak, Janet; Faraone, Stephen V.; Martelon, MaryKate; McKillop, Hannah N.; Biederman, Joseph

2013-01-01

272

Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q  

SciTech Connect

Familial spastic paraplegia (FSP) (MIM No.18260) constitutes a clinically and genetically diverse group of disorders that share the primary feature of progressive, severe, lower extremity spasticity. FSP is classified according to the mode of inheritance and whether progressive spasticity occurs in isolation ({open_quotes}uncomplicated FSP{close_quotes}) or with other neurologic abnormalities ({open_quotes}complicated FSP{close_quotes}), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, or deafness. Recently, autosomal dominant, uncomplicated FSP was shown to be genetically heterogeneous and tightly linked to a group of microsatellite markers on chromosome 14q in one large kindred. We examined 126 members of a non-consanguineous North American kindred of Irish descent. FSP was diagnosed in 31 living subjects who developed insidiously progressive gait disturbance between ages 12 and 35 years. Using genetic linkage analysis to microsatellite DNA polymorphisms, we showed that the FSP locus on chromosome 14q was exluded from linkage with the disorder in our family. Subsequently, we searched for genetic linkage between the disorder and microsatellite DNA polymorphisms spanning approximately 50% of the genome. We observed significantly positive, two-point maximum lod scores (Z) for markers on chromosome 15q: D15S128 (Z=9.70, {theta}=0.05), D15S165 (Z=3.30, {theta}=0.10), and UT511 (Z=3.86, {theta}=0.10). Our data clearly establishes that one locus for autosomal dominant, uncomplicated FSP is mapped to the pericentric region of chromosome 15q. Identifying genes responsible for chromosome 15q-linked and chromosome 14q-linked FSP will greatly advance our understanding of this condition and hopefully other inherited and degenerative brain and spinal cord disorders that are also characterized by axonal degeneration.

Fink, J.K.; Wu, C.T.B.; Jones, S.M.

1994-09-01

273

Family Togetherness  

Microsoft Academic Search

Members of Florence Kaslow's family of procreation share their insights into the myriad ways in which her professional contributions in family psychology and international psychology have had an impact on their family life. Particular attention is paid to the family life of psychotherapists, healthy family functioning, healthy long-term marriages, sex therapy, military psychology, family business consulting and the use of

Nadine J. Kaslow; Solis Kaslow; Howard I. Kaslow

2004-01-01

274

A homozygous p.Glu150Lys mutation in the opsin gene of two Pakistani families with autosomal recessive retinitis pigmentosa  

PubMed Central

Purpose To identify the gene mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in Pakistani families. Methods A cohort of consanguineous families with typical RP phenotype in patients was screened by homozygosity mapping using microsatellite markers that mapped close to 21 known arRP genes and five arRP loci. Mutation analysis was performed by direct sequencing of the candidate gene. Results In two families, RP21 and RP53, homozygosity mapping suggested RHO, the gene encoding rhodopsin, as a candidate disease gene on chromosome 3q21. In six out of seven affected members from the two families, direct sequencing of RHO identified a homozygous c.448G>A mutation resulting in the p.Glu150Lys amino acid change. This variant was first reported in PMK197, an Indian arRP family. Single nucleotide polymorphism analysis in RP21, RP53, and PMK197 showed a common disease-associated haplotype in the three families. Conclusions In two consanguineous Pakistani families with typical arRP phenotype in the patients, we identified a disease-causing mutation (p.Glu150Lys) in the RHO gene. Single nucleotide polymorphism analysis suggests that the previously reported Indian family (PMK197) and the two Pakistani families studied here share the RHO p.Glu150Lys mutation due to a common ancestry.

Azam, Maleeha; Khan, Muhammad Imran; Gal, Andreas; Hussain, Alamdar; Shah, Syed Tahir Abbas; Khan, Muhammad Shakil; Sadeque, Ahmed; Bokhari, Habib; Collin, Rob W.J.; Orth, Ulrike; van Genderen, Maria M.; den Hollander, A.I.; Cremers, Frans P. M.

2009-01-01

275

Familiality of Tourette Syndrome, Obsessive-Compulsive Disorder, and Attention-Deficit/Hyperactivity Disorder: Heritability Analysis in a Large Sib-Pair Sample  

ERIC Educational Resources Information Center

Objective: Tourette syndrome (TS) is a neuropsychiatric disorder with a genetic component that is highly comorbid with obsessive-compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD). However, the genetic relations between these disorders have not been clearly elucidated. This study examined the familial relations among TS,…

Mathews, Carol A.; Grados, Marco A.

2011-01-01

276

Attitudes towards people with mental illness among psychiatrists, psychiatric nurses, involved family members and the general population in a large city in Guangzhou, China  

PubMed Central

Purpose Stigma towards people with mental illness is believed to be widespread in low and middle income countries. Methods This study assessed the attitudes towards people with mental illness among psychiatrists, psychiatric nurses, involved family members of patients in a psychiatric facility and the general public using a standard 43-item survey (N?=?535). Exploratory factor analysis identified four distinctive attitudes which were then compared using Analysis of Covariance (ANCOVA) among the four groups, all with ties to the largest psychiatric facility in Guangzhou, China, adjusting for sociodemographic differences. Results Four uncorrelated factors expressed preferences for 1) community-based treatment, social integration and a biopsychosocial model of causation, 2) direct personal relationships with people with mental illness, 3) a lack of fear and positive views of personal interactions with people with mental illness, 4) disbelief in superstitious explanations of mental illness. Statistically significant differences favored community-based treatment and biopsychosocial causation (factor 1) among professional groups (psychiatrists and nurses) as compared with family members and the general public (p?family members, unexpectedly, showed far weaker personal preferences for direct personal relationships with people with mental illness than all three other groups (p?family members showed the least positive attitudes towards direct personal relationships with people with mental illness. These findings suggest support for a more extensive, formal system of care that gives family members some distance from the problems of their relatives and support in their care.

2014-01-01

277

A novel nonsense mutation in keratin 10 causes a familial case of recessive epidermolytic ichthyosis  

PubMed Central

Epidermolytic ichthyosis (EI) is a rare skin disorder characterized by generalized erythroderma and cutaneous blistering at birth, which is substituted by hyperkeratosis later in life. It is caused by autosomal dominant mutations in highly conserved regions of KRT1 and KRT10. To date, only four mutations with autosomal recessive inheritance of EI have been described in consanguineous families. All of them affect the 2B domain of KRT10. In the present study, we describe four patients with EI (including one lethal case) born from unaffected parents in a consanguineous family of a native Venezuelan community. The objective of this study was to characterize the clinical, genetic, and morphological aspects of the disease in this family, as well as understand its functional implications. Genomic DNA was sequenced for KRT10 and KRT1. Immunofluoresence for keratin expression was performed on cutaneous biopsies. After examination of cutaneous biopsies histology, our results showed hyperkeratosis and acantholysis with an expanded granular layer. Sequencing of KRT10 demonstrated a nonsense mutation (p.Tyr282Ter.) corresponding to the 1B domain of the protein in patients and a heterozygous pattern in other family members, resulting in complete absence of K10. The loss of K10 was compensated by upregulation of K14 and K17. In conclusion, this novel mutation in KRT10 is the first recessive genetic variation that is not located in the so called “hot spot” for recessive EI, suggesting that other areas of the gene are also susceptible for such mutations.

Gutierrez, Jeydith A; Hannoush, Zeina C; Vargas, Luis G; Momany, Allison; Garcia, Carmen C; Murray, Jeffrey C; Dunnwald, Martine

2013-01-01

278

Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family.  

PubMed

In this study, we have performed autozygosity mapping on a large consanguineous Pakistani family segregating with intellectual disability. We identified two large regions of homozygosity-by-descent (HBD) on 16q12.2-q21 and 16q24.1-q24.3. Whole exome sequencing (WES) was performed on an affected individual from the family, but initially, no obvious mutation was detected. However, three genes within the HBD regions that were not fully captured during the WES were Sanger sequenced and we identified a five base pair deletion (actually six base pairs deleted plus one base pair inserted) in exon 7 of the gene FBXO31. The variant segregated completely in the family, in recessive fashion giving a LOD score of 3.95. This variant leads to a frameshift and a premature stop codon and truncation of the FBXO31 protein, p.(Cys283Asnfs*81). Quantification of mRNA and protein expression suggests that nonsense-mediated mRNA decay also contributes to the loss of FBXO31 protein in affected individuals. FBXO31 functions as a centrosomal E3 ubiquitin ligase, in association with SKP1 and Cullin-1, involved in ubiquitination of proteins targeted for degradation. The FBXO31/SKP1/Cullin1 complex is important for neuronal morphogenesis and axonal identity. FBXO31 also plays a role in dendrite growth and neuronal migration in developing cerebellar cortex. Our finding adds further evidence of the involvement of disruption of the protein ubiquitination pathway in intellectual disability. PMID:24623383

Mir, Asif; Sritharan, Kumudesh; Mittal, Kirti; Vasli, Nasim; Araujo, Carolina; Jamil, Talal; Rafiq, Muhammad Arshad; Anwar, Zubair; Mikhailov, Anna; Rauf, Sobiah; Mahmood, Huda; Shakoor, Abdul; Ali, Sabir; So, Joyce; Naeem, Farooq; Ayub, Muhammad; Vincent, John B

2014-08-01

279

Protein Phosphatase 2B (PP2B, Calcineurin) in Paramecium: Partial Characterization Reveals That Two Members of the Unusually Large Catalytic Subunit Family Have Distinct Roles in Calcium-Dependent Processes?‡  

PubMed Central

We characterized the calcineurin (CaN) gene family, including the subunits CaNA and CaNB, based upon sequence information obtained from the Paramecium genome project. Paramecium tetraurelia has seven subfamilies of the catalytic CaNA subunit and one subfamily of the regulatory CaNB subunit, with each subfamily having two members of considerable identity on the amino acid level (?55% between subfamilies, ?94% within CaNA subfamilies, and full identity in the CaNB subfamily). Within CaNA subfamily members, the catalytic domain and the CaNB binding region are highly conserved and molecular modeling revealed a three-dimensional structure almost identical to a human ortholog. At 14 members, the size of the CaNA family is unprecedented, and we hypothesized that the different CaNA subfamily members were not strictly redundant and that at least some fulfill different roles in the cell. This was tested by selecting two phylogenetically distinct members of this large family for posttranscriptional silencing by RNA interference. The two targets resulted in differing effects in exocytosis, calcium dynamics, and backward swimming behavior that supported our hypothesis that the large, highly conserved CaNA family members are not strictly redundant and that at least two members have evolved diverse but overlapping functions. In sum, the occurrence of CaN in Paramecium spp., although disputed in the past, has been established on a molecular level. Its role in exocytosis and ciliary beat regulation in a protozoan, as well as in more complex organisms, suggests that these roles for CaN were acquired early in the evolution of this protein family.

Fraga, D.; Sehring, I. M.; Kissmehl, R.; Reiss, M.; Gaines, R.; Hinrichsen, R.; Plattner, H.

2010-01-01

280

Clinical and Molecular Evidence of Abnormal Processing and Trafficking of the Vasopressin Preprohormone in a Large Kindred with Familial Neurohypophyseal Diabetes Insipidus due to A Signal Peptide Mutation  

Microsoft Academic Search

The autosomal dominant form of familial neurohypophyseal dia- betes insipidus (adFNDI) is a rare disease characterized by postnatal onset of polyuria and a deficient neurosecretion of the antidiuretic hormone, arginine vasopressin (AVP). Since 1991, adFNDI has been linked to 31 different mutations of the gene that codes for the vaso- pressin-neurophysin II (AVP-NPII) precursor. The aims of the present study

CHARLOTTE SIGGAARD; SØREN RITTIG; THOMAS J. CORYDON; PER HOVE ANDREASEN; THOMAS G. JENSEN; BRAGE S. ANDRESEN; GARY L. ROBERTSON; NIELS GREGERSEN; LARS BOLUND; ERLING B. PEDERSEN

281

Severe mental retardation in six generations of a large South African family carrying a translocation t(6;10)(q27;q25.2).  

PubMed Central

Partial monosomy 10q25.2----qter, detected in a newborn baby with multiple congenital abnormalities, was found to be derived from a balanced maternal translocation t(6;10)(q27;q25.2). The pedigree of six generations of the family is presented. In an extensive cytogenetic study of this family, the chromosome complements of 57 subjects, potentially capable of carrying some form of this translocation, were analysed. A total of 14 male carriers (four obligatory) and 14 female carriers (three obligatory) of this translocation was found. Partial trisomy 10q25.2----qter, associated with severe mental retardation, occurred in nine cases, eight males and one female. Two of these eight males were detected prenatally and subsequently therapeutically aborted. The phenotypes of the family members with partial trisomy 10q25.2----qter are compared to each other and to those reported in publications. No further cases of partial monosomy 10q25.2----qter were encountered. A review of published reports of partial monosomy and partial trisomy 10qter is given. The apparent absence of infertility, the occurrence of many first trimester miscarriages, and the marked sex ratio are discussed. Images

Brusnicky, J; van Heerden, K M; de Jong, G; Cronje, A S; Retief, A E

1986-01-01

282

Mutations in MTMR13, a New Pseudophosphatase Homologue of MTMR2 and Sbf1, in Two Families with an Autosomal Recessive Demyelinating Form of Charcot-Marie-Tooth Disease Associated with Early-Onset Glaucoma  

PubMed Central

Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called “pseudophosphatases.” MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.

Azzedine, H.; Bolino, A.; Taieb, T.; Birouk, N.; Di Duca, M.; Bouhouche, A.; Benamou, S.; Mrabet, A.; Hammadouche, T.; Chkili, T.; Gouider, R.; Ravazzolo, R.; Brice, A.; Laporte, J.; LeGuern, E.

2003-01-01

283

A splice site mutation in the methyltransferase gene FTSJ1 in Xp11.23 is associated with non-syndromic mental retardation in a large Belgian family (MRX9)  

PubMed Central

Mental retardation is the most frequent cause of serious handicap in children and young adults. The underlying causes of this heterogeneous condition are both acquired and genetically based. A recently performed refinement of the linkage interval in a large Belgian family with mild to severe non-syndromic X linked mental retardation, classified as MRX9, revealed a candidate region of 11.3 Mb between markers DXS228 and DXS1204 on the short arm of the X chromosome. In order to identify the underlying disease gene in the MRX9 family, we established a gene catalogue for the candidate region and performed comprehensive mutation analysis by direct sequencing. A human homologue of the bacterial 23S rRNA methyltransferase Fstj, the FTSJ1 gene, is located within this region and displayed a sequence alteration in the conserved acceptor splice site of intron 3 (IVS3-2A>G) in all tested patients and carrier females of this family. In contrast, it was absent in all unaffected male family members tested. The mutation results in skipping of exon 4 and introduces a premature stop codon in exon 5, probably leading to a severely truncated protein. Our finding indicates that a protein, possibly associated with ribosomal stability, can be linked to X linked mental retardation (XLMR).

Ramser, J; Winnepenninckx, B; Lenski, C; Errijgers, V; Platzer, M; Schwartz, C; Meindl, A; Kooy, R

2004-01-01

284

Families & Friendships  

MedlinePLUS

... Families & Friendships Military Sexual Trauma Depression mild Traumatic Brain Injury Life Stress Health & Wellness Anger Stigma Suicide Prevention ... Post-Traumatic Stress Sleep Alcohol & Drugs mild Traumatic Brain Injury Resilience Families with Kids Depression Families & Friendships Tobacco ...

285

Family Disruptions  

MedlinePLUS

... PedFACTs) Teaching Package First Aid for Families (PedFACTs) Pediatric First Aid for Caregivers and Teachers (PedFACTs) Participant Manual Allergies and Asthma Family Life Health Management - Medical Home Family Dynamics ...

286

Foster Families  

MedlinePLUS

... foster family? Let's find out. What Are Foster Families? The word "foster" means to help someone (or ... home. Continue Why Do Kids Live With Foster Families? Most often, a kid goes into a foster ...

287

Family History  

MedlinePLUS

... Aneurysm Complications Post Treatment and Outcome GTranslate Understanding : Family History Familial intracranial aneurysms are generally defined as the presence of two or more family members among first- and second-degree relatives with ...

288

Family Functioning in Neglectful Families.  

ERIC Educational Resources Information Center

Comparison of family functioning in 103 neglectful and 102 nonneglectful low-income families found that neglectful mothers reported their families as having more family conflict and less expression of feelings, but not less cohesiveness. Observational measures indicated neglectful families were less organized, more chaotic, and less verbally…

Gaudin, James M., Jr.; And Others

1996-01-01

289

FAMILIAL SUICIDE  

PubMed Central

Seven completed suicides in a family of lower socioeconomic status and suburban domicile in Pondicherry are reported. The presence of bipolar affective disorder in the family members and the absence of exogenous factors are illustrated by utilising both family history method and family study method. The details collected formed the basis for the terminology ‘familial suicide’. The management of the index case, one of the only three surviving male members of the family, who presented with suicidal ruminations and depressive features, is described.

Unni, K.E. Sadanaandan

1996-01-01

290

Does Sex Moderate the Clinical Correlates of Pediatric Bipolar-I Disorder? Results from a Large Controlled Family-Genetic Study  

PubMed Central

Background Since little is known as to whether sex differences affect the clinical presentation of pediatric BP-I disorder, it is an area of high clinical, scientific and public health relevance. Methods Subjects are 239 BP-I probands (65 female probands, 174 male probands) and their 726 first-degree relatives, and 136 non-bipolar, non-ADHD control probands (37 female probands, 99 male probands) and their 411 first-degree relatives matched for age and sex. We modeled the psychiatric and cognitive outcomes as a function of BP-I status, sex, and the BP-I status-gender interaction. Results BP-I disorder was equally familial in both sexes. With the exception of duration of mania (shorter in females) and number of depressive episodes (more in females), there were no other meaningful differences between the sexes in clinical correlates of BP-I disorder. With the exception of a significant sex effect for panic disorder and a trend for substance use disorders (p=0.05) with female probands being at a higher risk than male probands, patterns of comorbidity were similar between the sexes. Despite the similarities, boys with BP-I disorder received more intensive and costly academic services than girls with the same disorder. Limitations Since we studied children referred to a family study of bipolar disorder, our findings may not generalize to clinic settings. Conclusions We found more similarities than differences between the sexes in the personal and familial correlates of BP-I disorder. Clinicians should consider bipolar disorder in the differential diagnosis of both boys and girls afflicted with symptoms suggestive of this disorder.

Wozniak, Janet; Biederman, Joseph; Martelon, MaryKate; Hernandez, Mariely; Woodworth, K. Yvonne; Faraone, Stephen V.

2013-01-01

291

The consequences of consanguinity on the rates of malformations and major medical conditions at birth and in early childhood in inbred populations.  

PubMed

The rate of malformations and major medical conditions in early childhood was analyzed in a single village according to the degree of relationship between the parents. In the village, 70-80% of the marriages are between descendants of the founders and therefore consanguineous. In the period 1992-2003, in 99 of 2,610 children, a major malformation was diagnosed at birth and seven additional fetuses were aborted because of a severe malformation. A significant medical condition was diagnosed in 38 additional children in early childhood. The total of 144 cases with malformations or a major medical condition represented 5.52% (95% CI: 4.64-6.4) of the live births. Three malformations/disorders were relatively frequent: Down syndrome, esophageal atresia, and profound deafness. The rate of malformations and significant medical conditions was 7.77% (95 CI: 5.68-9.86) when the parents were first cousins and 3.63% (95% CI: 2.11-5.15) when they were not related (P = 0.002, Fisher's exact test). Offspring of parents that were second cousins or closer but less than first cousin had a risk that was similar to the one of offspring of couples that were more distantly related. We propose therefore, that in inbred populations, all the couples that are not related as first cousins but in which the spouses are both descendants of the founders should be considered as related. The high prevalence of profound deafness in the village is due to mutations in the Connexin 26 gene, while the relatively high frequency of Down syndrome is not explained by maternal age only. PMID:20635393

Zlotogora, Joël; Shalev, Stavit A

2010-08-01

292

Family Literacy  

ERIC Educational Resources Information Center

Research indicates that family literacy programs can provide opportunities for educational success for parents and children. The benefits reaped by the children in family literacy workshops are presented.

Holloway, John H.

2004-01-01

293

Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models  

PubMed Central

Background Accurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias. Methods A cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. John's, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females. Results Lifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females compared to their male counterparts (Females = 23.7, 95%CI = (5.6, 137.9); Males = 6.8%, 95% CI = (2.3, 66.2)). However, the risk of developing CRC decreased with age among both genders. Conclusion The proposed modified segregation-based models used to estimate age-specific risks for HNPCC phenotypes can reduce bias due to ascertainment and missing genotype information as well as provide estimates of absolute and relative risks.

Kopciuk, Karen A; Choi, Yun-Hee; Parkhomenko, Elena; Parfrey, Patrick; McLaughlin, John; Green, Jane; Briollais, Laurent

2009-01-01

294

Sib-pair analysis detects elevated Lp(a) levels and large variation of Lp(a) concentration in subjects with familial defective ApoB.  

PubMed Central

Whether or not Lp(a) plasma levels are affected by the apoB R3500Q mutation, which causes Familial Defective apoB (FDB), is still a matter of debate. We have analyzed 300 family members of 13 unrelated Dutch index patients for the apoB mutation and the apolipoprotein(a) [apo(a)] genotype. Total cholesterol, LDL-cholesterol, and lipoprotein(a) [Lp(a)] concentrations were determined in 85 FDB heterozygotes and 106 non-FDB relatives. Mean LDL levels were significantly elevated in FDB subjects compared to non-FDB relatives (P < 0.001). Median Lp(a) levels were not different between FDB subjects and their non-FDB relatives. In contrast, sib-pair analysis demonstrated a significant effect of the FDB status on Lp(a) levels. In sib pairs identical by descent for apo(a) alleles but discordant for the FDB mutation (n = 11) each sib with FDB had a higher Lp(a) level than the corresponding non-FDB sib. Further, all possible sib pairs (n = 105) were grouped into three categories according to the absence/presence of the apoB R3500Q mutation in one or both subjects of a sib pair. The variability of differences in Lp(a) levels within the sib pairs increased with the number (0, 1, and 2) of FDB subjects present in the sib pair. This suggests that the FDB status increases Lp(a) level and variability, and that apoB may be a variability gene for Lp(a) levels in plasma.

van der Hoek, Y. Y.; Lingenhel, A.; Kraft, H. G.; Defesche, J. C.; Kastelein, J. J.; Utermann, G.

1997-01-01

295

Pro370Leu MYOC gene mutation in a large Chinese family with juvenile-onset open angle glaucoma: correlation between genotype and phenotype  

PubMed Central

Purpose Glaucoma is the leading cause of irreversible blindness worldwide. Most of the cases are primary open angle glaucoma (POAG). POAG is a genetically heterogenous disease; autosomal dominance is the most frequent type of monogenic inheritance. In this study, we identified the genotype of a MYOC mutation and investigated the phenotype of a Chinese juvenile-onset open angle glaucoma (JOAG) pedigree (GZ.1 pedigree). Methods Blood samples were obtained from 24 participants. We performed sequence and gene linkage analysis in the GZ.1 pedigree retrospectively. Comprehensive ophthalmologic examinations were performed for each family member. Pharmacological treatment or filtering surgery was performed as needed according to the intraocular pressure (IOP) of each individual. Results A Pro370Leu myocilin mutation located in exon 3 of MYOC was identified in 24 members of the GZ.1 pedigree. Sixteen patients had juvenile-onset primary open-angle glaucoma (JOAG), and the others participating in the project had no such genotype. Analysis of polymorphic microsatellite markers indicated that the disease in GZ.1 is autosomal dominant inheritance. The patients in GZ.1 are characterized by early age of onset (before 35 years of age), severe clinical presentations, and high intraocular pressure unresponsive to pharmacological treatment; requiring 89.5% of the patients to undergo filtering surgery. Fortunately, the success rate of surgery was high. None of the patients required further medical treatment and only one demonstrated low IOP fundus changes. Conclusions This is the first evidence of a founder effect for a Pro370Leu myocilin mutation in a Chinese POAG pedigree. The family with the Pro370Leu myocilin mutation presents with juvenile-onset glaucoma. After 10 years of follow-up, it is evident that the mutation is closely associated with the phenotype of the patients. Analysis of MYOC in JOAG patients may enable the identification of at-risk individuals and help prevent disease progression toward the degeneration of the optic nerve, and may also contribute to genetic counseling.

Zhuo, Ye-Hong; Wei, Yan-Tao; Bai, Yu-Jing; Duan, Shan; Lin, Ming-Kai; Saragovi, H. Uri

2008-01-01

296

Family Governance with Family Councils  

Microsoft Academic Search

From the third generation onwards, family firms could get into business threatening situations. This might depend on the growing number of owners, the increasing distance of family members from the firm, and the heterogeneity of their interests. Thus, agency prob- lems and negative conflicts might occur. This calls for the appropriate choice of family gov- ernance mechanisms. Family councils might

Klaus Brockhoff; Alexander Koeberle-Schmid

297

[C634R mutation of the protooncongene RET and molecular diagnosis in multiple endocrine neoplasia type 2 in a large Moroccan family].  

PubMed

Multiple endocrine neoplasia (MEN) 2A is an inherited disease characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma and/or hyperparathyroïdism. It has been shown to be associated with germline mutations in the RET proto-oncogene. Direct DNA testing, therefore allows the identification of subjects with asymptomatic MEN 2A who can be offered prophylactic thyroidectomy and biochemical screening as preventive measures. DNA analysis of RET exon 8, 10, 13, 14, 15 and 16 was performed by direct sequencing of PCR product on automated sequencer and or PCR-digestion. In this report, we describe a MEN2A family witch initially seemed a sporadic case of MTC. We first characterized the C634R RET mutation in the index and then we identified 3 carriers who developed the disease and 3 young carriers who were apparently asymptomatic. A genetic counselling and the management of the carriers were proposed. This study confirmed that genetic testing ; in order to detect gene carriers is technically possible in Morocco. This will contribute to the definition of a national policy of this cancer control. PMID:18495576

Benazzouz, Bouchra; Hafidi, Aïcha; Benkhira, Saïd; Chraibi, Abdelmajid; Kadiri, Abdelkrim; Hilal, Latifa

2008-04-01

298

Testicular Expressed Genes Are Missing in Familial X-Linked Kallmann Syndrome due to Two Large Different Deletions in Daughter’s X Chromosomes  

Microsoft Academic Search

Background: X-linked Kallmann syndrome (KS) is caused mainly by point mutations, in the KAL1 gene. Large deletions >1 Mb are rare events in the human population and commonly result in contiguous gene syndromes. Methods: A search for the mutation causing KS carried out on two pairs of first-degree cousins of 2 sisters. Results: Two different apparently independent deletions were found.

Eli Hershkovitz; Neta Loewenthal; Asaf Peretz; Ruti Parvari

2008-01-01

299

Family Violence and Family Physicians  

PubMed Central

The acronym IDEALS summarizes family physicians' obligations when violence is suspected: to identify family violence; document injuries; educate families and ensure safety for victims; access resources and coordinate care; co-operate in the legal process; and provide support for families. Failure to respond reflects personal and professional experience and attitudes, fear of legal involvement, and lack of knowledge. Risks of intervention include physician burnout, physician overfunctioning, escalation of violence, and family disruption.

Herbert, Carol P.

1991-01-01

300

RNA Interference Suppression of Genes in Glycosyl Transferase Families 43 and 47 in Wheat Starchy Endosperm Causes Large Decreases in Arabinoxylan Content1[C][W][OPEN  

PubMed Central

The cell walls of wheat (Triticum aestivum) starchy endosperm are dominated by arabinoxylan (AX), accounting for 65% to 70% of the polysaccharide content. Genes within two glycosyl transferase (GT) families, GT43 (IRREGULAR XYLEM9 [IRX9] and IRX14) and GT47 (IRX10), have previously been shown to be involved in the synthesis of the xylan backbone in Arabidopsis, and close homologs of these have been implicated in the synthesis of xylan in other species. Here, homologs of IRX10 TaGT47_2 and IRX9 TaGT43_2, which are highly expressed in wheat starchy endosperm cells, were suppressed by RNA interference (RNAi) constructs driven by a starchy endosperm-specific promoter. The total amount of AX was decreased by 40% to 50% and the degree of arabinosylation was increased by 25% to 30% in transgenic lines carrying either of the transgenes. The cell walls of starchy endosperm in sections of grain from TaGT43_2 and TaGT47_2 RNAi transgenics showed decreased immunolabeling for xylan and arabinoxylan epitopes and approximately 50% decreased cell wall thickness compared with controls. The proportion of AX that was water soluble was not significantly affected, but average AX polymer chain length was decreased in both TaGT43_2 and TaGT47_2 RNAi transgenics. However, the long AX chains seen in controls were absent in TaGT43_2 RNAi transgenics but still present in TaGT47_2 RNAi transgenics. The results support an emerging picture of IRX9-like and IRX10-like proteins acting as key components in the xylan synthesis machinery in both dicots and grasses. Since AX is the main component of dietary fiber in wheat foods, the TaGT43_2 and TaGT47_2 genes are of major importance to human nutrition.

Lovegrove, Alison; Wilkinson, Mark D.; Freeman, Jackie; Pellny, Till K.; Tosi, Paola; Saulnier, Luc; Shewry, Peter R.; Mitchell, Rowan A.C.

2013-01-01

301

Reading Comprehension in a Large Cohort of French First Graders from Low Socio-Economic Status Families: A 7-Month Longitudinal Study  

PubMed Central

Background The literature suggests that a complex relationship exists between the three main skills involved in reading comprehension (decoding, listening comprehension and vocabulary) and that this relationship depends on at least three other factors orthographic transparency, children’s grade level and socioeconomic status (SES). This study investigated the relative contribution of the predictors of reading comprehension in a longitudinal design (from beginning to end of the first grade) in 394 French children from low SES families. Methodology/Principal findings Reading comprehension was measured at the end of the first grade using two tasks one with short utterances and one with a medium length narrative text. Accuracy in listening comprehension and vocabulary, and fluency of decoding skills, were measured at the beginning and end of the first grade. Accuracy in decoding skills was measured only at the beginning. Regression analyses showed that listening comprehension and decoding skills (accuracy and fluency) always significantly predicted reading comprehension. The contribution of decoding was greater when reading comprehension was assessed via the task using short utterances. Between the two assessments, the contribution of vocabulary, and of decoding skills especially, increased, while that of listening comprehension remained unchanged. Conclusion/Significance These results challenge the ‘simple view of reading’. They also have educational implications, since they show that it is possible to assess decoding and reading comprehension very early on in an orthography (i.e., French), which is less deep than the English one even in low SES children. These assessments, associated with those of listening comprehension and vocabulary, may allow early identification of children at risk for reading difficulty, and to set up early remedial training, which is the most effective, for them.

Gentaz, Edouard; Sprenger-Charolles, Liliane; Theurel, Anne; Cole, Pascale

2013-01-01

302

Phase-diagram-guided method for growth of a large crystal of glycoside hydrolase family 45 inverting cellulase suitable for neutron structural analysis  

PubMed Central

Neutron protein crystallography (NPC) is a powerful tool for determining the hydrogen position and water orientation in proteins, but a much larger protein crystal is needed for NPC than for X-ray crystallography, and thus crystal preparation is a bottleneck. To obtain large protein crystals, it is necessary to know the properties of the target protein in the crystallization solution. Here, a crystal preparation method of fungal cellulase PcCel45A is reported, guided by the phase diagram. Nucleation and precipitation conditions were determined by sitting-drop vapor diffusion. Saturation and unsaturation conditions were evaluated by monitoring crystal dissolution, and a crystallization phase diagram was obtained. To obtain a large crystal, crystallization solution was prepared on a sitting bridge (diameter = 5?mm). Initial crystallization conditions were 40?µl of crystallization solution (40?mg?ml?1 protein with 30.5% 3-methyl-1,5-pentanediol in 50?mM tris-HCl pH 8.0) with a 1000?µl reservoir (61% 3-methyl-1,5,-pentanediol in 50?mM tris-HCl pH 8.0) at 293?K. After the first crystal appeared, the concentration of precipitant in the reservoir solution was reduced to 60% to prevent formation of further crystals. Finally, we obtained a crystal of 6?mm3 volume (3?mm × 2?mm × 1?mm), which was suitable for neutron diffraction.

Nakamura, Akihiko; Ishida, Takuya; Fushinobu, Shinya; Kusaka, Katsuhiro; Tanaka, Ichiro; Inaka, Koji; Higuchi, Yoshiki; Masaki, Mika; Ohta, Kazunori; Kaneko, Satoshi; Niimura, Nobuo; Igarashi, Kiyohiko; Samajima, Masahiro

2013-01-01

303

Family Reunification.  

ERIC Educational Resources Information Center

Full Circle Programs is an organization providing family preservation and reunification services. Full Circle responds to families uniquely, rather than according to predetermined models. Medical testing, counseling, and practical assistance are provided. (BC)

Brown, Carolyn L.; Little, Susan

1990-01-01

304

Family Policy.  

National Technical Information Service (NTIS)

The Directive supersedes Secretary of Defense Memorandum, 'Department of Defense Family Policy,' establishes policies, assigns responsibilities, and prescribes procedures on family policy for Department of Defense (DoD) military personnel in Active, Natio...

W. York

1988-01-01

305

Family Medicine.  

National Technical Information Service (NTIS)

The role, functions, and potential of family medicine are examined in a discussion drawing on observations of the University of Rochester Family Medicine Program at Highland Hospital, Rochester, New York. The discussion opens with a review of the factors ...

P. S. Warren

1970-01-01

306

Case report: a p.C618S RET proto-oncogene germline mutation in a large Chinese pedigree with familial medullary thyroid carcinoma.  

PubMed

We report a Chinese pedigree with familial medullary thyroid carcinoma. Direct sequencing of the entire coding sequences of Rearranged during Transfection (RET) identified a recurrent c.T1852A (p.C618S) mutation in 13 of 23 members. The polymorphisms c.A135G (p.A45A), c.A1296G (p.A432A), c.T2307G (p.L769L) and IVS19 + 15T > C were also found in 13 carriers, and c.G2073A (p.G691S) was found in 1 carrier. Of the 13 carriers, seven (mean age: 42.6 years, range: 27-64) presented MTC as the isolated clinical phenotype, with elevated basal serum calcitonin (average: 1077.9 ng/L, range: 504-2,652) and a mean diameter of thyroid nodules of 2.97 cm (range: 1.6-4.3); they underwent a total thyroidectomy with modified bilateral/unilateral neck dissection and/or level VI lymph node dissection. The other 6 carriers did not accept surgery (4 rejected, 2 awaited). These were 2 older patients (63 and 32 years) with elevated calcitonin (1359 and 41.4 ng/L) and multi-centric hypoechoic nodules (1.5 and 0.6 cm) with calcifications in both/left thyroid lobes; and Doppler ultrasound showed normal bilateral thyroids in 4 younger carriers (median age: 8.3 years, range: 4-12) but with increased calcitonin (average: 9.7 ng/L, range: 7.87-12.2) in 3 of them. The phenotype here is consistent with the clinical symptoms reported worldwide. We recommend that screening of hotspot regions of RET should be preferentially carried out, while whole-exon sequencing should be performed when clinical signs fail to reveal hotspot mutations or different phenotype discrepancies. Moreover, we strongly suggest prophylactic thyroidectomy should be performed before age 5 in carriers with p.C618S to prevent the occurrence and metastasis of MTC. PMID:22068382

Qi, X-P; Ying, R-B; Ma, J-M; Liu, W-T; Du, Z-F; Fei, J; Yang, C-P; Song, Q-Z; Jin, H-Y; Chen, Z-G; Han, J-S; Wang, J-Q; Chen, X-L; Zhao, Y; Lu, J-J; Zhang, X-N

2012-03-01

307

Family Support.  

ERIC Educational Resources Information Center

This "Feature Issue" of the quarterly journal "Impact" presents 19 brief articles on family support systems in the United States for persons with developmental disabilities and their families. Emphasis is on provisions of Public Law 99-457. Articles include: "Family Support in the United States: Setting a Course for the 1990s" (James Knoll);…

Wieck, Colleen, Ed.; McBride, Marijo, Ed.

1990-01-01

308

Family therapy.  

PubMed

Another major force not letting us succeed in the treatment of diabetes remains right inside the patients home, their family members. Hence, it is important to know the perception of the close family members about this simple and strong tool in diabetes, 'insulin'. The drug is nearing its century, it has not fully being accepted gracefully even in todays electronic savvy society. So, we need to strongly discover the reason for its non-acceptance, while trials are out inventing new drugs. One vital thing that can change this attitude is increasing the understanding of this drug, insulin in depth to close people around the patient, the 'family'. Underestimating family's perception about disease and treatment for diabetes is detrimental to both diseased and the doctor. This consists of a biopsychosocial model; biological, psychological and social factors. Family forms the most important part of it. The strategies in family therapy include psychodynamic, structural, strategic, and cognitive-behavioral component. Diabetes has and will continue to rise, so will be the treatment options. From the clinicians side its to fix fasting first but from patients its fix family first. Family therapy demonstrates the importance of insulin initiation and maintenance in insulin naive patients, and continuation for others. The specific needs of such patients and their impact on family life are met with family therapy. Who needs family therapy? Benefits of family therapy and a case based approach is covered. PMID:24251191

Altamash, Shaikh

2013-10-01

309

[Family Support.  

ERIC Educational Resources Information Center

The newsletter offers perspectives on the provision of family support services for families with disabled members. An introductory article by Madeleine Will, Assistant Secretary for Special Education and Rehabilitative Services, stresses the impressive coping skills exhibited by many such families and their relationship to service professionals.…

Focal Point, 1988

1988-01-01

310

Family therapy  

PubMed Central

Another major force not letting us succeed in the treatment of diabetes remains right inside the patients home, their family members. Hence, it is important to know the perception of the close family members about this simple and strong tool in diabetes, ‘insulin’. The drug is nearing its century, it has not fully being accepted gracefully even in todays electronic savvy society. So, we need to strongly discover the reason for its non-acceptance, while trials are out inventing new drugs. One vital thing that can change this attitude is increasing the understanding of this drug, insulin in depth to close people around the patient, the ‘family’. Underestimating family's perception about disease and treatment for diabetes is detrimental to both diseased and the doctor. This consists of a biopsychosocial model; biological, psychological and social factors. Family forms the most important part of it. The strategies in family therapy include psychodynamic, structural, strategic, and cognitive-behavioral component. Diabetes has and will continue to rise, so will be the treatment options. From the clinicians side its to fix fasting first but from patients its fix family first. Family therapy demonstrates the importance of insulin initiation and maintenance in insulin naive patients, and continuation for others. The specific needs of such patients and their impact on family life are met with family therapy. Who needs family therapy? Benefits of family therapy and a case based approach is covered.

Altamash, Shaikh

2013-01-01

311

Evolution of the Discs large gene family provides new insights into the establishment of apical epithelial polarity and the etiology of mental retardation.  

PubMed

Cell polarity is essential to the function of many cell types, such as epithelial cells and neurons. The Discs large (Dlg) scaffolding protein was identified in Drosophila as a major regulator of basolateral epithelial identity. Four Dlg orthologs (Dlg1 through 4) are found in vertebrates, and mutations in the human Dlg3 gene are associated with X-linked mental retardation. We recently found that Dlg3 controls apical epithelial polarity and tight junction formation and contributes to neural induction in mouse development.(1) During evolution, Dlg3 acquired specific PPxY motifs, which bind to the WW domains of the E3 ubiquitin ligases, Nedd4 and Nedd4-2. This interaction results in monoubiquitination of Dlg3, leading to directed microtubule-dependent protein trafficking, via the exocyst complex, in different polarized cell types. Directed trafficking of Dlg3 plays an important role, during both mammalian development and in adulthood, in the establishment and maintenance of specialized apical cell junctions, such as tight junctions in epithelial cells and synapses in neurons. PMID:22896795

Lickert, Heiko; Van Campenhout, Claude A

2012-05-01

312

Familial Clustering of Type 2 Diabetes among Omanis  

PubMed Central

Objective The aim of this study was to screen Omani individuals for the familial aggregation of type 2 diabetes mellitus. Methods A random cohort of 1182 Omani individuals visiting the Family Medicine Clinic at Sultan Qaboos University Hospital (SQUH), Muscat, Oman, for regular medical checkup, aged ?40 years, were sampled. Patients were categorized into three groups: (1) individuals who claim not to have diabetes and had no family history of diabetes; (2) individuals who claim not to have diabetes but had family history of diabetes; (3) individuals with diabetes. Only 16% of these Omani individuals had no diabetes and no family history of diabetes. Another separate random cohort of 234 Omani type 2 diabetes mellitus patients, from the Diabetes Clinic at SQUH, were interviewed and questioned about their family history of type 2 diabetes mellitus. Results Ninety five percent of the patients had a family history of diabetes. Eighty percent had first degree relatives with diabetes and 46% had second degree relatives with diabetes. At least one parent with diabetes was reported among 55% of these diabetics, while maternal diabetes (55%) was found to be higher than paternal diabetes (47%). However, only 15% had both parents with diabetes. Furthermore, almost half of the 234 diabetics were having at least one of the following relatives with diabetes: brother, sister, aunt or an uncle. Conclusion The findings of this study confirm familial aggregation of diabetes among the Omani population. Compared to other populations, familial aggregation of type 2 diabetes mellitus among Omanis is relatively very high, and is perhaps due to the very high degree of consanguinity among Omanis. Since almost everyone seems to have a genetic predisposition to diabetes, the dramatic lifestyle changes over the past 25 years, could tip the population into an epidemic of type 2 diabetes mellitus.

Al-Sinani, Sawsan; Al-Shafaee, Mohammed; Al-Mamari, Ali; Woodhouse, Nicholas; Al-Shafie, Omaima; Hassan, Mohammed; Al-Yahyaee, Said; Albarwani, Sulayma; Jaju, Deepali; Al-Hashmi, Khamis; Al-Abri, Mohammed; Rizvi, Syed; Bayoumi, Riad

2014-01-01

313

Family Interactions in Adoptive Compared to Nonadoptive Families  

PubMed Central

Despite the large and growing numbers of adoptive families, little research describes interactions in families with adopted adolescents. Yet, adopted adolescents’ increased risk for adjustment problems, combined with the association between family interactions and adolescent adjustment in nonadoptive families, raises questions about differences in adoptive and nonadoptive family interactions. We compared observed and self-reported family interactions between 284 adoptive and 208 nonadoptive families and within 123 families with 1 adopted and 1 nonadopted adolescent. Adolescents averaged 14.9 years of age. Comparisons were made using analysis of variance incorporating hierarchical linear methods in SAS PROC MIXED to control family-related correlations in the data. Parents and children reported more conflict in adoptive families when compared with nonadoptive families. Families with 1 adopted and 1 nonadopted adolescent reported more conflict between parents and adopted adolescents. Observed parental behavior was similar across adoptive and nonadoptive children although adopted adolescents were less warm and, in families with 2 adopted children, more conflictual than nonadopted adolescents. These findings suggest a need for further investigation of the association between family interactions and adopted adolescent problem behavior.

Rueter, Martha A.; Keyes, Margaret A.; Iacono, William G.; McGue, Matt

2009-01-01

314

Families affected by deafness: hospital services uptake in a multiethnic population  

PubMed Central

Aims: To examine the uptake of relevant hospital services by families with deaf children and to compare use of these services between Pakistani and white families. Methods: A total of 214 deaf children with amplification aids who attended their paediatric outpatient and school medical appointments from October 2000 to March 2003 were studied in an observational cohort study. Results: The demographic profile of both the Pakistani and white families was similar. Pakistani children had a statistically significant excess of the following risk factors: consanguineous marriages (86.4% Pakistani, 1.5% white), family history of deafness (66.4% Pakistani, 38.8% white), and family size (birth order >5: 12.8% Pakistani: 4.5% white). White children were more likely to have had post-meningitis deafness (1.4% Pakistani, 13.4% white) and congenital infections, or have dysmorphic features (5.0% Pakistani, 13.4% white). Overall the uptake of relevant hospital services by Pakistani and white families was very similar irrespective of an early or late diagnosis. There was an increased likelihood of white families declining cochlear implantation (17.6% Pakistani, 75.0% white). Conclusions: This study did not show significant differences in hospital service uptake despite different risk profiles for childhood deafness for both Pakistani and white families in Bradford. Among specialist services offered, cochlear implantation was more likely to be accessed by Pakistani families.

Yoong, S; Feltbower, R; Spencer, N; McKinney, P

2005-01-01

315

Familial hypercholesterolemia.  

PubMed

Familial homozygous hypercholesterolemia is a rare autosomal disorder characterized by high levels of cholesterol, extensive tendon xanthomatosis and premature development of atherosclerotic disease. Early coronary artery disease with myocardial infarctions and sudden deaths are common. We reported a family of familial hypercholesterolemia from the Kashmir valley of the Indian subcontinent. The appearance and the severity of the cutaneous xanthomas was found to be age related suggesting a role for the duration of hypercholesterolemia in the development of xanthomatosis. PMID:17457492

Koul, Parvaiz A; Jan, Rafi A; Wahid, Abdul B; Bhat, Tariq A; Mudassir, Syed M

2007-04-01

316

Roles within the Family  

MedlinePLUS

... Dynamics > Roles Within the Family Family Life Listen Roles Within the Family Article Body Families are not democracies. Each family ... household duties. It is useful to consider what roles each family member takes within the family, and whether everyone ...

317

Pattern Families  

NSDL National Science Digital Library

In this math activity, learners sort patterns into similar "families" or groups that have the same pattern, but different symbols. Then learners create their own patterns that fit into each family using stamps, stickers, and buttons. This activity guide contains a material list, sample questions to ask, literary connections, extensions, and alignment to local and national standards.

Houston, Children'S M.

2014-04-07

318

Family violence.  

PubMed

Family violence occurs in many forms; the most prominent are domestic violence, child abuse, and elder abuse. Family violence affects many persons at some point in their life and constitutes the majority of violent acts in our society. Although there has been considerable study of the patterns, risk factors, and interventions for each form of family violence, great controversy still exists within each area. There is growing recognition of an overlap in the patterns, causes, and effective interventions across types of family violence. There is also an increasing awareness of the value of greater integration of theory and research across areas into a family violence approach through an ecological perspective. This review focuses on current knowledge related to these problems and suggests integrative steps to advance knowledge. PMID:16318607

Tolan, Patrick; Gorman-Smith, Deborah; Henry, David

2006-01-01

319

A novel mutation of DNAH5 in chronic rhinosinusitis and primary ciliary dyskinesia in a Chinese family.  

PubMed

The genetic factors underlying the pathogenesis of chronic rhinosinusitis (CRS) remains unclear. We herein identified four related subjects with CRS and primary ciliary dyskinesia (PCD) from geographically disperse Chinese Han communities and performed exome capture and sequencing of one affected individual and unaffected parents. We found a novel mutation in DNAH5 (c. 8030G>A) in CRS and PCD which was different from those attributed to cystic fibrosis and a defect of cilia motility in a Chinese family through exome capture and sequencing. Our findings showed that c. 8030G>A of DNAH5 may be implicated as the disease-causing gene of CRS and PCD in this Chinese family, which may expand the understanding of clinicians on the pathogenesis of CRS. Moreover, the identification of this novel mutation in DNAH5 indirectly indicates that exome capture and sequencing are beneficial in the genetic research of midget consanguinity families. PMID:24150548

Zhang, Jing; Guan, Liping; Wen, Weiping; Lu, Yu; Zhu, Qianyan; Yuan, Huijun; Chen, Yulan; Wang, Hongtian; Zhang, Jianguo; Li, Huabin

2014-06-01

320

Family Health and Family Planning.  

ERIC Educational Resources Information Center

This document is made up of a selection of some of the papers distributed to participants in courses on "Family Health and Family Planning" which have been organized each year since 1973 by the International Children's Center and the World Health Organization Regional Office for Europe. Six courses, held between 1973 and 1978, brought together a…

World Health Organization, Copenhagen (Denmark). Regional Office for Europe.

321

Exome sequencing identifies a novel and a recurrent BBS1 mutation in Pakistani families with Bardet-Biedl syndrome  

PubMed Central

Purpose To determine the genetic cause of Bardet-Biedl syndrome (BBS) in two consanguineous Pakistani families. Methods Clinical characterization of the affected individuals in both families was performed with ophthalmic examination, electroretinography, electrocardiography, and liver and renal profiling. Seventeen genes are known to be associated with BBS, so exome sequencing was preferred over candidate gene sequencing. One affected individual from both families was selected for exome sequencing. Segregation of the identified variants was confirmed with Sanger sequencing. Results Retinitis pigmentosa, obesity, and learning difficulties were present in the affected individuals in both families. In family A, a sixth finger (polydactyly) of the proband’s sister was removed by a surgical operation leaving a scar on the little finger. Polydactyly was also present in both affected individuals from family B. All diagnostic symptoms were characteristic of BBS in both families. In both affected individuals from family A, exome sequencing identified a novel homozygous mutation (c.47+1G>T) in BBS1 that inactivates the splice donor site at the end of exon 1. In family B, a previously reported mutation, c.442G>A; p.(Asp148Asn), was detected. Conclusions Exome sequencing is an efficient and cost-effective technique for identifying mutations in genetically heterogeneous diseases. In addition, intrafamilial phenotypic variability in family A argues for the modifying effect of other still unknown modifier alleles.

Ajmal, Muhammad; Khan, Muhammad Imran; Neveling, Kornelia; Tayyab, Ali; Jaffar, Sulman; Sadeque, Ahmed; Ayub, Humaira; Abbasi, Nasir Mahmood; Riaz, Moeen; Micheal, Shazia; Gilissen, Christian; Ali, Syeda Hafiza Benish; Azam, Maleeha; Collin, Rob W. J.; Cremers, Frans P. M.

2013-01-01

322

A Family of Adders  

Microsoft Academic Search

Binary c arry-propagating addition can be efficiently expressed a s a prefix computation. Several examples of adders based on such a formulation have been published, and efficient implementations are numerous. Chief among the k nown constructions are those of Kogge & Stone and Ladner & Fischer. In this work we show that these are end cases of a large family

Simon Knowles

1999-01-01

323

A Family of Adders  

Microsoft Academic Search

Binary carry-propagating addition can be efficiently expressed as a prefix computation. Several examples of adders based on such a formulation have been published and efficient implementations are numerous. Chief among the known constructions are those of Kogge and Stone (1973) and Ladner and Fischer (1980). In this work we show that these are end cases of a large family of

Simon Knowles

2001-01-01

324

Family Meals  

MedlinePLUS

... You're setting the mood and modeling good manners and patience. Family meals are a good time ... potatoes? What's the most delicious food on the table? If you opened a restaurant, what kind would ...

325

Family Issues  

MedlinePLUS

... Self Advocacy Transitions Treatment Options Biomedical Treatments Nonmedical Interventions Related Approaches Evaluating Options Family Issues Stress Siblings Community Inclusion Autism and Faith Future Planning Government Benefits and Special Needs Trusts Letter of ...

326

Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.  

PubMed

Patients with primary microcephaly, an autosomal recessive trait, have mild to severe mental retardation without any other neurological deficits. It is a genetically heterogeneous disorder with six known loci: MCPH1 to MCPH6. Only the genes for MCPH1 and MCPH5 have been identified so far. We have ascertained nine consanguineous families with primary microcephaly from India. To establish linkage of these nine families to known MCPH loci, microsatellite markers were selected from the candidate regions of each of the six known MCPH loci and used to genotype the families. The results were suggestive of linkage of three families to the MCPH5 locus and one family to the MCPH2 locus. The remaining five families were not linked to any of the known loci. DNA-sequence analysis identified one known (Arg117X) and two novel (Trp1326X and Gln3060X) mutations in the three MCPH5-linked families in a homozygous state. Three novel normal population variants (i.e., c.7605G > A, c.4449G > A, and c.5961 A > G) were also detected in the ASPM gene. PMID:15355437

Kumar, A; Blanton, S H; Babu, M; Markandaya, M; Girimaji, S C

2004-10-01

327

Family with branchial arch anomalies, hearing loss, ear and commissural lip pits, and rib anomalies. A new autosomal recessive condition: branchio-oto-costal syndrome?  

PubMed

We report on a family in which 3 sibs were affected with conductive deafness, bilateral preauricular and commissural lip pits, monolateral branchial fistula, and rib anomalies. On the basis of parental consanguinity, lack of clinical variability and affected subjects of both sexes, this condition seems to be inherited as an autosomal recessive trait. We suggest that these findings comprise a new autosomal recessive entity of branchial, auricular and costal anomalies, for which we suggest the acronym BOC (branchio-oto-costal) syndrome. PMID:8986284

Clementi, M; Mammi, I; Tenconi, R

1997-01-10

328

Fact Families  

NSDL National Science Digital Library

In this lesson, the relationship of addition to subtraction is explored with books and with connecting cubes. Students search for related addition and subtraction facts for a given number using a virtual or actual calculator to find differences. They also investigate fact families when one addend is 0 as well as when the addends are the same. Students will: find missing addends, review the additive identity, generate fact families given two addends or given one addend and the sum.

Illuminations

2012-03-31

329

Normal Functioning Family  

MedlinePLUS

... Children > Family Life > Family Dynamics > Normal Functioning Family Family Life Listen Normal Functioning Family Article Body Is there any way to tell if my family is functioning normally? Many parents ask themselves this ...

330

Usefulness of cardiovascular family history data for population-based preventive medicine and medical research (The Health Family Tree Study and the NHLBI Family Heart Study)  

Microsoft Academic Search

Detailed medical family history data have been proposed to be effective in identifying high-risk families for targeted intervention. With use of a validated and standardized quantitative family risk score (FRS), the degree of familial aggregation of coronary heart disease (CHD), stroke, hypertension, and diabetes was obtained from 122,155 Utah families and 6,578 Texas families in the large, population-based Health Family

Roger R Williams; Steven C Hunt; Gerardo Heiss; Michael A Province; Jeannette T Bensen; Millicent Higgins; Robert M Chamberlain; Joan Ware; Paul N Hopkins

2001-01-01

331

Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene.  

PubMed Central

In a large kindred of 66 individuals, 22 were identified as heterozygous and 3 as homozygous for a mutation (pro664----leu) in the LDL-receptor gene that gives rise to familial hypercholesterolaemia (FH). All the heterozygotes had a raised level of plasma total cholesterol and low density lipoprotein cholesterol, but were remarkably free from premature coronary disease. Determination of apolipoprotein(a) (apo(a)) phenotype and lipoprotein(a) (Lp(a)) concentration in plasma revealed that in many instances, involving individuals with various apo(a) phenotypes, there was no difference in plasma Lp(a) concentration between an FH heterozygote and an unaffected sibling with the same apo(a) phenotype. No significant difference in Lp(a) concentration was observed between groups of FH and non-FH of the same apo(a) phenotype, although in each case the mean value for the FH group was greater than that for the non-FH group. There was also evidence for an inherited trait that markedly increased Lp(a) concentration, which did not segregate with apo(a) phenotype or the defective LDL-receptor allele. The data provide no evidence for a strong multiplicative interaction between the gene loci for apo(a) and the LDL receptor. Images

Soutar, A K; McCarthy, S N; Seed, M; Knight, B L

1991-01-01

332

Re-visioning the family life cycle theory and paradigm in marriage and family therapy  

Microsoft Academic Search

Theorizing, research, and psychotherapeutic practice in regard to family life course and family developmental theories have been largely dominated by the family life cycle (FLC) paradigm in psychological and psychotherapeutic disciplines. This article discusses some of the specific problems associated with the adoption of the FLC paradigm in marriage and family therapy (MFT). Four ideas are offered as ways to

Martin J. Erickson

1998-01-01

333

Homozygosity mapping in autosomal recessive retinitis pigmentosa families detects novel mutations  

PubMed Central

Purpose Autosomal recessive retinitis pigmentosa (arRP) is a genetically heterogeneous disease resulting in progressive loss of photoreceptors that leads to blindness. To date, 36 genes are known to cause arRP, rendering the molecular diagnosis a challenge. The aim of this study was to use homozygosity mapping to identify the causative mutation in a series of inbred families with arRP. Methods arRP patients underwent standard ophthalmic examination, Goldman perimetry, fundus examination, retinal OCT, autofluorescence measurement, and full-field electroretinogram. Fifteen consanguineous families with arRP excluded for USH2A and EYS were genotyped on 250 K SNP arrays. Homozygous regions were listed, and known genes within these regions were PCR sequenced. Familial segregation and mutation analyzes were performed. Results We found ten mutations, seven of which were novel mutations in eight known genes, including RP1, IMPG2, NR2E3, PDE6A, PDE6B, RLBP1, CNGB1, and C2ORF71, in ten out of 15 families. The patients carrying RP1, C2ORF71, and IMPG2 mutations presented with severe RP, while those with PDE6A, PDE6B, and CNGB1 mutations were less severely affected. The five families without mutations in known genes could be a source of identification of novel genes. Conclusions Homozygosity mapping combined with systematic screening of known genes results in a positive molecular diagnosis in 66.7% of families.

Marzouka, Nour al Dain; Hebrard, Maxime; Manes, Gael; Senechal, Audrey; Meunier, Isabelle; Hamel, Christian P.

2013-01-01

334

Resolving the Debate over Birth Order, Family Size, and Intelligence.  

ERIC Educational Resources Information Center

Investigated the relationship between birth order, family size, and intelligence quotient (IQ), evaluating sibling data from the National Longitudinal Survey of Youth and comparing results with those from other studies using within-family data. Results indicated that although low IQ parents were making large families, large families were not…

Rodgers, Joseph Lee; Cleveland, H. Harrington; van den Oord, Edwin; Rowe, David C.

2000-01-01

335

Family Hypnotherapy.  

ERIC Educational Resources Information Center

A therapeutic model to help families activate experiential and right hemispheric functioning through hypnosis is presented in detail, together with a clinical illustration. Different situations in which this model is effective are mentioned and one such set of circumstances is described. (Author)

Araoz, Daniel L.; Negley-Parker, Esther

1985-01-01

336

Serving Families.  

ERIC Educational Resources Information Center

Parent Services Project (PSP), the first comprehensive program of resources and mental health activities for parents offered at child care centers in the San Francisco Bay Area (California), has expanded to centers in six states, serving over 19,000 families. This report describes the program's history, aims, and achievements, along with specific…

Link, Geoffrey; Beggs, Marjorie; Seiderman, Ethel

337

Family Violence.  

ERIC Educational Resources Information Center

This quarterly publication, issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), contains articles dealing with family violence and alcohol abuse, children of alcoholic parents, training programs for counselors, and confidentiality of client records. The three articles on alcohol abuse suggest that: (1) there is a clear…

Sorgen, Carol, Ed.

1979-01-01

338

Unusual evolutionary conservation and further species-specific adaptations of a large family of nonclassical MHC class Ib genes across different degrees of genome ploidy in the amphibian subfamily Xenopodinae.  

PubMed

Nonclassical MHC class Ib (class Ib) genes are a family of highly diverse and rapidly evolving genes wherein gene numbers, organization, and expression markedly differ even among closely related species rendering class Ib phylogeny difficult to establish. Whereas among mammals there are few unambiguous class Ib gene orthologs, different amphibian species belonging to the anuran subfamily Xenopodinae exhibit an unusually high degree of conservation among multiple class Ib gene lineages. Comparative genomic analysis of class Ib gene loci of two divergent (~65 million years) Xenopodinae subfamily members Xenopus laevis (allotetraploid) and Xenopus tropicalis (diploid) shows that both species possess a large cluster of class Ib genes denoted as Xenopus/Silurana nonclassical (XNC/SNC). Our study reveals two distinct phylogenetic patterns among these genes: some gene lineages display a high degree of flexibility, as demonstrated by species-specific expansion and contractions, whereas other class Ib gene lineages have been maintained as monogenic subfamilies with very few changes in their nucleotide sequence across divergent species. In this second category, we further investigated the XNC/SNC10 gene lineage that in X. laevis is required for the development of a distinct semi-invariant T cell population. We report compelling evidence of the remarkable high degree of conservation of this gene lineage that is present in all 12 species of the Xenopodinae examined, including species with different degrees of ploidy ranging from 2, 4, 8 to 12 N. This suggests that the critical role of XNC10 during early T cell development is conserved in amphibians. PMID:24771209

Edholm, Eva-Stina; Goyos, Ana; Taran, Joseph; De Jesús Andino, Francisco; Ohta, Yuko; Robert, Jacques

2014-06-01

339

Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.  

PubMed

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, approximately 30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%-40% of the FHL cases and the FHL 1 locus on chromosome 9 for approximately 10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes. PMID:11179007

Göransdotter Ericson, K; Fadeel, B; Nilsson-Ardnor, S; Söderhäll, C; Samuelsson, A; Janka, G; Schneider, M; Gürgey, A; Yalman, N; Révész, T; Egeler, R; Jahnukainen, K; Storm-Mathiesen, I; Haraldsson, A; Poole, J; de Saint Basile, G; Nordenskjöld, M; Henter, J

2001-03-01

340

Family Structure and Family Processes in Mexican American Families  

PubMed Central

Despite increases in single-parent families among Mexican Americans (MA), few studies have examined the association of family structure and family adjustment. Utilizing a diverse sample of 738 Mexican American families (21.7% single parent), the current study examined differences across family structure on early adolescent outcomes, family functioning, and parent-child relationship variables. Results revealed that early adolescents in single parent families reported greater school misconduct, CD/ODD and MDD symptoms, and greater parent-child conflict than their counterparts in two parent families. Single parent mothers reported greater economic hardship, depression and family stress. Family stress and parent-child conflict emerged as significant mediators of the association between family structure and early adolescent outcomes, suggesting important processes linking MA single parent families and adolescent adjustment.

Zeiders, Katharine H.; Roosa, Mark W.; Tein, Jenn-Yun

2010-01-01

341

A Training Program for Statewide Family Planning  

ERIC Educational Resources Information Center

Describes training for a statewide family planning program involving a large number of agencies in North Carolina which are involved in delivery of family planning services. Focus is on the need for involvement, commitment, and skills within each agency so the family planning program could be optimally effective. (WL)

Smallegan, Marian; Gustaveson, Patricia

1976-01-01

342

Family Child Care Licensing Study, 2001.  

ERIC Educational Resources Information Center

This report presents the findings of the 2001 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 2000 study. Data on small family child care homes and group or large family child care homes are organized into the following 23 categories: (1) number of regulated…

Children's Foundation, Washington, DC.

343

Family Child Care Licensing Study, 2003.  

ERIC Educational Resources Information Center

This report presents the findings of the 2003 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 2002 study. Data on small family child care homes and group or large family child care homes are organized into the following 23 categories: (1) number of regulated…

Hollestelle, Kay; Koch, Pauline D.

344

Family Child Care Licensing Study, 2002.  

ERIC Educational Resources Information Center

This report presents the findings of the 2002 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 2001 study. Data on small family child care homes and group or large family child care homes are organized into the following 23 categories: (1) number of regulated…

Children's Foundation, Washington, DC.

345

Family Child Care Licensing Study, 2000.  

ERIC Educational Resources Information Center

This report presents the findings of the 2000 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 1999 study. Data on small family child care homes and group or large family child care homes are organized in 23 categories: (1) number of regulated homes; (2)…

Kelly, Nia, Comp.

346

Conservatism and monitoring by founding family owners  

Microsoft Academic Search

We study the role of conservatism in monitoring managers by founding family owners, the most predominant type of large, under-diversified shareholders in the U.S. We focus on the ownership of founding family members who are not CEOs. Unlike owners with diverse ownership or institutional investors, family owners have both the incentives and the means to monitor CEOs. While conservatism can

Shuping Chen; Xia Chen; Qiang Cheng; Amy Hutton

347

Natural Exponential Families with Quadratic Variance Functions  

Microsoft Academic Search

The normal, Poisson, gamma, binomial, and negative binomial distributions are univariate natural exponential families with quadratic variance functions (the variance is at most a quadratic function of the mean). Only one other such family exists. Much theory is unified for these six natural exponential families by appeal to their quadratic variance property, including infinite divisibility, cumulants, orthogonal polynomials, large deviations,

Carl N. Morris

1982-01-01

348

[Familial spastic paraplegia with amyotrophy. Clinical, electromyographic, histochemical study and microdissection].  

PubMed

Four cases of familial spastic paraplegia with amyotrophy in siblings from a consanguineous married are reported. The routine laboratory examination were normal. The electromiography and muscle biopsy processed by histochemistry showed signs of denervation with reinervation. The motor nerve conduction velocity was decreased in the peroneal nerve in 3 cases. The teased fiber preparation of sural nerves was abnormal in four cases. It was found increased of C, D and G fibers suggesting demyelination with secondary remyelination. The authors believe the abnormalities found could be due the distal axonal degeneration, with secondary regeneration and suggest the hypothesis that the fact is an axoplasmic flow defect in the central and peripheral nervous system. PMID:91360

Werneck, L C; Sanches, M C

1979-06-01

349

Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping  

SciTech Connect

Homozygosity mapping is a powerful strategy for mapping rare recessive traits in children of consanguineous marriages. Practical applications of this strategy are currently limited by the inability of conventional linkage analysis software to compute, in reasonable time, multipoint LOD scores for pedigrees with inbreeding loops. We have developed a new algorithm for rapid multipoint likelihood calculations in small pedigrees, including those with inbreeding loops. The running time of the algorithm grows, at most, linearly with the number of loci considered simultaneously. The running time is not sensitive to the presence of inbreeding loops, missing genotype information, and highly polymorphic loci. We have incorporated this algorithm into a software package, MAPMAKER/HOMOZ, that allows very rapid multipoint mapping of disease genes in nuclear families, including homozygosity mapping. Multipoint analysis with dozens of markers can be carried out in minutes on a personal workstation. 23 refs., 4 figs., 1 tab.

Kruglyak, L.; Daly, M.J. [Whitehead Institute for Biomedical Research, Cambridge, MA (United States); Lander, E.S. [Whitehead Institute for Biomedical Research, Cambridge, MA (United States)]|[Massachusetts Institute of Technology, Cambridge, MA (United States)

1995-02-01

350

Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping.  

PubMed

Homozygosity mapping is a powerful strategy for mapping rare recessive traits in children of consanguineous marriages. Practical applications of this strategy are currently limited by the inability of conventional linkage analysis software to compute, in reasonable time, multipoint LOD scores for pedigrees with inbreeding loops. We have developed a new algorithm for rapid multipoint likelihood calculations in small pedigrees, including those with inbreeding loops. The running time of the algorithm grows, at most, linearly with the number of loci considered simultaneously. The running time is not sensitive to the presence of inbreeding loops, missing genotype information, and highly polymorphic loci. We have incorporated this algorithm into a software package, MAPMAKER/HOMOZ, that allows very rapid multipoint mapping of disease genes in nuclear families, including homozygosity mapping. Multipoint analysis with dozens of markers can be carried out in minutes on a personal workstation. PMID:7847388

Kruglyak, L; Daly, M J; Lander, E S

1995-02-01

351

Familial paragangliomas  

PubMed Central

Paragangliomas are rare tumours of the autonomic nervous system and occur in sporadic and hereditary forms. They are usually benign and have a low mortality. However, they cause significant morbidity related to their mass effect. Genetic predisposition can occur within the familial tumour syndromes multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) and neurofibromatosis type 1 (NF-1), or be due to mutations in genes specific to the development of paraganglioma only. Compared to sporadic forms, familial paragangliomas tend to present at a younger age and at multiple sites. Tumours should be diagnosed and resected as early as possible, as it has been shown that morbidity is related to tumour size. This article gives an overview of the current literature on the origin of the different forms of paragangliomas, DNA diagnosis, as well as biochemical and radiological screening guidelines.

2006-01-01

352

A Lebanese family with autosomal recessive oculo-auriculo-vertebral (OAV) spectrum and review of the literature: is OAV a genetically heterogeneous disorder?  

PubMed Central

Oculo-auriculo-vertebral (OAV) spectrum summarizes a continuum of ocular, auricular, and vertebral anomalies. Goldenhar syndrome is a variant of this spectrum and is characterized by pre-auricular skin tags, microtia, facial asymmetry, ocular abnormalities, and vertebral anomalies of different sizes and shapes. Most cases are thought to be sporadic. However, a few families were reported to have an autosomal recessive inheritance and other families’ presentation of the syndrome strongly supported an autosomal dominant inheritance. We report OAV in a female infant presenting with tracheomalacia, diaphragmatic hernia, encephalomeningocele, sacral neural tube defect, and cardiac defect and her brother having no more than dysmorphic features. The mode of inheritance in this family supports an autosomal recessive inheritance where the transmission was from normal first-degree consanguineous parents to one of the sons and to the daughter. This report further broadens the clinical presentation and symptoms of OAV and supports the hypothesis advancing OAV as a genetically heterogeneous disorder.

Farra, Chantal; Yunis, Khaled; Yazbeck, Nadine; Majdalani, Marianne; Charafeddine, Lama; Wakim, Rima; Awwad, Johnny

2011-01-01

353

Family lifeline.  

PubMed

Bereavement care is a vital but under-funded part of palliative care services, and there is growing evidence that people who have lost a loved one are at increased risk of serious illness. The Hospice of St. Francis in Berkhamsted is providing innovative care for families of patients before and after death. 'Life-changing' initiatives include cookery classes and pony rides. PMID:22908761

Trueland, Jennifer

354

[Familial hypercholesterolemia].  

PubMed

Familial hypercholesterolemia is one of the most common hereditary metabolic disorders, untreated with grave cardiovascular consequences. A general practitioner will see at least one affected individual each month, but will rarely be aware of the diagnosis, though it is easily suspected: an LDL-cholesterol ??190?mg/dl, a family history of premature cardiovascular disease, or clinical signs as arcus lipoides, tendinous xanthomata, or a thickened Achilles' tendon must draw the attention to familial hypercholesterolemia. Because of the burden of high cholesterol levels from childhood on therapy should be initiated early enough, which has become greatly ameliorated since the introduction of statins. In conjunction with additional risk factors, notably low HDL-cholesterol or elevated lipoprotein(a) the cardiovascular sequelae can be dramatic and may call for more intense therapies. However, often the routine of successful cholesterol lowering covers the diagnosis nowadays, so that a heritable metabolic disorder is not suspected, which, however, prevents an effective prevention in relatives, particularly the children of the patient. PMID:23132157

Windler, E; Beil, F-U; Altenburg, C; Rinninger, F

2012-11-01

355

"Reading" Families: Deficit Discourse and Family Literacy.  

ERIC Educational Resources Information Center

Describes family literacy, examining how families are already read by teachers, researchers, policymakers, and the media and arguing that the rhetoric of family literacy has defined the family in somewhat pathological terms. The paper examines the continued pervasiveness of deficit discourses to describe families, noting why it prevails in the…

Whitehouse Marianne; Colvin, Carolyn

2001-01-01

356

Dual Career Families: A Family Therapy Perspective.  

ERIC Educational Resources Information Center

This literature review provides an overview of the impact of dual careers on family and family therapy. The dual career family currently represents the most common married unit. Because both work and family stress impact psychological well-being variables such as depression and self-esteem, family and work can not be understood as two separate and…

Hill, Nicole R.

357

Asteroid families  

NASA Astrophysics Data System (ADS)

Dynamical and physical investigations of asteroid families are reviewed. Particular attention is given to recent work carried out mainly by means of a combination of numerical integration and filtering techniques and aimed at assessing the accuracy of proper elements with respect to the linear theory as well as evaluating some aspects of the second-order fourth-degree analytical theory of Yuasa (1973). It is noted that recent numerical results show that the issue of proper elements has to be reconsidered, particularly concerning the effect of the proximity to the mean motion resonances.

Froeschle, Cl.; Froeschle, Ch.; Gonczi, R.; Farinella, P.; Carpino, M.

358

The Pfam Protein Families Database  

Microsoft Academic Search

Pfam is a large collection of protein multiple sequence alignments and profile hidden Markov models. Pfam is available on the WWW in the UK at http:\\/\\/www.sanger.ac.uk\\/Software\\/Pfam\\/ , in Sweden at http:\\/\\/www.cgr.ki.se\\/Pfam\\/ and in the US at http:\\/\\/ pfam.wustl.edu\\/ . The latest version (4.3) of Pfam contains 1815 families. These Pfam families match 63% of proteins in SWISS-PROT 37 and TrEMBL

Alex Bateman; Ewan Birney; Richard Durbin; Sean R. Eddy; Kevin L. Howe; Erik L. L. Sonnhammer

2000-01-01

359

Family and family therapy in the Netherlands.  

PubMed

This article describes how families are functioning in the Netherlands, and how family therapy is used in mental healthcare. In the open Dutch society, new ideas are easily incorporated, as exemplified by the rapid introduction and growth of family therapy in the 1980s. In recent decades, however, family therapy has lost ground to other treatment models that are more individually orientated, and adhere to stricter protocols. This decline of family therapy has been exacerbated by recent budget cuts in mental healthcare. In regular healthcare institutes family therapy now has a marginal position at best, although family treatment models are used in specific areas such as forensic treatments. In addition, the higher trained family therapists have found their own niches to work with couples and families. We argue that a stronger position of family therapy would be beneficial for patients and for families, in order to counteract the strong individualization of Dutch society. PMID:22515464

Wagenaar, Karin; Baars, Jan

2012-04-01

360

Family transitions and juvenile delinquency.  

PubMed

There is a large body of research that shows children from non-intact homes show higher rates of juvenile delinquency than children from intact homes, partially due to weaker parental control and supervision in non-intact homes. What has not been adequately addressed in the research is the influence of changes in family structure among individual adolescents over time on delinquent offending. Using the first and third waves of the National Youth Study, we assess the effect of family structure changes on changes in delinquent offending between waves through the intermediate process of changes in family time and parental attachment. Although prior research has documented adolescents in broken homes are more delinquent than youth in intact homes, the process of family dissolution is not associated with concurrent increases in offending. In contrast, family formation through marriage or cohabitation is associated with simultaneous increases in offending. Changes in family time and parental attachment account for a portion of the family formation effect on delinquency, and prior parental attachment and juvenile offending significantly condition the effect of family formation on offending. PMID:20879178

Schroeder, Ryan D; Osgood, Aurea K; Oghia, Michael J

2010-01-01

361

Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3.  

PubMed Central

Autosomal dominant cerebellar ataxia type III (ADCA III) is a relatively benign, late-onset, slowly progressive neurological disorder characterized by an uncomplicated cerebellar syndrome. Three loci have been identified: a moderately expanded CAG trinucleotide repeat in the SCA 6 gene, the SCA 5 locus on chromosome 11, and a third locus on chromosome 22 (SCA 10). We have identified two British families in which affected individuals do not have the SCA 6 expansion and in which the disease is not linked to SCA 5 or SCA 10. Both families exhibit the typical phenotype of ADCA III. Using a genomewide searching strategy in one of these families, we have linked the disease phenotype to marker D15S1039. Construction of haplotypes has defined a 7.6-cM interval between the flanking markers D15S146 and D15S1016, thereby assigning another ADCA III locus to the proximal long-arm of chromosome 15 (SCA 11). We excluded linkage of the disease phenotype to this region in the second family. These results indicate the presence of two additional ADCA III loci and more clearly define the genetic heterogeneity of ADCA III.

Worth, P F; Giunti, P; Gardner-Thorpe, C; Dixon, P H; Davis, M B; Wood, N W

1999-01-01

362

Positive Family Functioning.  

ERIC Educational Resources Information Center

The persistence of the nuclear family as the primary social unit in the United States and most all other societies, especially complex ones, is a fact. Values shape the definition of family, especially the "good family," and the "great debate" of this period on family failure, family corruption and the family's near demise originates in…

Sussman, Marvin B.

363

Reclaiming Family Privilege  

ERIC Educational Resources Information Center

The pull for family is strong, almost primeval, most likely it is evolutionary, and for those lacking the benefit of family or Family Privilege, the loss of family is painful and profoundly sad. Young people who struggle to cope without stable family connections are profoundly aware of their lack of "Family Privilege." In this article, the author…

Seita, John

2012-01-01

364

Final Evaluation Report: Family to Family Program.  

ERIC Educational Resources Information Center

This evaluation report of the Family to Family Program assesses parental attitudes towards their Family to Family experience and the functioning of their emotionally impaired children. It reviews issues of goal achievement; the impact on the targeted problem; service population demographics; and sustainability. Related topics include…

Ramey, Luellen; Meyer, David P.

365

The Family Hero in Black Alcoholism Families.  

ERIC Educational Resources Information Center

Uses data from 20 case studies of Black adult female children of alcoholic parents to discuss Family Hero role often assumed by oldest or only female child in Black alcoholism families. Explains how female-dominated survival role of Family Hero in Black families is significantly more related to racial and cultural factors than numbers alone may…

Brisbane, Francis L.

1989-01-01

366

Identification of a novel LCA5 mutation in a Pakistani family with Leber congenital amaurosis and cataracts  

PubMed Central

Purpose To determine the cause of Leber congenital amaurosis (LCA) and developmental cataracts in a consanguineous Pakistani family. Methods The diagnosis was established in all affected individuals of a Pakistani LCA family by medical history, funduscopy, and standard ERG. We performed genome-wide linkage analysis for mapping the disease locus in this family. Results Congenitally severely reduced visual acuity and nystagmus were reported for all patients who, in the later phase of the disease, also developed cataracts. LCA in the family cosegregated with homozygosity for a single nucleotide polymorphism (SNP) haplotype on chromosome 6p14.1. The respective candidate region contained Leber congenital amaurosis 5 (LCA5), a gene previously reported to underlie LCA. We subsequently identified a novel truncating mutation in exon 4 of LCA5, c.642delC, in homozygous state in all affected persons of the family. Conclusions We report a novel LCA5 mutation causing LCA in a Pakistani family. Developmental cataracts were present in two of the four patients, raising the possibility that LCA5 mutations may predispose to this additional ocular pathology.

Ahmad, Adeel; Daud, Shakeela; Kakar, Naseebullah; Nurnberg, Gudrun; Nurnberg, Peter; Babar, Masroor Ellahi; Thoenes, Michaela; Kubisch, Christian; Ahmad, Jamil

2011-01-01

367

Thankful for Family and Foods! (An ABLE Teaching Unit).  

ERIC Educational Resources Information Center

The teaching unit focuses on a month (November) of primary grade learning activities which focus on being thankful for food, family, and friends. Concepts stressed throughout the unit include: We are all part of the large family of Americans; Families are made up of a variety of people and our families are usually different from each other;…

Barringer, Mary Dean; And Others

368

The laminin family  

PubMed Central

Laminins are large molecular weight glycoproteins constituted by the assembly of three disulfide-linked polypeptides, the ?, ? and ? chains. The human genome encodes 11 genetically distinct laminin chains. Structurally, laminin chains differ by the number, size and organization of a few constitutive domains, endowing the various members of the laminin family with common and unique important functions. In particular, laminins are indispensable building blocks for cellular networks physically bridging the intracellular and extracellular compartments and relaying signals critical for cellular behavior, and for extracellular polymers determining the architecture and the physiology of basement membranes.

2013-01-01

369

The gp49A gene has extensive sequence conservation with the gp49B gene and provides gp49A protein, a unique member of a large family of activating and inhibitory receptors of the immunoglobulin superfamily  

Microsoft Academic Search

Members of the gp49-related family of mouse and human immunoglobulin (Ig) superfamily receptors have significant amino acid\\u000a sequence homology in their C2-type, Ig-like domains and include the killer cell Ig-like receptors (KIRs) for major histocompatibility\\u000a complex class I molecules. We now report the cloning, complete sequence, and organization of the mouse gp49A gene that encodes the only member of this

Michael J. McCormick; Mariana C. Castells; K. Frank Austen; Howard R. Katz

1999-01-01

370

Codependency: a family addiction.  

PubMed

Codependency is a common and treatable family-system illness that develops in reaction to the stress of addiction or another "shameful secret" in a family member. This stressful environment induces emotional changes in each family member and creates a variety of pathologic family roles. For the family physician, brief therapy for the codependent family can be visibly effective when combined with follow-up and referral to resources such as Al-Anon family groups. PMID:3565221

Mulry, J T

1987-04-01

371

Family and family therapy in Russia.  

PubMed

This article represents the information about family and family therapy in the context of culture, traditions and contemporary changes of social situations in Russia. The legislation of family rights are mentioned within items about marriage and family in the Constitution, Civil Code and Family Code of the Russian Federation which has changed during recent years. The definition of family and description of family structure are given through the prism of the current demographic situation, dynamics of statistics of marriage and divorce rates, mental disorders, disabilities and such phenomena as social abandonment. The actual curriculum, teaching of family therapy and its disadvantages, system of continuous education, supervision and initiatives of the Institute of Integrative Family Therapy in improvement of preparing of specialists who can provide qualified psychosocial assistance for the family according to the actual needs of society are noted. The directions of state and private practice of family counselling and therapy both for psychiatric patients and medical patients, for adults and children in a family systemic approach are highlighted with an indication of the spectrum of techniques and methods used by Russian professionals. The main obstacles and perspectives of development of family therapy in Russia are summarized. PMID:22515460

Bebtschuk, Marina; Smirnova, Daria; Khayretdinov, Oleg

2012-04-01

372

Family Reading Night  

ERIC Educational Resources Information Center

This book offers clear and practical guidelines to help engage families in student success. It shows families how to conduct a successful Family Reading Night at their school. Family Night themes include Scary Stories, Books We Love, Reading Olympics, Dr. Seuss, and other themes. Family reading nights invite parents to come to school with their…

Hutchins, Darcy; Greenfeld, Marsha; Epstein, Joyce

2007-01-01

373

Family Resiliency: A Neglected Family Construct.  

ERIC Educational Resources Information Center

Examines research on the construct of resiliency and examines factors that promote resiliency in individuals and families. Implications for family counselors, societal systems, and future research are discussed. (Author/MKA)

Buckley, Matthew R.; Thorngren, Jill M.; Kleist, David M.

1997-01-01

374

Family Preservation (Family Focus Research Project).  

National Technical Information Service (NTIS)

The Family Focus Research project provided a comprehensive evaluation of home-based crisis intervention strategies for families with children at risk of placement into substitute care. It examined the relative costs and benefits of three types of brief, i...

J. R. Taplin C. Rowland

1983-01-01

375

Family Capital: Implications for Interventions with Families  

ERIC Educational Resources Information Center

Social capital has been extensively discussed in the literature as building blocks that individuals and communities utilize to leverage system resources. Similarly, some families also create capital, which can enable members of the family, such as children, to successfully negotiate the outside world. Families in poverty confront serious…

Belcher, John R.; Peckuonis, Edward V.; Deforge, Bruce R.

2011-01-01

376

Linkage disequilibrium mapping places the gene causing familial Mediterranean fever close to D16S246  

SciTech Connect

This report presents refined genetic mapping data for the gene causing familial Mediterranean fever (FMF), a recessively inherited disorder of inflammation. We sampled 65 Jewish, Armenian, and Arab families and typed them for eight markers from chromosome 16p. Using a new algorithm that permits multipoint calculations for a dense map of markers in consanguineous families, we obtained a maximal LOD score of 49.2 at a location 1.6 cM centromeric to D16S246. A specific haplotype at D16S283-D16S94-D16S246 was found in 76% of Moroccan and 32% of non-Moroccan Jewish carrier chromosomes, but this haplotype was not overrepresented in Armenian or Arab FMF carriers. Moreover, the 2.5-kb allele at D16S246 was significantly associated with FMF in Moroccan and non-Moroccan Jews but not in Armenians or Arabs. Since the Moroccan Jewish community represents a relatively recently established and genetically isolated founder population, we analyzed the Moroccan linkage-disequilibrium data by using Luria-Delbruck formulas and simulations based on a Poisson branching process. These methods place the FMF susceptibility gene within 0.305 cM of D16S246 (2-LOD-unit range 0.02-0.64 cM). 41 refs., 3 figs., 5 tabs.

Levy, E. N.; Aksentijevich, I.; Pras, E. [National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD (United States)] [and others

1996-03-01

377

Glycogenosis type II: protein and DNA analysis in five South African families from various ethnic origins.  

PubMed Central

The molecular nature of lysosomal alpha-glucosidase deficiency was studied in five South African families with glycogenosis type II. Distinct ethnic origins were represented. Two new mutant acid alpha-glucosidase alleles were discovered. In two infantile patients from a consanguineous Indian family we found for the first time an acid alpha-glucosidase precursor of reduced size. The mutant precursor appeared normally glycosylated and phosphorylated but was not processed to mature enzyme. Abnormalities of the mRNA were not obvious, but digestion of genomic DNA with HindIII, BglII, and StuI revealed for each enzyme a fragment of increased length. Heterozygosity was demonstrated in the parents. Complete lack of acid alpha-glucosidase mRNA, as well as deficiency of precursor synthesis, was observed in two black baby girls from unrelated families. In these cases the length of all restriction-enzyme fragments was normal. Reduced enzyme synthesis but normal processing was registered in juvenile and young adult Cape colored patients. The extensive heterogeneity of glycogenosis type II is emphasized in these studies on various ethnic groups. The newly discovered mutants are valuable for the understanding of clinical diversity as a result of allelic variation. Images Figure 1 Figure 2 Figure 3 Figure 4

Van der Ploeg, A T; Hoefsloot, L H; Hoogeveen-Westerveld, M; Petersen, E M; Reuser, A J

1989-01-01

378

Homozygous TREM2 mutation in a family with atypical frontotemporal dementia.  

PubMed

TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20-50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging. PMID:24910390

Le Ber, Isabelle; De Septenville, Anne; Guerreiro, Rita; Bras, José; Camuzat, Agnès; Caroppo, Paola; Lattante, Serena; Couarch, Philippe; Kabashi, Edor; Bouya-Ahmed, Kawtar; Dubois, Bruno; Brice, Alexis

2014-10-01

379

Genetic homogeneity in Sjoegren-Larsson syndrome: Linkage to chromosome 17p in families of different non-Swedish ethnic origins  

SciTech Connect

Sjoegren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder that is characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. Three United States families, three Egyptian families, and one Israeli Arab family were investigated for linkage of the SLS gene to a region of chromosome 17. Pairwise and multipoint linkage analysis with nine markers mapped the SLS gene to the same region of the genome as that reported in Swedish SLS pedigrees. Examination of recombinants by haplotype analysis showed that the gene lies in the region containing the markers D17S953, D17S805, D17S689, and D17S842. D17S805 is pericentromeric on 17p. Patients in two consanguineous Egyptian families were homozygous at the nine marker loci tested, and another patient from a third family was homozygous for eight of the nine, suggesting that within each of these families the region of chromosome 17 carrying the SLS gene is identical by descent. Linkage of the SLS gene to chromosome 17p in families of Arabic, mixed European, Native American, and Swedish descent provides evidence for a single SLS locus and should prove useful for diagnosis and carrier detection in worldwide cases. 25 refs., 4 figs., 1 tab.

Rogers, G.R.; Lee, M.; Compton, J.G. [and others

1995-11-01

380

Families with Kids  

MedlinePLUS

... Families & Friendships Military Sexual Trauma Depression mild Traumatic Brain Injury Life Stress Health & Wellness Anger Stigma Suicide Prevention ... Post-Traumatic Stress Sleep Alcohol & Drugs mild Traumatic Brain Injury Resilience Families with Kids Depression Families & Friendships Tobacco ...

381

Family Activities for Fitness  

ERIC Educational Resources Information Center

This article discusses how families can increase family togetherness and improve physical fitness. The author provides easy ways to implement family friendly activities for improving and maintaining physical health. These activities include: walking, backyard games, and fitness challenges.

Grosse, Susan J.

2009-01-01

382

Improving Family Communications  

MedlinePLUS

... for Families (PedFACTs) Infant CPR Anytime® (English/Spanish) Pediatric First Aid for Caregivers and Teachers (PedFACTs) Participant Manual Allergies and Asthma Family Life Health Management - Medical Home Family Dynamics ...

383

Family in Crisis  

MedlinePLUS

... Family Life Health Management - Medical Home Family Dynamics Adoption & Foster Care Communication & Disciplines Types of Families Media ... About Breastfeeding Teen Parents Pacifier Safety Questions About Adoption Healthy Children Radio: Protecting Children From Sexual Abuse ( ...

384

Importance of Family Routines  

MedlinePLUS

... First Aid for Families (PedFACTs) Infant CPR Anytime® (English/Spanish) Pediatric First Aid for Caregivers and Teachers (PedFACTs) Participant Manual Infant CPR Anytime® Dark Skin (English/Spanish) Family Life Health Management - Medical Home Family ...

385

Families Experiencing Homelessness  

MedlinePLUS

... compound the stress the family feels. Families experiencing homelessness: Are typically comprised of a mother in her ... than other low-income families. 4 Mothers Experiencing Homelessness: The impact of homelessness on mothers is profound. ...

386

Family Adjustment to Aphasia  

MedlinePLUS

Family Adjustment to Aphasia Richard S. was a senior manager at a small company and next in line ... It also presents a great challenge to the family. There may be tension among family members and ...

387

Contacting My Donor Family  

MedlinePLUS

... My Donor Family Newsroom Minorities Contacting My Donor Family Writing anything can be a challenge. Staring at ... down to write a note to your donor family can feeling overwhelming. The good news is that ...

388

Media Time Family Pledge  

MedlinePLUS

... Media Time Family Pledge Family Life Listen Media Time Family Pledge Article Body At the beginning and ... them. Kids learn best with small lessons over time as opposed to one big lecture or sit- ...

389

Characteristics of familial and non-familial melanoma in Australia.  

PubMed

Between 6 and 14% of malignant melanomas have been reported to occur in a familial pattern. In this study 785 melanoma patients from the Victorian Melanoma Service and the private practice of a dermatologist were assessed for the total number of melanocytic naevi, the number of dysplastic naevi and other clinical characteristics categorized according to whether there was a family history of melanoma. It was found that the presence of 100 or more naevi, six or more dysplastic naevi and blue eyes in a patient with melanoma were significantly associated with a family history of melanoma. Patients with two or more family members with melanoma were significantly more likely to develop melanoma at a younger age and to develop multiple melanomas. This study concludes that large numbers of melanocytic naevi and dysplastic naevi in melanoma patients are useful characteristics in practice to identify patients at risk of familial occurrence of melanoma. Family members of these patients should receive a medical assessment for their pigmented lesions. PMID:9835460

Ang, C G; Kelly, J W; Fritschi, L; Dowling, J P

1998-10-01

390

Family members' influence on family meal vegetable choices  

PubMed Central

Objective Characterize the process of family vegetable selection (especially cruciferous, deep orange, and dark green leafy vegetables); demonstrate the usefulness of Exchange Theory (how family norms and past experiences interact with rewards and costs) for interpreting the data. Design Eight focus groups, two with each segment (men/women vegetable-likers/dislikers based on a screening form). Participants completed a vegetable intake form. Setting Rural Appalachian Pennsylvania. Participants 61 low-income, married/cohabiting men (n=28) and women (n=33). Analysis Thematic analysis within Exchange Theory framework for qualitative data. Descriptive analysis, t-tests and chi-square tests for quantitative data. Results Exchange Theory proved useful for understanding that regardless of sex or vegetable-liker/disliker status, meal preparers see more costs than rewards to serving vegetables. Past experience plus expectations of food preparer role and of deference to family member preferences supported a family norm of serving only vegetables acceptable to everyone. Emphasized vegetables are largely ignored due to unfamiliarity; family norms prevented experimentation and learning through exposure. Conclusions and Implications Interventions to increase vegetable consumption of this audience could 1) alter family norms about vegetables served, 2) change perceptions of past experiences, 3) reduce social and personal costs of serving vegetables and 4) increase tangible and social rewards of serving vegetables.

Wenrich, Tionni R.; Brown, J. Lynne; Miller-Day, Michelle; Kelley, Kevin J.; Lengerich, Eugene J.

2010-01-01

391

Work/Family Conflicts: Policy Implications.  

ERIC Educational Resources Information Center

In the past 20 years, the percentage of married women in the Canadian labor force has risen dramatically. Despite women's increased participation in the labor force, child care and housework are still largely done by women. While the difficulty of combining work and family responsibilities can result in work/family conflicts, a variety of…

Baker, Maureen

392

Fourth lepton family is natural in technicolor  

Microsoft Academic Search

Imagine discovering a new fourth family of leptons at the Large Hadron Collider (LHC) but no signs of an associated fourth family of quarks. What would that imply? An intriguing possibility is that the new fermions needed to compensate for the new leptons gauge anomalies simultaneously address the big hierarchy problem of the standard model. A natural way to accomplish

Mads T. Frandsen; Isabella Masina; Francesco Sannino

2010-01-01

393

Familial mesothelioma: a report of two families  

SciTech Connect

Five reports of familial mesothelioma in which mesotheliomas occurred in two or more family members have been recorded in the medical literature. In this report, we describe two examples of familial mesothelioma. In one family, three brothers who worked in the asbestos insulation industry developed mesothelioma. In the second family, the father, who was occupationally exposed to asbestos, died from a tubulopapillary peritoneal mesothelioma 11 years before his son died from an identical histologic type of peritoneal mesothelioma. Our report, as with those previously recorded, suggests that genetic factors may be important in the genesis of some mesotheliomas.

Hammar, S.P.; Bockus, D.; Remington, F.; Freidman, S.; LaZerte, G.

1989-02-01

394

Family structure, family organization, and quality of family life  

Microsoft Academic Search

This study examines how family organization is associated with the quality of family life for parents in first marriages,\\u000a remarriages with biological children, and several types of stepfamilies. Data are drawn from the 1987–1988 National Survey\\u000a of Families and Households; only married couples in which both spouses participated in the survey and who had children under\\u000a age 19 in the

Patricia Voydanoff; Mark A. Fine; Brena W. Donnelly

1994-01-01

395

Segregation of a Latent High Adiposity Phenotype in Families with a History of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants with Large Effects in Diabetes-Related Obesity  

PubMed Central

Background We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH?) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+. Methods Normoglycaemic participants were categorised either FH+ (?1 1st degree relative with T2DM, 50F/30M, age 45±14 (SD) yr) or FH? (71F/51M, age 43±14 yr). Log-transformed anthropometric measurements (height, hip and waist circumferences) and lean, bone and fat mass (Dual Energy X-ray Absorptiometry) data were analysed by rotated Factor Analysis. The age- and gender-adjusted distributions of indices of adiposity in FH+ were assessed by fits to a bimodal model and by relative risk ratios (RR, FH+/FH?) and interpreted in a purely genetic model of FH effects. Results The two orthogonal factors extracted, interpretable as Frame and Adiposity accounted for 80% of the variance in the input data. FH+ was associated with significantly higher Adiposity scores (p<0.01) without affecting Frame scores. Adiposity scores in FH+ conformed to a bimodal normal distribution, consistent with dominant expression of major susceptibility genes with 59% (95% CI 40%, 74%) of individuals under the higher mode. Calculated risk allele frequencies were 0.09 (0.02, 0.23) in FH?, 0.36 (0.22, 0.48) in FH+ and 0.62 (0.36, 0.88) in unobserved T2DM-affected family members. Conclusions The segregation of Adiposity in T2DM-affected families is consistent with dominant expression of rare risk variants with major effects, which are expressed in over half of FH+ and which can account for most T2DM-associated obesity in our population. The calculated risk allele frequency in FH? suggests that rare genetic variants could also account for a substantial fraction of the prevalent obesity in this society.

Jenkins, Arthur B.; Batterham, Marijka; Samocha-Bonet, Dorit; Tonks, Katherine; Greenfield, Jerry R.; Campbell, Lesley V.

2013-01-01

396

Families and family therapy in Hong Kong.  

PubMed

Family therapy views humans not as separate entities, but as embedded in a network of relationships, highlighting the reciprocal influences of one's behaviours on one another. This article gives an overview of family demographics and the implementation of family therapy in Hong Kong. We start with a review of the family demographics in Hong Kong and brief notes on families in mainland China. Demographics show that the landscape has changed markedly in the past decade, with more cross-border marriages, an increased divorce rate, and an ageing overall population - all of which could mean that there is increasing demand for professional family therapy interventions. However, only a limited number of professionals are practising the systems-based approach in Hong Kong. Some possible reasons as to why family therapy is not well disseminated and practised are discussed. These reasons include a lack of mental health policy to support family therapy, a lack of systematic family therapy training, and a shortage of skilled professionals. Furthermore, challenges in applying the western model in Chinese culture are also outlined. We conclude that more future research is warranted to investigate how family therapy can be adapted for Chinese families. PMID:22515459

Tse, Samson; Ng, Roger M K; Tonsing, Kareen N; Ran, Maosheng

2012-04-01