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1.
Clin Genet ; 78(5): 424-31, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20618352

RESUMO

Bardet-Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome-wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472-2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population.


Assuntos
Síndrome de Bardet-Biedl/genética , Etnicidade/genética , Efeito Fundador , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único , Sítios de Splice de RNA/genética , População Branca/genética
2.
Clin Genet ; 74(3): 274-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18492089

RESUMO

Charcot-Marie-Tooth disease (CMT) constitutes a large group of genetically heterogeneous disorders of the peripheral nervous system. Autosomal recessive forms of CMT are less common in the general population but account for the vast majority of CMT phenotypes in communities with a high prevalence of consanguinity. At least 10 genetic loci cause autosomal recessive forms of CMT. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are among the most frequent genetic causes of autosomal recessive forms of CMT. To date, 28 mutations in GDAP1 gene have been linked with the disease. Here, we report a novel GDAP1 mutation in an Old Order Amish family with CMT. To ascertain the Amish CMT locus, we performed a genome-wide single nucleotide polymorphism (SNP) analysis on one of three patients from a consanguineous pedigree. Assuming mutation homogeneity, the analysis sought large homozygous SNP blocks that also contained known CMT loci. The largest homozygous SNP block in the patient was localized to chromosome 8q13.1-21.3 and contained the GDAP1 gene. Sequence analysis revealed a novel homozygous mutation, c.692C>T, at codon 231 (p.P231L) in exon 5 of GDAP1 in all patients. Neither the unaffected individuals in the family nor the healthy control samples were homozygous for this mutation. Our findings suggested that this novel mutation in GDAP1 gene is associated with an autosomal recessive form of CMT in Ohio Old Order Amish community.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Genes Recessivos , Mutação , Proteínas do Tecido Nervoso/genética , Sequência de Bases , Análise Mutacional de DNA , Família , Genótipo , Humanos , Dados de Sequência Molecular , Ohio , Linhagem , Polimorfismo de Nucleotídeo Único
3.
Am J Transplant ; 6(3): 557-64, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16468966

RESUMO

An 8.5-year-old girl with classical maple syrup urine disease (MSUD) required liver transplantation for hypervitaminosis A and was effectively cured of MSUD over an 8-year clinical follow-up period. We developed a collaborative multidisciplinary effort to evaluate the effects of elective liver transplantation in 10 additional children (age range 1.9-20.5 years) with classical MSUD. Patients were transplanted with whole cadaveric livers under a protocol designed to optimize safe pre- and post-transplant management of MSUD. All patients are alive and well with normal allograft function after 106 months of follow-up in the index patient and a median follow-up period of 14 months (range 4-18 months) in the 10 remaining patients. Leucine, isoleucine and valine levels stabilized within 6 hours post-transplant and remained so on an unrestricted protein intake in all patients. Metabolic cure was documented as a sustained increase in weight-adjusted leucine tolerance, normalization of plasma concentration relationships among branched-chain and other essential and nonessential amino acids, and metabolic and clinical stability during protein loading and intercurrent illnesses. Costs and risks associated with surgery and immune suppression were similar to other pediatric liver transplant populations.


Assuntos
Procedimentos Cirúrgicos Eletivos/métodos , Transplante de Fígado , Doença da Urina de Xarope de Bordo/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Leucina/sangue , Doença da Urina de Xarope de Bordo/sangue , Fatores de Tempo , Resultado do Tratamento
4.
Am J Med Genet C Semin Med Genet ; 121C(1): 18-31, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12888983

RESUMO

The Old Order Mennonites of southeastern Pennsylvania are a religious isolate with origins in 16th-century Switzerland. The Swiss Mennonites immigrated to Pennsylvania over a 50-year period in the early 18th century. The history of this population in the United States provides insight into the increased incidence of several genetic diseases, most notably maple syrup urine disease (MSUD), Hirschsprung disease (HSCR), and congenital nephrotic syndrome. A comparison between the Old Order Mennonites and the Old Order Amish demonstrates the unique genetic heritage of each group despite a common religious and geographic history. Unexpectedly, several diseases in both groups demonstrate allelic and/or locus heterogeneity. The population genetics of the 1312T --> A BCKDHA gene mutation, which causes classical MSUD, are presented in detail. The incidence of MSUD in the Old Order Mennonites is estimated to be 1/358 births, yielding a corrected carrier frequency of 7.96% and a mutation allele frequency of 4.15%. Analysis of the population demonstrates that repeated cycles of sampling effects, population bottlenecks, and subsequent genetic drift were important in shaping the current allele frequencies. A linkage disequilibrium analysis of 1312T --> A mutation haplotypes is provided and discussed in the context of the known genealogical history of the population. Finally, data from microsatellite marker genotyping within the Old Order Mennonite population are provided that show a significant but modest decrease in genetic diversity and elevated levels of background linkage disequilibrium.


Assuntos
Etnicidade/genética , Doenças Genéticas Inatas/genética , Variação Genética , Genética Populacional , Doença da Urina de Xarope de Bordo/genética , Mutação/genética , Cromossomos Humanos Par 19/genética , Consanguinidade , Frequência do Gene , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Repetições de Microssatélites/genética , Pennsylvania , Dinâmica Populacional , Protestantismo , Análise de Sequência de DNA
5.
Gastroenterology ; 119(1): 188-95, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10889168

RESUMO

BACKGROUND & AIMS: The mechanism for abnormal hepatic bile acid transport was investigated in an 18-month-old Amish boy who presented with pruritus, poor growth, and severe bleeding episodes. Serum bilirubin, gamma-glutamyltranspeptidase, and cholesterol levels were normal, but prothrombin time and partial thromboplastin time were prolonged and bone alkaline phosphatase level was elevated. METHODS AND RESULTS: Cholic acid plus chenodeoxycholic acid levels measured by capillary gas-chromatography were 32 times higher than control in serum (34.7 vs. 1.1+/-0.4 microg/dL) but were not detected in liver and were reduced in gallbladder bile. Treatment with ursodiol, a more hydrophilic bile acid, improved pruritus, produced 37% weight gain, and after 2 years reduced serum primary bile acid concentrations about 85%, while accounting for 71% of serum and 24% of biliary bile acid conjugates. On ursodiol therapy, hepatic bile acid synthesis was enhanced 2-fold compared with controls, and microscopy revealed chronic hepatitis without cholestasis. Three younger sisters with elevated serum bile acids responded positively to ursodiol. Microsatellite markers for the FIC1 (gene for Byler's disease) region in these 4 children were inconsistent with linkage to FIC1. CONCLUSIONS: Conjugated cholic acid and chenodeoxycholic acid were synthesized in the liver and secreted into bile but could not reenter the liver from portal blood and accumulated in serum. In contrast, unconjugated ursodiol entered the liver and was conjugated and secreted into bile. Thus, the enterohepatic circulation of all conjugated bile acids was interrupted at the hepatic sinusoidal basolateral membrane. Unconjugated ursodiol bypassed the hepatic uptake block to enlarge the biliary and intestinal bile acid pools. A mutation in FIC1 recognized among the Amish and linkage of the disorder to FIC1 were excluded.


Assuntos
Adenosina Trifosfatases/genética , Ácidos e Sais Biliares/metabolismo , Colagogos e Coleréticos/uso terapêutico , Etnicidade/genética , Ligação Genética/genética , Fígado/metabolismo , Ácido Ursodesoxicólico/uso terapêutico , Ácidos e Sais Biliares/biossíntese , Transporte Biológico/efeitos dos fármacos , Ácido Quenodesoxicólico/sangue , Ácido Quenodesoxicólico/urina , Colagogos e Coleréticos/metabolismo , Ácido Cólico/sangue , Ácido Cólico/urina , Feminino , Humanos , Lactente , Masculino , Linhagem , Pennsylvania/etnologia , Ácido Ursodesoxicólico/metabolismo
7.
Genome Res ; 8(2): 111-23, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9477339

RESUMO

Genetic studies of complex hereditary disorders require for their mapping the determination of genotypes at several hundred polymorphic loci in several hundred families. Because only a minority of markers are expected to show linkage and association in family data, a simple screen of genetic markers to identify those showing linkage in pooled DNA samples can greatly facilitate gene identification. All studies involving pooled DNA samples require the comparison of allele frequencies in appropriate family samples and subsamples. We have tested the accuracy of allele frequency estimates, in various DNA samples, by pooling DNA from multiple individuals prior to PCR amplification. We have used the ABI 377 automated DNA sequencer and GENESCAN software for quantifying total amplification using a 5' fluorescently labeled forward PCR primer and relative peak heights to estimate allele frequencies in pooled DNA samples. In these studies, we have genotyped 11 microsatellite markers in two separate DNA pools, and an additional four markers in a third DNA pool, and compared the estimated allele frequencies with those determined by direct genotyping. In addition, we have evaluated whether pooled DNA samples can be used to accurately assess allele frequencies on transmitted and untransmitted chromosomes, in a collection of families for fine-structure gene mapping using allelic association. Our studies show that accurate, quantitative data on allele frequencies, suitable for identifying markers for complex disorders, can be identified from pooled DNA samples. This approach, being independent of the number of samples comprising a pool, promises to drastically reduce the labor and cost of genotyping in the initial identification of disease loci. Additional applications of DNA pooling are discussed. These developments suggest that new statistical methods for analyzing pooled DNA data are required.


Assuntos
Alelos , Mapeamento Cromossômico/métodos , Frequência do Gene , Doenças Genéticas Inatas/genética , Primers do DNA , Corantes Fluorescentes , Testes Genéticos/métodos , Genótipo , Humanos , Desequilíbrio de Ligação , Repetições de Microssatélites , Reação em Cadeia da Polimerase , Polimorfismo Genético
8.
Am J Hum Genet ; 60(1): 133-42, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8981956

RESUMO

Nail-patella syndrome (NPS), or onychoosteodysplasia, is an autosomal dominant, pleiotropic disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and nephropathy. Previous studies have demonstrated linkage of the nail-patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. As a first step toward isolating the NPS gene, we present linkage analysis with 13 polymorphic markers in five families with a total of 69 affected persons. Two-point linkage analysis with the program MLINK showed tight linkage of NPS and the anonymous markers D9S112 (LOD = 27.0; theta = .00) and D9S315 (LOD = 22.0; theta = .00). Informative recombination events place the NPS locus within a 1-2-cM interval between D9S60 and the adenylate kinase gene (AK1).


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 9 , Síndrome da Unha-Patela/genética , Feminino , Ligação Genética , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Linhagem
9.
Hum Mol Genet ; 4(5): 821-30, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7633441

RESUMO

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births. Recently, linkage of an incompletely penetrant, dominant form of HSCR was reported, followed by identification of mutations in the RET receptor tyrosine kinase. To determine the frequency of RET mutations in HSCR and correlate genotype with phenotype, we have screened for mutations among 80 HSCR probands representing a wide range of phenotypes and family structures. Polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis of RET's 20 exons for mutations among probands revealed eight putative mutations (10%). Sequence changes, which included missense, frameshift and complex mutations, were detected in both familial and isolated cases, among patients with both long- and short-segment HSCR and in three kindreds with other phenotypes (maternal deafness, talipes and malrotation of the gut, respectively). Two mutations (C609Y and C620R) we identified have previously been associated with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC) and, on rare occasions, HSCR. Thus, while HSCR family members may be at risk for developing neuroendocrine tumors, it follows that identical mutations in RET may be able to participate in the pathogenesis of distinct phenotypes. Our data suggest that: (i) the overall frequency of RET mutations in HSCR patients is low and therefore, other genetic and/or environmental determinants contribute to the majority of HSCR susceptibility, and (ii) at present, there is no obvious relationship between RET genotype and HSCR phenotype.


Assuntos
Proteínas de Drosophila , Doença de Hirschsprung/enzimologia , Doença de Hirschsprung/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Sequência de Bases , DNA/genética , Análise Mutacional de DNA , Éxons , Feminino , Genótipo , Doença de Hirschsprung/etiologia , Humanos , Masculino , Dados de Sequência Molecular , Neoplasia Endócrina Múltipla Tipo 2a/genética , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-ret
10.
Cell ; 79(7): 1257-66, 1994 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-8001158

RESUMO

Hirschsprung's disease (HSCR) is characterized by an absence of enteric ganglia in the distal colon and a failure of innervation in the gastrointestinal tract. We recently mapped a recessive susceptibility locus (HSCR2) to human chromosome 13q22, which we now demonstrate to be the endothelin-B receptor gene (EDNRB). We identified in HSCR patients a G-->T missense mutation in EDNRB exon 4 that substitutes the highly conserved Trp-276 residue in the fifth transmembrane helix of the G protein-coupled receptor with a Cys residue (W276C). The mutant W276C receptor exhibited a partial impairment of ligand-induced Ca2+ transient levels in transfected cells. The mutation is dosage sensitive, in that W276C homozygotes and heterozygotes have a 74% and a 21% risk, respectively, of developing HSCR. Genotype analysis of patients in a Mennonite pedigree shows HSCR to be a multigenic disorder.


Assuntos
Doença de Hirschsprung/genética , Mutação Puntual , Receptores de Endotelina/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Células CHO , Cálcio/metabolismo , Mapeamento Cromossômico , Cromossomos Humanos Par 13 , Cricetinae , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Linhagem , Polimorfismo Conformacional de Fita Simples , Receptor de Endotelina B , Transfecção
11.
Hum Mol Genet ; 3(8): 1217-25, 1994 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7987295

RESUMO

Hirschsprung disease (HSCR) is a congenital disorder of unknown etiology characterized by the absence of enteric ganglia in the distal colon. We have ascertained a large, inbred, Mennonite kindred which demonstrates a high incidence of Hirschsprung disease (HSCR). Genealogical analysis of all kinship relationships identified a single common ancestral couple for all parents of affected offspring. Segregation analysis yielded a segregation ratio of 10.67% for males and 5.45% for females. We searched for locations of the gene(s) responsible for HSCR in this pedigree by genotyping three small multicase families and locating genomic regions demonstrating identity-by-descent followed by linkage disequilibrium analysis of 28 additional nuclear families. Based on this novel strategy, we report the mapping of a new locus for HSCR to chromosome 13q22. Nine microsatellite markers spanning 10 cM in this region were genotyped on thirty-one nuclear families. Significant nonrandom association was detected with alleles at markers D13S162, D13S160, D13S170, and AFM240zg9. In addition, our studies reveal preliminary evidence for a genetic modifier of HSCR in this kindred on chromosome 21q22.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 13 , Genes Recessivos/genética , Doença de Hirschsprung/genética , Feminino , Haplótipos , Humanos , Masculino , Linhagem
12.
Nat Genet ; 4(4): 351-6, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8401581

RESUMO

Hirschsprung disease (HSCR) is characterized by a congenital absence of enteric ganglia along a variable length of the intestine. Although long considered to be a multifactorial disease, we have identified linkage in a subset of five HSCR families to the pericentromeric region of chromosome 10, thereby providing monogenic inheritance in some families. A maximum two-point lod score of 3.37 (theta = 0.045) was observed between HSCR and D10S176, under an incompletely penetrant dominant model. Multipoint, affecteds-only and non-parametric analyses supported this finding and localize this gene to a region of approximately 7 centiMorgans, in close proximity to the locus for multiple endocrine neoplasia type 2 (MEN2). The co-occurrence of these two entities in some families might be attributable to shared pathogenetic origins.


Assuntos
Centrômero , Cromossomos Humanos Par 10 , Doença de Hirschsprung/genética , Alelos , Mapeamento Cromossômico , Família , Feminino , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Masculino , Linhagem
13.
Am J Hum Genet ; 53(1): 71-9, 1993 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8317501

RESUMO

We have carried out a linkage analysis on 11 families segregating gene(s) for hereditary multiple exostoses (EXT). Four highly informative, short tandem-repeat (STR) markers that have been physically mapped to an interval surrounding the Langer-Giedion chromosomal region (8q24.11-q24.13) were used in a multipoint linkage analysis. Significant evidence for linkage of EXT with genetic heterogeneity was found. A model of heterogeneity with linkage of the disease gene to the STR markers in 70% of the families (with a 95% confidence interval of 26%-96%) produced a maximum LOD score of 8.11, with the most likely position of EXT between D8S85 and D8S199. Thus there are at least two genes that are capable of causing hereditary multiple exostoses, one in the Langer-Giedion region and one at another, unlinked location.


Assuntos
Exostose Múltipla Hereditária/genética , Linhagem Celular , DNA , Feminino , Frequência do Gene , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Linhagem , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico
14.
Cornea ; 11(4): 302-8, 1992 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1358551

RESUMO

Members in three generations of a family whose propositus had keratoconus were examined by biomicroscopy, with a corneoscope and a computer-assisted videophoto-keratoscope. Keratoconus was detected in eight of 15 family members with vertical transmission consistent with autosomal dominant inheritance. Affected individuals displayed variable topographic features. Abortive "nipple-type" cones were identified in some individuals in successive generations using the computer-assisted videophotokeratoscope and more advanced nipple-type cones detected on biomicroscopy of other family members. We selected a COL6A1 cDNA (the gene encoding the alpha 1 chain of type VI collagen) as a "candidate gene" to determine cosegregation with the disease locus. Linkage analysis excluded a gene locus for keratoconus on the most telomeric region of chromosome 21 in this family.


Assuntos
Ligação Genética , Ceratocone/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Cromossomos Humanos Par 21 , Colágeno/genética , DNA/análise , Sondas de DNA , Haplótipos , Humanos , Ceratocone/patologia , Pessoa de Meia-Idade , Biologia Molecular , Linhagem , Polimorfismo de Fragmento de Restrição
15.
J Clin Invest ; 89(5): 1674-80, 1992 May.
Artigo em Inglês | MEDLINE | ID: mdl-1569206

RESUMO

To examine the associations among fibrillin gene mutations, protein function, and Marfan syndrome phenotype, we screened for alterations in the fibrillin coding sequence in patients with a range of manifestations and clinical severity. A cysteine to serine substitution at codon 1409 (C1409S) was identified in an epidermal growth factor (EGF)-like motif from one fibrillin allele which segregates with the disease phenotype through three generations of a family affected with the Marfan syndrome. This alteration was not observed in 60 probands from other families or in 88 unrelated normal individuals. The altered cysteine is completely conserved in all EGF-like motifs identified in fibrillin, and in all proteins that contain this motif. These observations strongly indicate that C1409S is the disease-producing mutation in this family. The phenotype of individuals carrying C1409S varied widely with respect to onset of disease, organ-system involvement, and clinical severity; certain affected adults were unaware of their status before being diagnosed through this investigation. We conclude that fibrillin gene defects cause familial Marfan syndrome, that mutations in the EGF-like motif of the fibrillin gene are not uniformly associated with severe disease, and that fibrillin genotype is not the sole determinant of Marfan phenotype.


Assuntos
Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Sequência de Aminoácidos , Sequência de Bases , Sequência Consenso , DNA/genética , Fator de Crescimento Epidérmico/química , Fibrilinas , Humanos , Dados de Sequência Molecular , Mutação , Oligodesoxirribonucleotídeos/química , Linhagem , Alinhamento de Sequência
16.
Nature ; 352(6333): 337-9, 1991 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-1852208

RESUMO

Marfan syndrome is an inherited disorder of connective tissue manifested in the ocular, skeletal and cardiovascular systems. It is inherited as an autosomal dominant with high penetrance, but has great clinical variability. Linkage studies have mapped the Marfan locus to chromosome 15q15-21.3. There have been no reports of genetic heterogeneity in the syndrome. Following the identification of fibrillin (a glycoprotein component of the extracellular microfibril), immunohistopathological quantification of the protein in skin and fibroblast culture, and examination of fibrillin synthesis, extracellular transport, and incorporation into the extracellular matrix (D. M. Milewicz, R.E.P., E. S. Crawford and P. H. Byers, manuscript in preparation) have demonstrated abnormalities of fibrillin metabolism in most patients. A portion of the complementary DNA encoding fibrillin has been cloned and mapped by in situ hybridization to chromosome 15. Here we report that the fibrillin gene is linked to the Marfan phenotype (theta = 0.00; logarithm of the odds (lod) = 3.9) and describe a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. We thus implicate fibrillin as the protein defective in patients with the Marfan syndrome.


Assuntos
Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Adulto , Sequência de Aminoácidos , Sequência de Bases , Fibrilinas , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase
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