Assuntos
Neoplasias Encefálicas/genética , Cistos do Sistema Nervoso Central/genética , Cromossomos Humanos Par 22/genética , Demência Vascular/genética , Triagem de Portadores Genéticos , Haplótipos/genética , Neoplasias Encefálicas/etnologia , Cistos do Sistema Nervoso Central/etnologia , Demência Vascular/etnologia , Humanos , Judeus/genética , MasculinoAssuntos
Calsequestrina/genética , Catecolaminas/fisiologia , Mutação de Sentido Incorreto , Taquicardia Ventricular/genética , Antagonistas Adrenérgicos beta/uso terapêutico , Sequência de Bases , Calsequestrina/química , Calsequestrina/fisiologia , Criança , Pré-Escolar , Cromossomos Humanos Par 1/genética , Sequência Conservada , DNA/genética , Eletrocardiografia , Etnicidade/genética , Feminino , Genes Recessivos , Ligação Genética , Humanos , Israel , Masculino , Modelos Moleculares , Polimorfismo Genético , Propranolol/uso terapêutico , Conformação Proteica , Taquicardia Ventricular/tratamento farmacológico , Taquicardia Ventricular/fisiopatologiaRESUMO
Catecholamine-induced polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress. Two modes of inheritance have been described: autosomal dominant and autosomal recessive. Mutations in the ryanodine receptor 2 gene (RYR2), which encodes a cardiac sarcoplasmic reticulum (SR) Ca(2+)-release channel, were recently shown to cause the autosomal dominant form of the disease. In the present report, we describe a missense mutation in a highly conserved region of the calsequestrin 2 gene (CASQ2) as the potential cause of the autosomal recessive form. The CASQ2 protein serves as the major Ca(2+) reservoir within the SR of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor. The mutation, which is in full segregation in seven Bedouin families affected by the disorder, converts a negatively charged aspartic acid into a positively charged histidine, in a highly negatively charged domain, and is likely to exert its deleterious effect by disrupting Ca(2+) binding.
Assuntos
Calsequestrina/genética , Catecolaminas/farmacologia , Sequência Conservada/genética , Etnicidade/genética , Genes Recessivos/genética , Mutação de Sentido Incorreto/genética , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/genética , Idade de Início , Sequência de Aminoácidos , Sequência de Bases , Calsequestrina/química , Criança , Análise Mutacional de DNA , Eletrocardiografia , Éxons/genética , Feminino , Humanos , Israel , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Conformação Proteica , Alinhamento de SequênciaRESUMO
BACKGROUND: Fourteen loci have been associated with autosomal dominant cataract, but only one with the recessive form of the disease. OBJECTIVES: To find the chromosomal location of a gene causing autosomal recessive cataract in three inbred Arab families. METHODS: A single nucleotide polymorphism-based genome-wide search, with the Effvmetrix GeneChip HuSNP genotyping array, was performed on a pooled DNA sample from six affected family members in a search for regions showing homozygosity. Using conventional microsatellite markers, regions of homozygosity were further analyzed in all the families. RESULTS: A region on chromosome 3p spanning 43 megabases showed homozygosity with 13 consecutive SNPs. Three microsatellite markers from this region yielded lod scores > 3.00. A maximal two-point lod of 4.83 was obtained with the marker D3S1298 at theta = 0.004. Haplotype analysis placed the disease gene in a 20 Mb interval between D3S1768 and D3S2409. CONCLUSIONS: A gene causing autosomal recessive cataract maps to the short arm of chromosome 3.
Assuntos
Catarata/genética , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 3/genética , Árabes/genética , Consanguinidade , Feminino , Ligação Genética , Genótipo , Haplótipos , Humanos , Masculino , Repetições de Microssatélites , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death in response to physiological or emotional stress. In 2 families with autosomal dominant inheritance, the disease gene was mapped to chromosome 1q42-43. The objectives of this study were to characterize the clinical features of the disease in a Bedouin tribe from Israel and to map the disease gene. METHODS AND RESULTS: In this Bedouin tribe, 9 children (age, 7+/-4 years) from 7 related families have died suddenly during the past decade, and 12 other children suffered from recurrent syncope and seizures starting at the age of 6+/-3 years. Parents of affected individuals were asymptomatic and were all related (first-, second-, or third-degree cousins). Segregation analysis suggested autosomal recessive inheritance. All 12 symptomatic patients and 1 asymptomatic sibling (mean age, 13+/-7 years) were found to have a relative resting bradycardia (64+/-13 bpm, versus 93+/-12 bpm in the unaffected siblings), as well as PVT induced by treadmill or isoproterenol infusion and appearing at a mean sinus rate of 110+/-10 bpm. Patients responded favorably to treatment with beta-blockers. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 16-megabase interval on chromosome 1p13-21. A maximal lod score of 8.24 was obtained with D1S189 at theta=0.00. Sequencing of KCND3, a gene that encodes an I(tO) potassium channel transporter, did not reveal any significant sequence alterations. CONCLUSIONS: This unique form of autosomal recessive PVT affects young children and may be lethal if left untreated. Linkage analysis maps this disorder to chromosome 1p13-21.
Assuntos
Árabes/genética , Catecolaminas/metabolismo , Cromossomos Humanos Par 1/genética , Esforço Físico , Taquicardia Ventricular/etnologia , Taquicardia Ventricular/fisiopatologia , Adolescente , Agonistas Adrenérgicos beta , Antagonistas Adrenérgicos beta/uso terapêutico , Bradicardia/diagnóstico , Bradicardia/epidemiologia , Criança , Mapeamento Cromossômico , Comorbidade , Consanguinidade , Morte Súbita Cardíaca/epidemiologia , Eletrocardiografia , Teste de Esforço , Genes Recessivos , Ligação Genética , Marcadores Genéticos , Humanos , Isoproterenol , Israel/epidemiologia , Escore Lod , Convulsões/epidemiologia , Síncope/epidemiologia , Taquicardia Ventricular/tratamento farmacológicoRESUMO
Idiopathic ventricular fibrillation in patients with an electrocardiogram (ECG) pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 (now frequently called Brugada syndrome) is associated with a high incidence of syncopal episodes or sudden death. The disease is inherited as an autosomal dominant trait. Mutations in SCN5A, a cardiac sodium channel gene, have been recently associated with Brugada syndrome. We have analyzed 7 patients from Israel affected with Brugada syndrome. The families of these patients are characterized by a small number of symptomatic members. Sequencing analysis of SCN5A revealed two novel mutations, G35S and R104Q, in two Brugada patients, and a possible R34C polymorphism in two unrelated controls. No mutations were detected in 5 other patients, suggesting genetic heterogeneity. Low penetrance is probably the cause for the small number of symptomatic members in the two families positive for the SCN5A mutations.