A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.

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.

A gene causing autosomal recessive cataract maps to the short arm of chromosome 3.

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.

Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia: clinical features and assignment of the disease gene to chromosome 1p13-21.

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.

Genetic analysis of Brugada syndrome in Israel: two novel mutations and possible genetic heterogeneity.

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.

A nonsense mutation (W9X) in CRYAA causes autosomal recessive cataract in an inbred Jewish Persian family.

PURPOSE: To identify the genetic defect causing autosomal recessive cataract in two inbred families. METHODS: Linkage analysis was performed with polymorphic markers close to 14 loci previously shown to be involved in autosomal dominant congenital cataract. In one of the families a gene segregating with the disease was analyzed by single-strand conformation polymorphism (SSCP) and eventually sequenced. RESULTS: Three polymorphic markers close to the CRYAA gene located on chromosome 21q segregated with the disease phenotype in one of the families, but not in the other. Sequencing of the CRYAA in this Jewish Persian family revealed a G-to-A substitution, resulting in the formation of a premature stop codon (W9X). CONCLUSIONS: A nonsense mutation in the CRYAA gene causes autosomal recessive cataract in one family. This constitutes the first description of the molecular defect underlying nonsyndromic autosomal recessive congenital cataract. That there was no linkage to this locus in another family provides evidence for genetic heterogeneity.