title: 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.
abstract: 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.
authors.affiliation: Danek Gartner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Lahat
authors.forename: E
authors.initials: E
authors.lastname: Pras
authors.forename: T
authors.initials: T
authors.lastname: Olender
authors.forename: N
authors.initials: N
authors.lastname: Avidan
authors.forename: E
authors.initials: E
authors.lastname: Ben-Asher
authors.forename: O
authors.initials: O
authors.lastname: Man
authors.forename: E
authors.initials: E
authors.lastname: Levy-Nissenbaum
authors.forename: A
authors.initials: A
authors.lastname: Khoury
authors.forename: A
authors.initials: A
authors.lastname: Lorber
authors.forename: B
authors.initials: B
authors.lastname: Goldman
authors.forename: D
authors.initials: D
authors.lastname: Lancet
authors.forename: M
authors.initials: M
authors.lastname: Eldar
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D001483:Base Sequence; D002155:Calsequestrin / Q000737:chemistry / Q000235:genetics*; D002395:Catecholamines / Q000494:pharmacology*; D002648:Child; D017124:Conserved Sequence / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005006:Ethnicity / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007557:Israel; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011487:Protein Conformation; D016415:Sequence Alignment; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000235:genetics*
chemical_list: C443109:CASQ2 protein, human; D002155:Calsequestrin; D002395:Catecholamines