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

Am J Hum Genet. 2001 Dec;69(6):1378-84. doi: 10.1086/324565. Epub 2001 Oct 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Amino Acid Sequence
  • Base Sequence
  • Calsequestrin / chemistry
  • Calsequestrin / genetics*
  • Catecholamines / pharmacology*
  • Child
  • Conserved Sequence / genetics*
  • DNA Mutational Analysis
  • Electrocardiography
  • Ethnic Groups / genetics*
  • Exons / genetics
  • Female
  • Genes, Recessive / genetics*
  • Humans
  • Israel
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Pedigree
  • Protein Conformation
  • Sequence Alignment
  • Tachycardia, Ventricular / chemically induced*
  • Tachycardia, Ventricular / genetics*

Substances

  • CASQ2 protein, human
  • Calsequestrin
  • Catecholamines