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 characte rized by episodes of syncope, seizures, or sudden death, in response to phy sical activity or emotional stress. Two modes of inheritance have been desc ribed: autosomal dominant and autosomal recessive. Mutations in the ryanodi ne receptor 2 gene (RYR2), which encodes a cardiac sarcoplasmic reticulum ( SR) Ca2+-release channel, were recently shown to cause the autosomal domina nt form of the disease. In the present report, we describe a missense mutat ion 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 Ca2+ reservoir within the SR of cardiac myocytes and is part o f a protein complex that contains the ryanodine receptor. The mutation, whi ch is in full segregation in seven Bedouin families affected by the disorde r, converts a negatively charged aspartic acid into a positively charged hi stidine, in a highly negatively charged domain, and is likely to exert its deleterious effect by disrupting Ca2+ binding.