Functional analysis reveals splicing mutations of the CASQ2 gene in patients with CPVT: implication for genetic counselling and clinical management

• Published in: Human mutation Vol. 32; no. 9; pp. 995 - 999
• Main Authors: Roux-Buisson, Nathalie, Rendu, John, Denjoy, Isabelle, Guicheney, Pascale, Goldenberg, Alice, David, Nadine, Faivre, Laurence, Barthez, Olivier, Danieli, Gian Antonio, Marty, Isabelle, Lunardi, Joel, Fauré, Julien
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-09-2011; Hindawi Limited; Wiley
• Subjects: Base Sequence; Calsequestrin - genetics; calsequestrin 2; Cardiology and cardiovascular system; CPVT; Family; Female; Genetic Counseling; Genetics; HEK293 Cells; Human genetics; Human health and pathology; Humans; Life Sciences; Male; minigene; Molecular Sequence Data; Mutation - genetics; Pedigree; Polymorphism, Single Nucleotide - genetics; RNA Splicing; synonymous variations; Tachycardia, Ventricular - genetics; Tachycardia, Ventricular - therapy; synonymous variations; CPVT; calsequestrin 2; minigene
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21537

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and severe arrhythmogenic disorder. Although usually transmitted in a recessive form, few cases of dominant mutations have been reported. Thirteen mutations in the CASQ2 gene have been reported so far in association with CPVT. We performed molecular analysis of the CASQ2 gene in 43 probands with CPVT and identified eight mutations in five patients. Six mutations were novel: one was a single nucleotide deletion, three affected consensus splice sites, and two had unknown consequences: the c.939 + 5G>C and the synonymous c.381C>T variations. We demonstrated that these two variations affected CASQ2 splicing using a splicing minigene assay. These data increased significantly the number of CASQ2 mutations described in association with CPVT, revealed the high prevalence of splicing and truncating mutations in this gene and brought new insight regarding the dominant inheritance of the disease. Moreover, our report of the first splicing abnormalities in CASQ2 caused by intronic mutation or synonymous change underlines the absolute necessity to perform extensive molecular analysis for genetic diagnosis and counseling of CPVT.Hum Mutat 32:1–5, 2011. © 2011 Wiley‐Liss, Inc.