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Functional analysis reveals splicing mutations of the CASQ2 gene in patients with CPVT: implication for genetic counselling and clinical management
Author(s) -
RouxBuisson Nathalie,
Rendu John,
Denjoy Isabelle,
Guicheney Pascale,
Goldenberg Alice,
David Nadine,
Faivre Laurence,
Barthez Olivier,
Danieli Gian Antonio,
Marty Isabelle,
Lunardi Joel,
Fauré Julien
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21537
Subject(s) - catecholaminergic polymorphic ventricular tachycardia , minigene , biology , genetics , rna splicing , mutation , intron , gene , penetrance , exon , alternative splicing , ryanodine receptor 2 , phenotype , rna , ryanodine receptor , intracellular
Abstract 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.