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A Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias.
MedLine Citation:
PMID:  25210054     Owner:  NLM     Status:  Publisher    
BACKGROUND: -Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multi-generational family.
METHODS AND RESULTS: -A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole-exome sequencing and further functionally evaluated by patch-clamp studies using HEK293 cells. Of 37 living family-members, a total of 13 individuals demonstrated 50 or more multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in one individual during follow-up. Exome-sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Nav1.5 sodium channel protein that co-segregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, while action potential simulations suggested that it lowered the excitability threshold of cardiac cells.
CONCLUSIONS: -Gain-of-function of Nav1.5 may cause familial forms of exercise-induced polymorphic ventricular arrhythmias.
Heikki Swan; Mohamed Yassine Amarouch; Jaakko Leinonen; Annukka Marjamaa; Jan P Kucera; Päivi J Laitinen-Forsblom; Annukka M Lahtinen; Aarno Palotie; Kimmo Kontula; Lauri Toivonen; Hugues Abriel; Elisabeth Widen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-9-10
Journal Detail:
Title:  Circulation. Cardiovascular genetics     Volume:  -     ISSN:  1942-3268     ISO Abbreviation:  Circ Cardiovasc Genet     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101489144     Medline TA:  Circ Cardiovasc Genet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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