OBJECTIVES: The goal of this study was to investigate the genotype-to-phenotype relationship between SCN5A gene mutation and progressive cardiac conduction defect in order to gain insights into the pathophysiologic mechanisms of the disease. BACKGROUND: Progressive cardiac conduction defect is a frequent disease commonly attributed to degeneration and fibrosis of the His bundle and its branches. In a French family, we have identified a splicing mutation in the SCN5A gene leading to hereditary progressive cardiac conduction defect. METHODS: We have extended the size of the pedigree and phenotyped and genotyped all family members, and also investigated in vitro the functional consequences of the mutation. RESULTS: Among 65 potentially affected members, 25 individuals were carriers of the IVS.22+2 T-->C SCN5A mutation. In relation to aging, gene carriers exhibit various types of conduction defects. P-wave, PR, and QRS duration increased progressively with age in gene carriers and in noncarriers. Whatever the age, conduction parameters were longer in gene carriers. The widening in the QRS complex with aging was more pronounced in gene carriers older than 40 years. Functional studies show that the IVS.22+2 T-->C SCN5A mutation lead to exon 22 skipping and to a complete loss of function of the affected allele, but to a normal trafficking of the mutated gene product. CONCLUSIONS: Our findings demonstrate that hereditary Lenègre disease is caused by a haploinsufficiency mechanism, which in combination with aging leads to progressive alteration in conduction velocity.
OBJECTIVES: The goal of this study was to investigate the genotype-to-phenotype relationship between SCN5A gene mutation and progressive cardiac conduction defect in order to gain insights into the pathophysiologic mechanisms of the disease. BACKGROUND: Progressive cardiac conduction defect is a frequent disease commonly attributed to degeneration and fibrosis of the His bundle and its branches. In a French family, we have identified a splicing mutation in the SCN5A gene leading to hereditary progressive cardiac conduction defect. METHODS: We have extended the size of the pedigree and phenotyped and genotyped all family members, and also investigated in vitro the functional consequences of the mutation. RESULTS: Among 65 potentially affected members, 25 individuals were carriers of the IVS.22+2 T-->C SCN5A mutation. In relation to aging, gene carriers exhibit various types of conduction defects. P-wave, PR, and QRS duration increased progressively with age in gene carriers and in noncarriers. Whatever the age, conduction parameters were longer in gene carriers. The widening in the QRS complex with aging was more pronounced in gene carriers older than 40 years. Functional studies show that the IVS.22+2 T-->C SCN5A mutation lead to exon 22 skipping and to a complete loss of function of the affected allele, but to a normal trafficking of the mutated gene product. CONCLUSIONS: Our findings demonstrate that hereditary Lenègre disease is caused by a haploinsufficiency mechanism, which in combination with aging leads to progressive alteration in conduction velocity.
Authors: Ajit Vikram; Christopher M Lewarchik; Jin-Young Yoon; Asma Naqvi; Santosh Kumar; Gina M Morgan; Julia S Jacobs; Qiuxia Li; Young-Rae Kim; Modar Kassan; Jing Liu; Mohanad Gabani; Ajay Kumar; Haider Mehdi; Xiaodong Zhu; Xiaoqun Guan; William Kutschke; Xiaoming Zhang; Ryan L Boudreau; Shengchuan Dai; Daniel S Matasic; Saet-Byel Jung; Kenneth B Margulies; Vikas Kumar; Markus M Bachschmid; Barry London; Kaikobad Irani Journal: Nat Med Date: 2017-02-13 Impact factor: 53.440
Authors: Beatriz Ortiz-Bonnin; Susanne Rinné; Robin Moss; Anne K Streit; Michael Scharf; Katrin Richter; Anika Stöber; Arne Pfeufer; Gunnar Seemann; Stefan Kääb; Britt-Maria Beckmann; Niels Decher Journal: Pflugers Arch Date: 2016-06-11 Impact factor: 3.657
Authors: Anne-Laure Leoni; Bruno Gavillet; Jean-Sébastien Rougier; Céline Marionneau; Vincent Probst; Solena Le Scouarnec; Jean-Jacques Schott; Sophie Demolombe; Patrick Bruneval; Christopher L H Huang; William H Colledge; Andrew A Grace; Hervé Le Marec; Arthur A Wilde; Peter J Mohler; Denis Escande; Hugues Abriel; Flavien Charpentier Journal: PLoS One Date: 2010-02-19 Impact factor: 3.240