BACKGROUND: We studied a large family affected by an autosomal dominant cardiac conduction disorder associated with sinus node dysfunction, arrhythmia, and right and occasionally left ventricular dilatation and dysfunction. Previous linkage analysis mapped the disease phenotype to a 30-cM region on chromosome 3p22-p25 (CMD1E). This region also contains a locus for right ventricular cardiomyopathy (ARVD5) and the cardiac sodium channel gene (SCN5A), mutations that cause isolated progressive cardiac conduction defect (Lenegre syndrome), long-QT syndrome (LQT3), and Brugada syndrome. METHODS AND RESULTS: Family members were studied, and the positional candidate gene SCN5A was screened for mutations. We identified, by direct sequencing, a heterozygous G-to-A mutation at position 3823 that changed an aspartic acid to asparagine (D1275N) in a highly conserved residue of exon 21. This mutation was present in all affected family members, was absent in 300 control chromosomes, and predicted a change of charge within the S3 segment of domain III. CONCLUSIONS: Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction and support the hypothesis that genes encoding ion channels can be implicated in dilated cardiomyopathies.
BACKGROUND: We studied a large family affected by an autosomal dominant cardiac conduction disorder associated with sinus node dysfunction, arrhythmia, and right and occasionally left ventricular dilatation and dysfunction. Previous linkage analysis mapped the disease phenotype to a 30-cM region on chromosome 3p22-p25 (CMD1E). This region also contains a locus for right ventricular cardiomyopathy (ARVD5) and the cardiac sodium channel gene (SCN5A), mutations that cause isolated progressive cardiac conduction defect (Lenegre syndrome), long-QT syndrome (LQT3), and Brugada syndrome. METHODS AND RESULTS: Family members were studied, and the positional candidate gene SCN5A was screened for mutations. We identified, by direct sequencing, a heterozygous G-to-A mutation at position 3823 that changed an aspartic acid to asparagine (D1275N) in a highly conserved residue of exon 21. This mutation was present in all affected family members, was absent in 300 control chromosomes, and predicted a change of charge within the S3 segment of domain III. CONCLUSIONS: Our findings expand the clinical spectrum of disorders of the cardiac sodium channel to include cardiac dilation and dysfunction and support the hypothesis that genes encoding ion channels can be implicated in dilated cardiomyopathies.
Authors: Ryota Terada; Sonisha Warren; Jonathan T Lu; Kenneth R Chien; Andy Wessels; Hideko Kasahara Journal: Cardiovasc Res Date: 2011-02-01 Impact factor: 10.787
Authors: Honghuang Lin; Jessica van Setten; Albert V Smith; Nathan A Bihlmeyer; Helen R Warren; Jennifer A Brody; Farid Radmanesh; Leanne Hall; Niels Grarup; Martina Müller-Nurasyid; Thibaud Boutin; Niek Verweij; Henry J Lin; Ruifang Li-Gao; Marten E van den Berg; Jonathan Marten; Stefan Weiss; Bram P Prins; Jeffrey Haessler; Leo-Pekka Lyytikäinen; Hao Mei; Tamara B Harris; Lenore J Launer; Man Li; Alvaro Alonso; Elsayed Z Soliman; John M Connell; Paul L Huang; Lu-Chen Weng; Heather S Jameson; William Hucker; Alan Hanley; Nathan R Tucker; Yii-Der Ida Chen; Joshua C Bis; Kenneth M Rice; Colleen M Sitlani; Jan A Kors; Zhijun Xie; Chengping Wen; Jared W Magnani; Christopher P Nelson; Jørgen K Kanters; Moritz F Sinner; Konstantin Strauch; Annette Peters; Melanie Waldenberger; Thomas Meitinger; Jette Bork-Jensen; Oluf Pedersen; Allan Linneberg; Igor Rudan; Rudolf A de Boer; Peter van der Meer; Jie Yao; Xiuqing Guo; Kent D Taylor; Nona Sotoodehnia; Jerome I Rotter; Dennis O Mook-Kanamori; Stella Trompet; Fernando Rivadeneira; André Uitterlinden; Mark Eijgelsheim; Sandosh Padmanabhan; Blair H Smith; Henry Völzke; Stephan B Felix; Georg Homuth; Uwe Völker; Massimo Mangino; Timothy D Spector; Michiel L Bots; Marco Perez; Mika Kähönen; Olli T Raitakari; Vilmundur Gudnason; Dan E Arking; Patricia B Munroe; Bruce M Psaty; Cornelia M van Duijn; Emelia J Benjamin; Jonathan Rosand; Nilesh J Samani; Torben Hansen; Stefan Kääb; Ozren Polasek; Pim van der Harst; Susan R Heckbert; J Wouter Jukema; Bruno H Stricker; Caroline Hayward; Marcus Dörr; Yalda Jamshidi; Folkert W Asselbergs; Charles Kooperberg; Terho Lehtimäki; James G Wilson; Patrick T Ellinor; Steven A Lubitz; Aaron Isaacs Journal: Circ Genom Precis Med Date: 2018-05