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Titin mutation in familial restrictive cardiomyopathy

Item Type:Article
Title:Titin mutation in familial restrictive cardiomyopathy
Creators Name:Peled, Y. and Gramlich, M. and Yoskovitz, G. and Feinberg, M.S. and Afek, A. and Polak-Charcon, S. and Pras, E. and Sela, B.A. and Konen, E. and Weissbrod, O. and Geiger, D. and Gordon, P.M.K. and Thierfelder, L. and Freimark, D. and Gerull, B. and Arad, M.
Abstract:BACKGROUND: Familial restrictive cardiomyopathy (RCM) caused by a single gene mutation is the least common of the inherited cardiomyopathies. Only a few RCM-causing mutations have been described. Most mutations causing RCM are located in sarcomere protein genes which also cause hypertrophic cardiomyopathy (HCM). Other genes associated with RCM include the desmin and familial amyloidosis genes. In the present study we describe familial RCM with severe heart failure triggered by a de novo mutation in TTN, encoding the huge muscle filament protein titin. METHODS AND RESULTS: Family members underwent physical examination, ECG and Doppler echocardiogram studies. The family comprised 6 affected individuals aged 12-35years. Linkage to candidate loci was performed, followed by gene sequencing. Candidate loci/gene analysis excluded 18 candidate genes but showed segregation with a common haplotype surrounding the TTN locus. Sequence analysis identified a de novo mutation within exon 266 of the TTN gene, resulting in the replacement of tyrosine by cysteine. p.Y7621C affects a highly conserved region in the protein within a fibronectin-3 domain, belonging to the A/I junction region of titin. No other disease-causing mutation was identified in cardiomyopathy genes by whole exome sequencing. CONCLUSIONS: Our study shows, for the first time, that mutations in TTN can cause restrictive cardiomyopathy. The giant filament titin is considered to be a determinant of a resting tension of the sarcomere and this report provides genetic evidence of its crucial role in diastolic function.
Keywords:Restrictive Cardiomyopathy, Heart Failure, Titin, Autosomal Dominant, Diastolic
Source:International Journal of Cardiology
Page Range:24-30
Date:15 January 2014
Official Publication:https://doi.org/10.1016/j.ijcard.2013.11.037
PubMed:View item in PubMed

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