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A novel titin mutation in adult-onset familial dilated cardiomyopathy

Item Type:Article
Title:A novel titin mutation in adult-onset familial dilated cardiomyopathy
Creators Name:Yoskovitz, G. and Peled, Y. and Gramlich, M. and Lahat, H. and Resnik-Wolf, H. and Feinberg, M.S. and Afek, A. and Pras, E. and Arad, M. and Gerull, B. and Freimark, D.
Abstract:Familial dilated cardiomyopathy is a major cause of advanced heart failure and heart transplantation. In most families, the disease-causing mutation is unknown, and relatives should therefore undergo periodic screening to facilitate early diagnosis and therapy. In the present study, we describe a novel titin truncation mutation causing adult-onset familial dilated cardiomyopathy in an Israeli Arab family. The family members underwent physical examination, electrocardiography, and Doppler echocardiography. Linkage to candidate loci was performed, followed by gene sequencing. We identified 13 clinically affected family members (8 men and 5 women, mean age 47 ± 12 years). Compared with their healthy first-degree relatives, the affected relatives had a larger end-diastolic left ventricular dimension (60 ± 10 vs 49 ± 4 mm, p <0.001), lower ejection fraction (43 ± 11% vs 60 ± 6%, p <0.001), and markedly higher end-systolic volume indexes but no difference in wall thickness or diastolic function. The linkage studies or direct sequencing excluded LMNA, MYH7, TNNT2, TNNI3, SCN5A, DES, SGCD, ACTC, PLN, and MYH6 but established linkage to the TTN locus at chromosome 2q31, yielding a maximum (2-point) LOD score of 3.44. Sequence analysis identified an insertion (c.58880insA), causing protein truncation after 19,628 amino acids (p.S19628IfsX1). No founder effect was found among the Israeli Arabs. In conclusion, titin is a giant protein with a key role in sarcomere assembly, force transmission, and maintenance of resting tension. Although some mutations result in skeletal myopathy, others cause isolated, maturity-onset cardiomyopathy.
Keywords:Arabs, Dilated Cardiomyopathy, Frameshift Mutation, Genetic Linkage, Haplotypes, Israel, Muscle Proteins, Pair 2 Human Chromosomes, Pedigree, Protein Kinases
Source:American Journal of Cardiology
Page Range:1644-1650
Date:1 June 2012
Official Publication:https://doi.org/10.1016/j.amjcard.2012.01.392
PubMed:View item in PubMed

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