Format

Send to

Choose Destination
Int J Cardiol. 2014 Jan 15;171(1):24-30. doi: 10.1016/j.ijcard.2013.11.037. Epub 2013 Nov 25.

Titin mutation in familial restrictive cardiomyopathy.

Author information

1
Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel.
2
Max Delbrueck Center for Molecular Medicine, Berlin, Germany; Department of Cardiology, University of Tuebingen, Germany.
3
Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel; Gertner Institute of Medical Genetics, Tel Aviv University, Tel Aviv, Israel.
4
Department of Pathology, Tel Aviv University, Tel Aviv, Israel.
5
Gertner Institute of Medical Genetics, Tel Aviv University, Tel Aviv, Israel.
6
Institute of Chemical Pathology, Tel Aviv University, Tel Aviv, Israel.
7
Department of Diagnostic Imaging, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
8
Computer Science Department, The Technion, Haifa, Israel.
9
Alberta Children's Hospital Research Institute Genomics and Bioinformatics Facility, University of Calgary, Calgary, Canada.
10
Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
11
Max Delbrueck Center for Molecular Medicine, Berlin, Germany; Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
12
Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel. Electronic address: michael.arad@sheba.health.gov.il.

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 12-35 years. 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:

Autosomal dominant; Diastolic; Heart failure; Restrictive cardiomyopathy; Titin

PMID:
24315344
DOI:
10.1016/j.ijcard.2013.11.037
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center