title: Titin mutation in familial restrictive cardiomyopathy.
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.
  
  
  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.
authors: Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel.
authors: Yael
authors: Y
authors: Peled
authors: Max Delbrueck Center for Molecular Medicine, Berlin, Germany; Department of Cardiology, University of Tuebingen, Germany.
authors: Michael
authors: M
authors: Gramlich
authors: Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel; Gertner Institute of Medical Genetics, Tel Aviv University, Tel Aviv, Israel.
authors: Guy
authors: G
authors: Yoskovitz
authors: Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel.
authors: Micha S
authors: MS
authors: Feinberg
authors: Department of Pathology, Tel Aviv University, Tel Aviv, Israel.
authors: Arnon
authors: A
authors: Afek
authors: Department of Pathology, Tel Aviv University, Tel Aviv, Israel.
authors: Sylvie
authors: S
authors: Polak-Charcon
authors: Gertner Institute of Medical Genetics, Tel Aviv University, Tel Aviv, Israel.
authors: Elon
authors: E
authors: Pras
authors: Institute of Chemical Pathology, Tel Aviv University, Tel Aviv, Israel.
authors: Ben-Ami
authors: BA
authors: Sela
authors: Department of Diagnostic Imaging, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Eli
authors: E
authors: Konen
authors: Computer Science Department, The Technion, Haifa, Israel.
authors: Omer
authors: O
authors: Weissbrod
authors: Computer Science Department, The Technion, Haifa, Israel.
authors: Dan
authors: D
authors: Geiger
authors: Alberta Children's Hospital Research Institute Genomics and Bioinformatics Facility, University of Calgary, Calgary, Canada.
authors: Paul M K
authors: PM
authors: Gordon
authors: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors: Ludwig
authors: L
authors: Thierfelder
authors: Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel.
authors: Dov
authors: D
authors: Freimark
authors: Max Delbrueck Center for Molecular Medicine, Berlin, Germany; Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada.
authors: Brenda
authors: B
authors: Gerull
authors: Heart Failure Service and Heart Institute, Tel Aviv University, Tel Aviv, Israel. Electronic address: michael.arad@sheba.health.gov.il.
authors: Michael
authors: M
authors: Arad
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002313:Cardiomyopathy, Restrictive / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D064211:Connectin / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017433:Protein Structure, Secondary; D055815:Young Adult
chemical_list: D064211:Connectin; C577285:TTN protein, human
keywords: Autosomal dominant; Diastolic; Heart failure; Restrictive cardiomyopathy; Titin