title: Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes.
abstract: BACKGROUND
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks.
  
  
  RESULTS
  All 312 titin exons known to be expressed in human cardiac titin and the complete 3' untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%).
  
  
  CONCLUSIONS
  Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.
authors.affiliation: Adult Medical Genetics Program and Division of Cardiology, University of Colorado Denver, Aurora, USA. Matthew.taylor@ucdenver.edu
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.forename: Sharon
authors.initials: S
authors.lastname: Graw
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Carl
authors.initials: C
authors.lastname: Barnes
authors.forename: Dobromir
authors.initials: D
authors.lastname: Slavov
authors.forename: Francesca
authors.initials: F
authors.lastname: Brun
authors.forename: Bruno
authors.initials: B
authors.lastname: Pinamonti
authors.forename: Ernesto E
authors.initials: EE
authors.lastname: Salcedo
authors.forename: William
authors.initials: W
authors.lastname: Sauer
authors.forename: Stylianos
authors.initials: S
authors.lastname: Pyxaras
authors.forename: Brian
authors.initials: B
authors.lastname: Anderson
authors.forename: Bernd
authors.initials: B
authors.lastname: Simon
authors.forename: Julius
authors.initials: J
authors.lastname: Bogomolovas
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D064211:Connectin; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D017354:Point Mutation; D011494:Protein Kinases / Q000235:genetics*; D013577:Syndrome
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases