title: Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy.
abstract: Dilated cardiomyopathy (DCM) is an etiologically heterogeneous cardiac disease characterized by left ventricular dilation and systolic dysfunction. Approximately 25-30% of DCM patients show a family history of mainly autosomal dominant inheritance. We and others have previously demonstrated that mutations in the giant muscle filament titin (TTN) can cause DCM. However, the prevalence of titin mutations in familial DCM is unknown. In this paper, we report a novel heterozygous 1-bp deletion mutation (c.62890delG) in TTN that cosegregates with DCM in a large Australian pedigree (A3). The TTN deletion mutation c.62890delG causes a frameshift, thereby generating a truncated A-band titin due to a premature stop codon (p.E20963KfsX10) and the addition of ten novel amino acid residues. The clinical phenotype of DCM in kindred A3 demonstrates incomplete penetrance and variable expressivity. Finally, protein analysis of a skeletal muscle biopsy sample from an affected member did not reveal the predicted truncated titin isoform although the aberrant mRNA was present, suggesting posttranslational modification and degradation of the truncated protein. The identification of a novel disease-causing mutation in the giant titin gene in a third large family with DCM indicates that mutations in titin may account for a significant portion of the genetic etiology in familial DCM.
authors.affiliation: Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13092, Berlin-Buch, Germany. b.gerull@mdc-berlin.de
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
authors.forename: John
authors.initials: J
authors.lastname: Atherton
authors.forename: Anke
authors.initials: A
authors.lastname: Geupel
authors.forename: Sabine
authors.initials: S
authors.lastname: Sasse-Klaassen
authors.forename: Arnd
authors.initials: A
authors.lastname: Heuser
authors.forename: Michael
authors.initials: M
authors.lastname: Frenneaux
authors.forename: Mark
authors.initials: M
authors.lastname: McNabb
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Ludwig
authors.initials: L
authors.lastname: Thierfelder
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D064211:Connectin; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism; D010375:Pedigree; D011489:Protein Denaturation; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D011499:Protein Processing, Post-Translational
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases