title: A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is characterized by idiopathic dilatation and systolic contractile dysfunction of the ventricle(s) leading to an impaired systolic function. The origin of DCM is heterogeneous, but genetic transmission of the disease accounts for up to 50% of the cases. Mutations in alpha-tropomyosin (TPM1), a thin filament protein involved in structural and regulatory roles in muscle cells, are associated with hypertrophic cardiomyopathy (HCM) and very rarely with DCM.
  
  
  RESULTS
  Here we present a large four-generation family in which DCM is inherited as an autosomal dominant trait. Six family members have a cardiomyopathy with the age of diagnosis ranging from 5 months to 52 years. The youngest affected was diagnosed with dilated and non-compaction cardiomyopathy (NCCM) and died at the age of five. Three additional children died young of suspected heart problems. We mapped the phenotype to chromosome 15 and subsequently identified a missense mutation in TPM1, resulting in a p.D84N amino acid substitution. In addition we sequenced 23 HCM/DCM genes using next generation sequencing. The TPM1 p.D84N was the only mutation identified. The mutation co-segregates with all clinically affected family members and significantly weakens the binding of tropomyosin to actin by 25%.
  
  
  CONCLUSIONS
  We show that a mutation in TPM1 is associated with DCM and a lethal, early onset form of NCCM, probably as a result of diminished actin binding caused by weakened charge-charge interactions. Consequently, the screening of TPM1 in patients and families with DCM and/or (severe, early onset forms of) NCCM is warranted. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.
authors.affiliation: Department of Anatomy, Embryology & Physiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Judith B A
authors.initials: JB
authors.lastname: van de Meerakker
authors.forename: Imke
authors.initials: I
authors.lastname: Christiaans
authors.forename: Phil
authors.initials: P
authors.lastname: Barnett
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Lekanne Deprez
authors.forename: Aho
authors.initials: A
authors.lastname: Ilgun
authors.forename: Olaf R F
authors.initials: OR
authors.lastname: Mook
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Jan
authors.initials: J
authors.lastname: Lam
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Antoon F M
authors.initials: AF
authors.lastname: Moorman
authors.forename: Alex V
authors.initials: AV
authors.lastname: Postma
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; C490775:TPM1 protein, human; D014335:Tropomyosin