title: Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  This study was initiated to identify the disease-causing genetic defect in a family with hypertrophic cardiomyopathy (HCM) and high incidence of sudden death.
  
  
  BACKGROUND
  Familial hypertropic cardiomyopathy (FHC) is an autosomal dominant transmitted disorder that is genetically and clinically heterogeneous. Mutations in 11 genes have been associated with the pathogenesis of the disease.
  
  
  METHODS
  We studied a large FHC family, first by linkage analysis, to identify the gene involved, and subsequently screened the gene, encoding alpha-tropomyosin (TPM1), for mutations by using single-strand conformation polymorphism and sequencing analysis.
  
  
  RESULTS
  Twelve family members presented clinical features of HCM, five of whom died at young age, while others had only mild clinical features. Marker analysis showed linkage for the TPM1 gene on chromosome 15q22 (maximal logarithm of the odds score is 5.16, theta = 0); subsequently, a novel missense mutation (Glu62Gln) was identified.
  
  
  CONCLUSIONS
  The novel mutation identified in TPM1 is associated with the clinical features of cardiac hypertrophy in all but one genetically affected member of this large family. The clinical data suggest a malignant phenotype at young age with a variable clinical manifestation and penetrance at older age. The Glu62Gln mutation is the sixth TPM1 mutation identified as the cause of FHC, indicating that mutations in this gene are very rare. This is the first reported amino acid substitution at the f-position within the coiled-coil structure of the tropomyosin protein.
authors.affiliation: Department of Genetics and Cell Biology, University of Maastricht, Joseph Bechlaan 113, 6229 GR Maastricht, the Netherlands. roselie.jongbloed@gen.unimaas.nl
authors.forename: Roselie J
authors.initials: RJ
authors.lastname: Jongbloed
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Marcelis
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Judith M
authors.initials: JM
authors.lastname: Schmeitz-Mulkens
authors.forename: Willem G
authors.initials: WG
authors.lastname: Van Dockum
authors.forename: Joep P
authors.initials: JP
authors.lastname: Geraedts
authors.forename: Hubert J
authors.initials: HJ
authors.lastname: Smeets
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D002648:Child; D002874:Chromosome Mapping; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D017421:Sequence Analysis; D014335:Tropomyosin / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; C490775:TPM1 protein, human; C097163:Tm2 protein, Drosophila; D014335:Tropomyosin