Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences

J Mol Cell Cardiol. 2005 Feb;38(2):387-93. doi: 10.1016/j.yjmcc.2004.12.006. Epub 2005 Jan 27.

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder caused by mutations in sarcomeric proteins. Cardiac troponin I (cTnI) is a key switch molecule in the sarcomere. Mutations in cTnI have been identified in <1% of genotyped HCM families.

Methods: To study the prevalence, clinical significance and functional consequences of cTnI mutations, genetic testing was performed in 120 consecutive Australian families with HCM referred to a tertiary referral centre, and results correlated with clinical phenotype. Each cTnI mutation identified was tested in a mammalian two-hybrid system to evaluate the functional effects of these mutations on troponin complex interactions.

Results: Disease-causing missense mutations were identified in four families (3.3%). Two mutations were located at the same codon in exon 7 (R162G, R162P), and two in exon 8 (L198P, R204H). All four mutations change amino acid residues which are highly conserved and were not found in normal populations. Follow-up family screening has identified a total of seven clinically affected members in these four families, with a further four members who carry the gene mutation but have no clinical evidence of disease. Age at clinical presentation was variable (range 15-68 years) and the mean septal wall thickness was 19.3 +/- 4.6 mm (range 7-33 mm) in clinically affected individuals, including children. In all four families, at least one member had a sudden cardiac death event, including previous cardiac arrest, indicating a more malignant form of HCM. All four mutations disrupted functional interactions with troponin C and T and this may account for the increased severity of disease in these families.

Conclusions: Gene mutations in cTnI occur in Australian families with HCM with a prevalence higher than previously reported and may be associated with a clinically more malignant course, reflecting significant disruptions to troponin complex interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • Australia
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / pathology
  • Cardiomyopathy, Hypertrophic / physiopathology*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pedigree
  • Polymorphism, Genetic / genetics
  • Protein Binding
  • Sequence Alignment
  • Troponin C / metabolism
  • Troponin I / chemistry
  • Troponin I / genetics*
  • Troponin I / metabolism*

Substances

  • Troponin C
  • Troponin I