title: Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences.
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.
authors.affiliation: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, Sydney, NSW 2042, Australia.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Doolan
authors.forename: Molly
authors.initials: M
authors.lastname: Tebo
authors.forename: Jodie
authors.initials: J
authors.lastname: Ingles
authors.forename: Lan
authors.initials: L
authors.lastname: Nguyen
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tsoutsman
authors.forename: Lien
authors.initials: L
authors.lastname: Lam
authors.forename: Christine
authors.initials: C
authors.lastname: Chiu
authors.forename: Jessica
authors.initials: J
authors.lastname: Chung
authors.forename: Robert G
authors.initials: RG
authors.lastname: Weintraub
authors.forename: Christopher
authors.initials: C
authors.lastname: Semsarian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001315:Australia; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011485:Protein Binding; D016415:Sequence Alignment; D019209:Troponin C / Q000378:metabolism; D019210:Troponin I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019209:Troponin C; D019210:Troponin I