Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients With Dilated Cardiomyopathy

Circ Cardiovasc Genet. 2009 Aug;2(4):306-13. doi: 10.1161/CIRCGENETICS.108.846733. Epub 2009 May 15.

Abstract

Background: A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation.

Methods and results: We recently undertook bidirectional resequencing of TNNT2, the cardiac troponin T gene, in 313 probands with DCM. We identified 6 TNNT2 protein-altering variants in 9 probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the 9 probands had DCM without a family history, and 5 probands had familial DCM. Only 1 mutation (Lys210del) could be attributed as definitively causative from previous reports. Four of the 5 missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, and Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree, and molecular genetic data, these 5 mutations were considered possibly or likely disease causing. To further clarify their potential pathophysiologic impact, we undertook functional studies of these mutations in cardiac myocytes reconstituted with mutant troponin T proteins. We observed decreased Ca(2+) sensitivity of force development, a hallmark of DCM, in support of the conclusion that these mutations are disease causing.

Conclusions: We conclude that the combination of clinical, pedigree, molecular genetic, and functional data strengthen the interpretation of TNNT2 mutations in DCM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Substitution
  • Calcium / metabolism
  • Cardiomyopathy, Dilated / diagnosis
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Hypertrophic / genetics
  • Child
  • Child, Preschool
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Middle Aged
  • Mutation, Missense
  • Pedigree
  • Troponin T / genetics*

Substances

  • TNNT2 protein, human
  • Troponin T
  • Calcium