title: Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy.
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.
  
  
  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.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA. rhershberger@med.miami.edu
authors.forename: Ray E
authors.initials: RE
authors.lastname: Hershberger
authors.forename: Jose Renato
authors.initials: JR
authors.lastname: Pinto
authors.forename: Sharie B
authors.initials: SB
authors.lastname: Parks
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Kushner
authors.forename: Duanxiang
authors.initials: D
authors.lastname: Li
authors.forename: Susan
authors.initials: S
authors.lastname: Ludwigsen
authors.forename: Jason
authors.initials: J
authors.lastname: Cowan
authors.forename: Ana
authors.initials: A
authors.lastname: Morales
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Parvatiyar
authors.forename: James D
authors.initials: JD
authors.lastname: Potter
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D020107:Troponin T / Q000235:genetics*
chemical_list: C545568:TNNT2 protein, human; D020107:Troponin T; D002118:Calcium