Published online before print May 15, 2009, doi: 10.1161/CIRCGENETICS.108.846733
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Original Articles |
Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients With Dilated Cardiomyopathy
From the Division of Cardiovascular Medicine, Department of Medicine (R.E.H., D.L., J.C., A.M.) and the Department of Molecular and Cellular Pharmacology (J.R.P., M.S.P., J.D.P.), University of Miami Miller School of Medicine, Miami, Fla; and the Division of Cardiovascular Medicine (S.B.P., J.D.K., S.L.), Oregon Health & Science University, Portland, Ore.
Correspondence to Ray E. Hershberger, MD, Division of Cardiovascular Medicine, Clinical Research Building, C-205, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136. E-mail rhershberger{at}med.miami.edu
Received January 2, 2009; accepted April 20, 2009.
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 Ca2+ 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.
Key Words: dilated cardiomyopathy • genetics • troponin T
CLINICAL PERSPECTIVE
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.846733/DC1.