This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 108/4/445    most recent 01.CIR.0000080896.52003.DFv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Driest, S. L. Articles by Ackerman, M. J. Search for Related Content PubMed PubMed Citation Articles by Van Driest, S. L. Articles by Ackerman, M. J. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Clinical genetics Genomics Hypertrophy Myocardial cardiomyopathy disease Genetics of cardiovascular disease

(Circulation. 2003;108:445.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Prevalence and Spectrum of Thin Filament Mutations in an Outpatient Referral Population With Hypertrophic Cardiomyopathy

Sara L. Van Driest, BA; Erik G. Ellsworth, BS; Steve R. Ommen, MD; A. Jamil Tajik, MD; Bernard J. Gersh, MB, ChB, DPhil; Michael J. Ackerman, MD, PhD

From the Department of Molecular Pharmacology and Experimental Therapeutics (S.L.V.D., M.J.A.), Mayo Medical School (E.G.E.), Department of Internal Medicine/Division of Cardiovascular Diseases (S.R.O., A.J.T., B.J.G., M.J.A.), Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology (A.J.T., M.J.A.), Mayo Clinic, Rochester, Minn.

Correspondence to Michael J. Ackerman, MD, PhD, Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, Rochester, MN 55905. E-mail ackerman.michael{at}mayo.edu

Received February 26, 2003; revision received April 29, 2003; accepted May 5, 2003.

Background— Thin filament mutations are reported to cause 20% of cases of hypertrophic cardiomyopathy (HCM), and they have been associated with specific phenotypes. However, the frequency of these mutations and their associated phenotype(s) from a large tertiary referral center population are unknown.

Methods and Results— DNA was obtained from 389 unrelated patients with HCM. A mutational analysis of all protein coding exons of cardiac troponin T, cardiac troponin I, -tropomyosin, and cardiac actin was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. The clinical data were extracted from patient records and maintained independent of the patient genotype. Overall, only 18 patients (4.6%) harbored isolated thin filament mutations: 8 had troponin T mutations, 6 had troponin I mutations, 3 had -tropomyosin mutations, and 1 had an actin mutation. Of the 12 unique missense mutations identified, 9 (75%) were novel mutations. As a group, patients with thin filament mutations were not significantly different from the rest of the cohort in age at diagnosis, left ventricular wall thickness, left ventricular outflow tract obstruction, or family history of HCM or sudden cardiac death.

Conclusions— Mutations in genes encoding thin filament proteins are less prevalent in HCM than previously estimated. Patients with mutations in troponin T, troponin I, -tropomyosin, and actin do not invariably present with any distinct clinical feature, thus limiting the utility of gene status for risk stratification or of clinical phenotype in guiding individual genetic screening at this time.

Key Words: hypertrophy • cardiomyopathy • genetics • death, sudden

This article has been cited by other articles:

				J. R. Pinto, M. S. Parvatiyar, M. A. Jones, J. Liang, M. J. Ackerman, and J. D. Potter A Functional and Structural Study of Troponin C Mutations Related to Hypertrophic Cardiomyopathy J. Biol. Chem., July 10, 2009; 284(28): 19090 - 19100. [Abstract] [Full Text] [PDF]

				M. Penicka, P. Gregor, R. Kerekes, D. Marek, K. Curila, J. Krupicka, and for the Candesartan use in Hypertrophic And Non-ob The Effects of Candesartan on Left Ventricular Hypertrophy and Function in Nonobstructive Hypertrophic Cardiomyopathy: A Pilot, Randomized Study J. Mol. Diagn., January 1, 2009; 11(1): 35 - 41. [Abstract] [Full Text] [PDF]

				Y. Wen, J. R. Pinto, A. V. Gomes, Y. Xu, Y. Wang, Y. Wang, J. D. Potter, and W. G. L. Kerrick Functional Consequences of the Human Cardiac Troponin I Hypertrophic Cardiomyopathy Mutation R145G in Transgenic Mice J. Biol. Chem., July 18, 2008; 283(29): 20484 - 20494. [Abstract] [Full Text] [PDF]

				I. Olivotto, F. Girolami, M. J. Ackerman, S. Nistri, J. M. Bos, E. Zachara, S. R. Ommen, J. L. Theis, R. A. Vaubel, F. Re, et al. Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy Mayo Clin. Proc., June 1, 2008; 83(6): 630 - 638. [Abstract] [Full Text] [PDF]

				H. Matsson, J. Eason, C. S. Bookwalter, J. Klar, P. Gustavsson, J. Sunnegardh, H. Enell, A. Jonzon, M. Vikkula, I. Gutierrez, et al. Alpha-cardiac actin mutations produce atrial septal defects Hum. Mol. Genet., January 15, 2008; 17(2): 256 - 265. [Abstract] [Full Text] [PDF]

				M. Medin, M. Hermida-Prieto, L. Monserrat, R. Laredo, J. C. Rodriguez-Rey, X. Fernandez, and A. Castro-Beiras Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation Eur J Heart Fail, January 1, 2007; 9(1): 37 - 43. [Abstract] [Full Text] [PDF]

				S. G. Sirenko, J. D. Potter, and B. C. Knollmann Differential effect of troponin T mutations on the inotropic responsiveness of mouse hearts - role of myofilament Ca2+ sensitivity increase J. Physiol., August 15, 2006; 575(1): 201 - 213. [Abstract] [Full Text] [PDF]

				C. Y. Ho and C. E. Seidman A Contemporary Approach to Hypertrophic Cardiomyopathy Circulation, June 20, 2006; 113(24): e858 - e862. [Full Text] [PDF]

				C. S. Bookwalter and K. M. Trybus Functional Consequences of a Mutation in an Expressed Human {alpha}-Cardiac Actin at a Site Implicated in Familial Hypertrophic Cardiomyopathy J. Biol. Chem., June 16, 2006; 281(24): 16777 - 16784. [Abstract] [Full Text] [PDF]

				L. Song, S. R. DePalma, M. Kharlap, A. G. Zenovich, A. Cirino, R. Mitchell, B. McDonough, B. J. Maron, C. E. Seidman, J.G. Seidman, et al. Novel Locus for an Inherited Cardiomyopathy Maps to Chromosome 7 Circulation, May 9, 2006; 113(18): 2186 - 2192. [Abstract] [Full Text] [PDF]

				J. Binder, S. R. Ommen, B. J. Gersh, S. L. Van Driest, A. J. Tajik, R. A. Nishimura, and M. J. Ackerman Echocardiography-Guided Genetic Testing in Hypertrophic Cardiomyopathy: Septal Morphological Features Predict the Presence of Myofilament Mutations Mayo Clin. Proc., April 1, 2006; 81(4): 459 - 467. [Abstract] [Full Text] [PDF]

				J. H. Brown, Z. Zhou, L. Reshetnikova, H. Robinson, R. D. Yammani, L. S. Tobacman, and C. Cohen Structure of the mid-region of tropomyosin: Bending and binding sites for actin PNAS, December 27, 2005; 102(52): 18878 - 18883. [Abstract] [Full Text] [PDF]

				O. M. Hernandez, D. Szczesna-Cordary, B. C. Knollmann, T. Miller, M. Bell, J. Zhao, S. G. Sirenko, Z. Diaz, G. Guzman, Y. Xu, et al. F110I and R278C Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy Affect Muscle Contraction in Transgenic Mice and Reconstituted Human Cardiac Fibers J. Biol. Chem., November 4, 2005; 280(44): 37183 - 37194. [Abstract] [Full Text] [PDF]

				M. J. Perkins, S. L. Van Driest, E. G. Ellsworth, M. L. Will, B. J. Gersh, S. R. Ommen, and M. J. Ackerman Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy Eur. Heart J., November 2, 2005; 26(22): 2457 - 2462. [Abstract] [Full Text] [PDF]

				M. J. Ackerman, S. L. Van Driest, and M. Bos Are Longitudinal, Natural History Studies the Next Step in Genotype-Phenotype Translational Genomics in Hypertrophic Cardiomyopathy? J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1744 - 1746. [Full Text] [PDF]

				M. Arad, M. Penas-Lado, L. Monserrat, B. J. Maron, M. Sherrid, C. Y. Ho, S. Barr, A. Karim, T. M. Olson, M. Kamisago, et al. Gene Mutations in Apical Hypertrophic Cardiomyopathy Circulation, November 1, 2005; 112(18): 2805 - 2811. [Abstract] [Full Text] [PDF]

				J. Mogensen and W. J. McKenna Reply J. Am. Coll. Cardiol., July 5, 2005; 46(1): 181 - 181. [Full Text] [PDF]

				S. L. Van Driest, S. R. Ommen, A. J. Tajik, B. J. Gersh, and M. J. Ackerman Yield of Genetic Testing in Hypertrophic Cardiomyopathy Mayo Clin. Proc., June 1, 2005; 80(6): 739 - 744. [Abstract] [PDF]

				S. L. Van Driest, S. R. Ommen, A. J. Tajik, B. J. Gersh, and M. J. Ackerman Sarcomeric Genotyping in Hypertrophic Cardiomyopathy Mayo Clin. Proc., April 1, 2005; 80(4): 463 - 469. [Abstract] [PDF]

				J. Mogensen, R. T. Murphy, T. Kubo, A. Bahl, J. C. Moon, I. C. Klausen, P. M. Elliott, and W. J. McKenna Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2315 - 2325. [Abstract] [Full Text] [PDF]

				C. A. MacRae and P. T. Ellinor Genetic screening and risk assessment in hypertrophic cardiomyopathy J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2326 - 2328. [Full Text] [PDF]

				J. A. Towbin and R. J. Solaro Genetics of dilated cardiomyopathy: More genes that kill J. Am. Coll. Cardiol., November 16, 2004; 44(10): 2041 - 2043. [Full Text] [PDF]

				S. L. Van Driest, V. C. Vasile, S. R. Ommen, M. L. Will, A. J. Tajik, B. J. Gersh, and M. J. Ackerman Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1903 - 1910. [Abstract] [Full Text] [PDF]

				S. L. Van Driest, M. A. Jaeger, S. R. Ommen, M. L. Will, B. J. Gersh, A. J. Tajik, and M. J. Ackerman Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy J. Am. Coll. Cardiol., August 4, 2004; 44(3): 602 - 610. [Abstract] [Full Text] [PDF]