You are here

Molecular and Functional Characterization of Novel Hypertrophic Cardiomyopathy Susceptibility Mutations in TNNC1-encoded Troponin C

Title: Molecular and Functional Characterization of Novel Hypertrophic Cardiomyopathy Susceptibility Mutations in TNNC1-encoded Troponin C.
175 views
63 downloads
Name(s): Landstrom, Andrew, author
Parvatiyar, Michelle, author
Pinto, Jose, author
Marquardt, Michelle, author
Bos, J., author
Tester, David, author
Ommen, Steve, author
Potter, James, author
Ackerman, Michael, author
Type of Resource: text
Genre: Text
Issuance: serial
Date Issued: 2008
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to this report, cTnC had not been classified as a HCM-susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients enrolled over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric-HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. This study may help to further define TNNC1 as an HCM-susceptibility gene, a classification that has already been established for the other members of the troponin complex.
Identifier: FSU_migr_biomed_faculty_publications-0058 (IID), 10.1016/j.yjmcc.2008.05.003 (DOI)
Keywords: amino acid sequence, amino acid substitution, cardiomyopathy, hypertrophic, cells, cultured, cohort studies, genetic predisposition to disease, molecular sequence data, mutation, missense, Troponin C
Uncontrolled subjects: Adolescent, Adult, Amino Acid Sequence, Amino Acid Substitution, Animals, Cardiomyopathy, Hypertrophic, Cells, Cultured, Cohort Studies, Female, Genetic Predisposition to Disease, Humans, Male, Mice, Middle Aged, Molecular Sequence Data, Mutation, Missense, Rats, Swine, Troponin C
Note: Originally published in Journal'>http://www.sciencedirect.com/science/article/pii/S0022282808004173">Journal of Molecular and Cellular Cardiology.
Citation: Landstrom AP1, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, & Ackerman MJ. (2008). Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol, 45(2):281-8. doi: 10.1016/j.yjmcc.2008.05.003.
Subject(s): Amino acids
Peptides
Proteins
Cardiovascular system -- Diseases
Cells
Genetics
Investigations
Macromolecules
Medical sciences
Pathology
Symptoms
Links: http://dx.doi.org/10.1016/j.yjmcc.2008.05.003
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_migr_biomed_faculty_publications-0058
Owner Institution: FSU
Is Part of Series: Department of Biomedical Sciences Faculty Publications.
Is Part Of: Journal of Molecular and Cellular Cardiology.
Issue: 2, 45

Choose the citation style.
Landstrom, A., Parvatiyar, M., Pinto, J., Marquardt, M., Bos, J., Tester, D., … Ackerman, M. (2008). Molecular and Functional Characterization of Novel Hypertrophic Cardiomyopathy Susceptibility Mutations in TNNC1-encoded Troponin C. Journal Of Molecular And Cellular Cardiology. Retrieved from http://dx.doi.org/10.1016/j.yjmcc.2008.05.003