Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

Andrew P. Landstrom, Michelle S. Parvatiyar, Jose R. Pinto, Michelle L. Marquardt, J. Martijn Bos, David J. Tester, Steve R. Ommen, James D. Potter, Michael J. Ackerman

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

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 Ca2+-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 Ca2+ 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.

Original languageEnglish
Pages (from-to)281-288
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume45
Issue number2
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

Fingerprint

Troponin C
Hypertrophic Cardiomyopathy
Mutation
Genes
Tropomyosin
Troponin T
Troponin
Troponin I
Missense Mutation
Sudden Death
Athletes
Open Reading Frames
Heart Ventricles
Actins
Cause of Death

Keywords

  • Calcium
  • Genetics
  • HCM
  • Hypertrophic cardiomyopathy
  • Mutation
  • TnC
  • Troponin C

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. / Landstrom, Andrew P.; Parvatiyar, Michelle S.; Pinto, Jose R.; Marquardt, Michelle L.; Bos, J. Martijn; Tester, David J.; Ommen, Steve R.; Potter, James D.; Ackerman, Michael J.

In: Journal of Molecular and Cellular Cardiology, Vol. 45, No. 2, 01.08.2008, p. 281-288.

Research output: Contribution to journalArticle

Landstrom, AP, 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', Journal of Molecular and Cellular Cardiology, vol. 45, no. 2, pp. 281-288. https://doi.org/10.1016/j.yjmcc.2008.05.003
Landstrom, Andrew P. ; Parvatiyar, Michelle S. ; Pinto, Jose R. ; Marquardt, Michelle L. ; Bos, J. Martijn ; Tester, David J. ; Ommen, Steve R. ; Potter, James D. ; Ackerman, Michael J. / Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. In: Journal of Molecular and Cellular Cardiology. 2008 ; Vol. 45, No. 2. pp. 281-288.
@article{b672662aa68a49b6b9dc9dc8fdca78ec,
title = "Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C",
abstract = "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 Ca2+-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 Ca2+ 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.",
keywords = "Calcium, Genetics, HCM, Hypertrophic cardiomyopathy, Mutation, TnC, Troponin C",
author = "Landstrom, {Andrew P.} and Parvatiyar, {Michelle S.} and Pinto, {Jose R.} and Marquardt, {Michelle L.} and Bos, {J. Martijn} and Tester, {David J.} and Ommen, {Steve R.} and Potter, {James D.} and Ackerman, {Michael J.}",
year = "2008",
month = "8",
day = "1",
doi = "10.1016/j.yjmcc.2008.05.003",
language = "English",
volume = "45",
pages = "281--288",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C

AU - Landstrom, Andrew P.

AU - Parvatiyar, Michelle S.

AU - Pinto, Jose R.

AU - Marquardt, Michelle L.

AU - Bos, J. Martijn

AU - Tester, David J.

AU - Ommen, Steve R.

AU - Potter, James D.

AU - Ackerman, Michael J.

PY - 2008/8/1

Y1 - 2008/8/1

N2 - 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 Ca2+-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 Ca2+ 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.

AB - 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 Ca2+-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 Ca2+ 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.

KW - Calcium

KW - Genetics

KW - HCM

KW - Hypertrophic cardiomyopathy

KW - Mutation

KW - TnC

KW - Troponin C

UR - http://www.scopus.com/inward/record.url?scp=48849100715&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=48849100715&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2008.05.003

DO - 10.1016/j.yjmcc.2008.05.003

M3 - Article

C2 - 18572189

AN - SCOPUS:48849100715

VL - 45

SP - 281

EP - 288

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 2

ER -