Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform

Gayathri Venkatraman, Aldrin V. Gomes, W. Glenn Kerrick, James D. Potter

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and ΔK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI-troponin C (TnC) or ssTnI-TnC significantly increased Ca2+ sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and ΔK210), when reconstituted with either cardiac TnI-TnC or SsTnI·TnC, significantly decreased Ca2+ sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca2+ sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The ΔK210 mutation caused a greater decrease in Ca2+ sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI·TnC or ssTnI-TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca2+ sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.

Original languageEnglish
Pages (from-to)17584-17592
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number18
DOIs
StatePublished - May 6 2005

Fingerprint

Troponin T
Troponin
Dilated Cardiomyopathy
Protein Isoforms
Troponin C
Mutation
Troponin I
Fibers
Myosins
Fetal Heart
Cardiomyopathies
Swine
Phenotype

ASJC Scopus subject areas

  • Biochemistry

Cite this

Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform. / Venkatraman, Gayathri; Gomes, Aldrin V.; Kerrick, W. Glenn; Potter, James D.

In: Journal of Biological Chemistry, Vol. 280, No. 18, 06.05.2005, p. 17584-17592.

Research output: Contribution to journalArticle

Venkatraman, Gayathri ; Gomes, Aldrin V. ; Kerrick, W. Glenn ; Potter, James D. / Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 18. pp. 17584-17592.
@article{0724231b77e34e7580c7bbf7ca88ccf8,
title = "Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform",
abstract = "The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and ΔK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI-troponin C (TnC) or ssTnI-TnC significantly increased Ca2+ sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and ΔK210), when reconstituted with either cardiac TnI-TnC or SsTnI·TnC, significantly decreased Ca2+ sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca2+ sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The ΔK210 mutation caused a greater decrease in Ca2+ sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI·TnC or ssTnI-TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca2+ sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.",
author = "Gayathri Venkatraman and Gomes, {Aldrin V.} and Kerrick, {W. Glenn} and Potter, {James D.}",
year = "2005",
month = "5",
day = "6",
doi = "10.1074/jbc.M409337200",
language = "English",
volume = "280",
pages = "17584--17592",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "18",

}

TY - JOUR

T1 - Characterization of troponin T dilated cardiomyopathy mutations in the fetal troponin isoform

AU - Venkatraman, Gayathri

AU - Gomes, Aldrin V.

AU - Kerrick, W. Glenn

AU - Potter, James D.

PY - 2005/5/6

Y1 - 2005/5/6

N2 - The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and ΔK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI-troponin C (TnC) or ssTnI-TnC significantly increased Ca2+ sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and ΔK210), when reconstituted with either cardiac TnI-TnC or SsTnI·TnC, significantly decreased Ca2+ sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca2+ sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The ΔK210 mutation caused a greater decrease in Ca2+ sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI·TnC or ssTnI-TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca2+ sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.

AB - The major goal of this study was to elucidate how troponin T (TnT) dilated cardiomyopathy (DCM) mutations in fetal TnT and fetal troponin affect the functional properties of the fetal heart that lead to infantile cardiomyopathy. The DCM mutations R141W and ΔK210 were created in the TnT1 isoform, the primary isoform of cardiac TnT in the embryonic heart. In addition to a different TnT isoform, a different troponin I (TnI) isoform, slow skeletal TnI (ssTnI), is the dominant isoform in the embryonic heart. In skinned fiber studies, TnT1-wild-type (WT)-treated fibers reconstituted with cardiac TnI-troponin C (TnC) or ssTnI-TnC significantly increased Ca2+ sensitivity of force development when compared with TnT3-WT-treated fibers at both pH 7.0 and pH 6.5. Porcine cardiac fibers treated with TnT1 that contained the DCM mutations (R141W and ΔK210), when reconstituted with either cardiac TnI-TnC or SsTnI·TnC, significantly decreased Ca2+ sensitivity of force development compared with TnT1-WT at both pH values. The R141W mutation, which showed no significant change in the Ca2+ sensitivity of force development in the TnT3 isoform, caused a significant decrease in the TnT1 isoform. The ΔK210 mutation caused a greater decrease in Ca2+ sensitivity and maximal isometric force development compared with the R141W mutation in both the fetal and adult TnT isoforms. When complexed with cardiac TnI·TnC or ssTnI-TnC, both TnT1 DCM mutations strongly decreased maximal actomyosin ATPase activity as compared with TnT1-WT. Our results suggest that a decrease in maximal actomyosin ATPase activity in conjunction with decreased Ca2+ sensitivity of force development may cause a severe DCM phenotype in infants with the mutations.

UR - http://www.scopus.com/inward/record.url?scp=23344435710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23344435710&partnerID=8YFLogxK

U2 - 10.1074/jbc.M409337200

DO - 10.1074/jbc.M409337200

M3 - Article

VL - 280

SP - 17584

EP - 17592

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 18

ER -