scholarly journals BIOPHYSICAL CHARACTERIZATION OF FAMILIAL HYPERTROPHIC CARDIOMYOPATHY-RELATED TROPONIN T MUTATIONS

2014 ◽  
Vol 30 (10) ◽  
pp. S120-S121
Author(s):  
A.Y. Li ◽  
B. Liang ◽  
G. Tibbits
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Troponin T ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Biophysical Characterization

scholarly journals Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models

2009 ◽  
Vol 297 (2) ◽  
pp. H614-H626 ◽  
Author(s):  
Pia J. Guinto ◽  
Todd E. Haim ◽  
Candice C. Dowell-Martino ◽  
Nathaniel Sibinga ◽  
Jil C. Tardiff
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Ventricular Myocytes ◽  
Troponin T ◽  
Early Time ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Compensatory Mechanism ◽  
Missense Mutations ◽  
Tail Domain ◽  
Cellular Mechanics

Naturally occurring mutations in cardiac troponin T (cTnT) result in a clinical subset of familial hypertrophic cardiomyopathy. To determine the mechanistic links between thin-filament mutations and cardiovascular phenotypes, we have generated and characterized several transgenic mouse models carrying cTnT mutations. We address two central questions regarding the previously observed changes in myocellular mechanics and Ca2+ homeostasis: 1) are they characteristic of all severe cTnT mutations, and 2) are they primary (early) or secondary (late) components of the myocellular response? Adult left ventricular myocytes were isolated from 2- and 6-mo-old transgenic mice carrying missense mutations at residue 92, flanking the TNT1 NH2-terminal tail domain. Results from R92L and R92W myocytes showed mutation-specific alterations in contraction and relaxation indexes at 2 mo with improvements by 6 mo. Alterations in Ca2+ kinetics remained consistent with mechanical data in which R92L and R92W exhibited severe diastolic impairments at the early time point that improved with increasing age. A normal regulation of Ca2+ kinetics in the context of an altered baseline cTnI phosphorylation suggested a pathogenic mechanism at the myofilament level taking precedence for R92L. The quantitation of Ca2+-handling proteins in R92W mice revealed a synergistic compensatory mechanism involving an increased Ser16 and Thr17 phosphorylation of phospholamban, contributing to the temporal onset of improved cellular mechanics and Ca2+ homeostasis. Therefore, independent cTnT mutations in the TNT1 domain result in primary mutation-specific effects and a differential temporal onset of altered myocellular mechanics, Ca2+ kinetics, and Ca2+ homeostasis, complex mechanisms which may contribute to the clinical variability in cTnT-related familial hypertrophic cardiomyopathy mutations.

Phenotypic Variation of Familial Hypertrophic Cardiomyopathy Caused by the Phe110→Ile Mutation in Cardiac Troponin T

Cardiology ◽  
2000 ◽  
Vol 93 (3) ◽  
pp. 155-162 ◽  
Author(s):  
Tong-Lang Lin ◽  
Sahoko Ichihara ◽  
Yoshiji Yamada ◽  
Tetsuo Nagasaka ◽  
Hitoshi Ishihara ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Phenotypic Variation ◽  
Cardiac Troponin ◽  
Troponin T ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cardiac Troponin T

Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in troponin T, via reduced expression of phospholamban

2018 ◽  
Vol 124 ◽  
pp. 115-116
Author(s):  
Shamim Chowdhury ◽  
Jillian Simon ◽  
David Ryba ◽  
Noorzahan Begum ◽  
Evangelia Kranias ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Troponin T ◽  
Familial Hypertrophic Cardiomyopathy
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