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Analysis of the Molecular Pathogenesis of Cardiomyopathy-Causing cTnT Mutants I79N, ΔE96, and ΔK210

Title: Analysis of the Molecular Pathogenesis of Cardiomyopathy-Causing cTnT Mutants I79N, ΔE96, and ΔK210.
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Name(s): Bai, Fan, author
Caster, Hannah, author
Pinto, Jose, author
Kawai, Masataka, author
Type of Resource: text
Genre: Text
Issuance: serial
Date Issued: 2013
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Three troponin T (TnT) mutants that cause hypertrophic, restrictive, and dilated cardiomyopathy (I79N, ΔE96, and ΔK210, respectively), were examined using the thin-filament extraction/reconstitution technique. Effects of Ca(2+), ATP, phosphate, and ADP concentrations on force and its transients were studied at 25°C. Maximal Ca(2+) tension (THC) and Ca(2+)-activatable tension (Tact), respectively, were similar among I79N, ΔE96, and WT, whereas ΔK210 led to a significantly lower THC (∼20% less) and Tact (∼25% less) than did WT. In pCa solution containing 8 mM Pi and ionic strength adjusted to 200 mM, the Ca(2+) sensitivity (pCa50) of I79N (5.63 ± 0.02) and ΔE96 (5.60 ± 0.03) was significantly greater than that of WT (5.45 ± 0.04), but the pCa50 of ΔK210 (5.54 ± 0.04) remained similar to that of WT. Five equilibrium constants were deduced using sinusoidal analysis. All three mutants showed significantly lower K0 (ADP association constant) and larger K4 (equilibrium constant of force generation step) relative to the corresponding values for WT. I79N and ΔK210 were associated with a K2 (equilibrium constant of cross-bridge detachment step) significantly lower than that of ΔE96 and WT. These results demonstrated that at pCa 4.66, the force/cross-bridge is ∼18% less in I79N and ∼41% less in ΔK210 than that in WT. These results indicate that the molecular pathogenesis of the cardiac TnT mutation-related cardiomyopathies is different for each mutation.
Identifier: FSU_migr_biomed_faculty_publications-0051 (IID), 10.1016/j.bpj.2013.04.001 (DOI)
Keywords: adenosine diphosphate, adenosine triphosphate, calcium, cardiomyopathies, cattle, mutation, phosphates, Troponin T
Uncontrolled subjects: Adenosine Diphosphate, Adenosine Triphosphate, Animals, Calcium, Cardiomyopathies, Cattle, Humans, Mutation, Phosphates, Troponin T
Note: Originally published in Biophysical'>http://www.sciencedirect.com/science/article/pii/S0006349513003925">Biophysical Journal.
Citation: Bai F, Caster HM, Pinto JR, Kawai M. (2013). Analysis of the molecular pathogenesis of cardiomyopathy-causing cTnT mutants I79N, ΔE96, and ΔK210. Biophys J, 104(9):1979-88. doi: 10.1016/j.bpj.2013.04.001.
Subject(s): Amino acids
Peptides
Proteins
Cardiovascular system -- Diseases
Genetics
Heterocyclic compounds
Inorganic compounds
Macromolecules
Medical sciences
Nucleic acids
Nucleosides
Links: http://dx.doi.org/10.1016/j.bpj.2013.04.001
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_migr_biomed_faculty_publications-0051
Owner Institution: FSU
Is Part of Series: Department of Biomedical Sciences Faculty Publications.
Is Part Of: Biophysical Journal.
Issue: 9, 104

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Bai, F., Caster, H., Pinto, J., & Kawai, M. (2013). Analysis of the Molecular Pathogenesis of Cardiomyopathy-Causing cTnT Mutants I79N, ΔE96, and ΔK210. Biophysical Journal. Retrieved from http://dx.doi.org/10.1016/j.bpj.2013.04.001