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Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy.

ABSTRACT: Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canine (dystrophin) dilated cardiomyopathies. This review gives an overview of the work carried out in cardiac troponin T and dystrophin to date in both human and animal dilated cardiomyopathy.

SUBMITTER: England J

PROVIDER: S-EPMC5715711 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy.

England Jennifer J Loughna Siobhan S Rutland Catrin Sian CS

Journal of cardiovascular development and disease 20170707 3

Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canine ( ...[more]

PMID: 29367539

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Project description:BackgroundHypertrophic (HCM) and dilated (DCM) cardiomyopathies result from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca(2+) desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis.Methods and findingsWe ablated Tnnt2 to produce heterozygous Tnnt2(+/-) mice, and crossbreeding produced homozygous null Tnnt2(-/-) embryos. We also generated transgenic mice overexpressing wildtype (TG(WT)) or DCM mutant (TG(K210Delta)) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2(+/-)/TG(WT)) or mutant (Tnnt2(+/-)/TG(K210Delta)) transgenes. Tnnt2(+/-) mice relative to wildtype had significantly reduced transcript (0.82+/-0.06[SD] vs. 1.00+/-0.12 arbitrary units; p = 0.025), but not protein (1.01+/-0.20 vs. 1.00+/-0.13 arbitrary units; p = 0.44). Tnnt2(+/-) mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2(+/-)/TG(K210Delta) mice had severe DCM, TG(K210Delta) mice had only mild DCM (FS 18+/-4 vs. 29+/-7%; p<0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2(+/-)/TG(K210Delta) relative to TG(K210Delta) mice (2.42+/-0.08, p = 0.03). Tnnt2(+/-)/TG(K210Delta) muscle showed Ca(2+) desensitization (pCa(50) = 5.34+/-0.08 vs. 5.58+/-0.03 at sarcomere length 1.9 microm, p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2(-/-) embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres.ConclusionsAbsence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca(2+) desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity.

Dataset Information

Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy.

Publications

Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy.

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