Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosin

Zaklyazminskaya, E.V.; Nefedova, V.V.; Koubassova, N.A.; Kotlukova, N.P.; Kopylova, G.V.; Kochurova, A.M.; Shchepkin, D.V.; Ryabkova, N.S.; Katrukha, I.A.; Kleymenov, S.Y.; Bershitsky, S.Y.; Matyushenko, A.M.; Tsaturyan, A.K.; Levitsky, D.I.

Авторы: Zaklyazminskaya Elena V., Nefedova Victoria V., Koubassova Natalia A., Kotlukova Natalia P., Kopylova Galina V., Kochurova Anastasia M., Shchepkin Daniil V., Ryabkova Natalia S., Katrukha Ivan A., Kleymenov Sergey Y., Bershitsky Sergey Y., Matyushenko Alexander M., Tsaturyan Andrey K., Levitsky Dmitrii I.
Журнал: International Journal of Molecular Sciences
Том: 25
Номер: 23
Год издания: 2024
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 13059
DOI: 10.3390/ijms252313059
Аннотация: Pediatric dilated cardiomyopathy (DCM) is a rare heart muscle disorder leading to the enlargement of all chambers and systolic dysfunction. We identified a novel de novo variant, c.88A>G (p.Lys30Glu, K30E), in the TPM1 gene encoding the major cardiac muscle tropomyosin (Tpm) isoform, Tpm1.1. The variant was found in a proband with DCM and left ventricular non-compaction who progressed to terminal heart failure at the age of 3 years and 8 months. To study the properties of the mutant protein, we produced recombinant K30E Tpm and used various biochemical and biophysical methods to compare its properties with those of WT Tpm. The K30E substitution decreased the thermal stability of Tpm and its complex with actin and significantly reduced the sliding velocity of the regulated thin filaments over a surface covered by ovine cardiac myosin in an in vitro motility assay across the entire physiological range of Ca2+ concentration. Our molecular dynamics simulations suggest that the charge reversal of the 30th residue of Tpm alters the actin monomer to which it is bound. We hypothesize that this rearrangement of the actin–Tpm interaction may hinder the transition of a myosin head attached to a nearby actin from a weakly to a strongly bound, force-generating state, thereby reducing myocardial contractility. The impaired myosin interaction with regulated actin filaments and the decreased thermal stability of the actin–Tpm complex at a near physiological temperature likely contribute to the pathogenicity of the variant and its causative role in progressive DCM.
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Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosinстатья

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