Divergent Molecular Phenotypes in Point Mutations at the Same Residue in Beta-Myosin Heavy Chain Lead to Distinct Cardiomyopathies

Lehman, S. J.; Meller, A.; Solieva, S. O.; Lotthammer, J. M.; Greenberg, L.; Langer, S. J.; Greenberg, M. J.; Tardiff, J. C.; Bowman, G. R.; Leinwand, L. A.

doi:10.1101/2023.07.03.547580

bioRxiv · 10.1101/2023.07.03.547580

Divergent Molecular Phenotypes in Point Mutations at the Same Residue in Beta-Myosin Heavy Chain Lead to Distinct Cardiomyopathies

Lehman, S. J.·Meller, A.·Solieva, S. O.·Lotthammer, J. M.·Greenberg, L.·Langer, S. J.·Greenberg, M. J.·Tardiff, J. C.·Bowman, G. R.·Leinwand, L. A.

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Abstract

In genetic cardiomyopathies, a frequently described phenomenon is how similar mutations in one protein can lead to discrete clinical phenotypes. One example is illustrated by two mutations in beta myosin heavy chain ({beta}-MHC) that are linked to hypertrophic cardiomyopathy (HCM) (Ile467Val, I467V) and left ventricular non-compaction (LVNC) (Ile467Thr, I467T). To investigate how these missense mutations lead to independent diseases, we studied the molecular effects of each mutation using recombinant human {beta}-MHC Subfragment 1 (S1) in vitro assays. Both HCM-I467V and LVNC-I467T S1 mutations exhibited similar mechanochemical functions, including unchanged ATPase and enhanced actin velocity but had distinct effects on the basal activity of myosin. HCM-I467V S1 showed no change in basal ATPase activity of myosin while LVNC-I467T reduced the basal ATPase activity by 50%. Molecular dynamics simulations reveal that I467T allosterically disrupts nucleotide binding of myosin, which may contribute to the uncoupled reduced basal activity and enhanced actin velocity observed in this mutation. These contrasting molecular effects may lead to contractile dysregulation that initiates LVNC-associated signaling pathways that progress the phenotype. Together, analysis of these mutations provides evidence that phenotypic complexity originates at the molecular level and is critical to understanding disease progression and developing therapies.

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Lehman, S. J., Meller, A., Solieva, S. O., Lotthammer, J. M., Greenberg, L., Langer, S. J., Greenberg, M. J., Tardiff, J. C., Bowman, G. R., Leinwand, L. A.. 2023-07-03. Divergent Molecular Phenotypes in Point Mutations at the Same Residue in Beta-Myosin Heavy Chain Lead to Distinct Cardiomyopathies. https://doi.org/10.1101/2023.07.03.547580

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