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Pediatric and adult-onset HCM mutations in the myosin motor domain have similar properties

Vera, Carlos D, Johnson, Chloe A, Walklate, Jonathan, Adhikari, Arjun, Ujfalusi, Zoltan, Svicevic, Marina, Mijailovich, Srba M, Combs, Ariana, Langer, Stephen J., Ruppel, Kathleen M., and others. (2019) Pediatric and adult-onset HCM mutations in the myosin motor domain have similar properties. BioRXiv (pre-print server), . (Submitted) (doi:10.1101/622738)

Abstract

Hypertrophic Cardiomyopathy (HCM) is a common genetic disorder that typically involves left ventricular hypertrophy and abnormal cardiac contractility. Mutations in β-MyHC are a major cause of HCM and are typically characterized with cardiac hypercontractility, but the specific mechanistic changes to myosin function that lead to the disease remain incompletely understood. Predicting the severity of any single β-MyHC mutation is hindered by a lack of detailed evaluation at the molecular level. In addition, since the cardiomyopathy can take 20 - 40 years to develop, the severity of the mutations must be somewhat subtle. We hypothesized that mutations which result in childhood cardiomyopathies may show a more severe indication of molecular changes in myosin and be therefore easier to identify. In this work, we performed steady-state and transient kinetics analysis of the myosin carrying one of eight miss sense mutations in the motor domain. Five of these have been identified in childhood cardiomyopathies. The derived parameters were used to model the ATP driven cross bridge. Contrary to our hypothesis, the results show no clear differences between early and late onset HCM mutations. Despite the lack of distinction between early and late onset HCM, the predicted A·M·D occupancy for [A] = 3 Kapp along with the closely related Duty Ratio (DR) and the measured ATPases all change in parallel (in both sign and degree of change) compared to the WT values. Six of the eight HCM mutations are clearly distinct from a set of DCM mutations previously characterized.

Item Type: Article
DOI/Identification number: 10.1101/622738
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michael Geeves
Date Deposited: 04 Jun 2019 09:45 UTC
Last Modified: 09 Oct 2019 10:54 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/74236 (The current URI for this page, for reference purposes)
Geeves, Michael A.: https://orcid.org/0000-0002-9364-8898
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