RT Journal Article
SR Electronic
T1 Pediatric and adult-onset HCM mutations in the myosin motor domain have similar properties
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 622738
DO 10.1101/622738
A1 Carlos D Vera
A1 Chloe A Johnson
A1 Jonathan Walklate
A1 Arjun Adhikari
A1 Zoltan Ujfalusi
A1 Marina Svicevic
A1 Srba M Mijailovich
A1 Ariana Combs
A1 Stephen J. Langer
A1 Kathleen M. Ruppel
A1 James A. Spudich
A1 Leslie A. Leinwand
A1 Michael A. Geeves
YR 2019
UL http://biorxiv.org/content/early/2019/04/30/622738.abstract
AB 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.