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Effects of myosin variants on interacting heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes

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Title: Effects of myosin variants on interacting heads motif explain distinct hypertrophic and dilated cardiomyopathy phenotypes
Authors: Alamo, L
Ware, JS
Pinto, A
Gillilan, RE
Seidman, JG
Seidman, CE
Padron, R
Item Type: Journal Article
Abstract: Cardiac β-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human β-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10−19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.
Issue Date: 13-Jun-2017
Date of Acceptance: 5-May-2017
URI: http://hdl.handle.net/10044/1/50842
DOI: https://dx.doi.org/10.7554/eLife.24634
ISSN: 2050-084X
Publisher: ELIFE SCIENCES PUBLICATIONS LTD
Journal / Book Title: ELIFE
Volume: 6
Copyright Statement: © 2017 Alamo et al. This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 107469/Z/15/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
BINDING-PROTEIN-C
BETA-CARDIAC MYOSIN
SUPER-RELAXED STATE
SKELETAL-MUSCLE
GENETIC-VARIATION
HEAVY-MEROMYOSIN
FORCE GENERATION
CHAIN MUTATIONS
MOLECULAR MOTOR
THICK FILAMENT
cardiomyopathy
diastolic heart disease
human
human biology
human mutation
medicine
myosin interacting-heads motif
super-relaxation
β-cardiac myosin
Publication Status: Published
Open Access location: https://elifesciences.org/articles/24634
Article Number: ARTN e24634
Appears in Collections:National Heart and Lung Institute



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