In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament

Samantha P. Harris, Ross G. Lyons, Kristina L. Bezold

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

In the 20 years since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM), an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins, including the myosin essential and regulatory light chains and cardiac myosin binding protein (cMyBP)-C. However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM-causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin-driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.

Original languageEnglish (US)
Pages (from-to)751-764
Number of pages14
JournalCirculation Research
Volume108
Issue number6
DOIs
StatePublished - Mar 18 2011

Fingerprint

Hypertrophic Cardiomyopathy
Myosins
Carrier Proteins
Mutation
Cardiac Myosins
Myosin Light Chains
Proteins
Familial Hypertrophic Cardiomyopathy
Muscle Contraction
Cardiomyopathies
Phenotype

Keywords

  • hypertrophic cardiomyopathy
  • myosin binding protein-C
  • myosin essential light chain
  • myosin regulatory light chain

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

In the thick of it : HCM-causing mutations in myosin binding proteins of the thick filament. / Harris, Samantha P.; Lyons, Ross G.; Bezold, Kristina L.

In: Circulation Research, Vol. 108, No. 6, 18.03.2011, p. 751-764.

Research output: Contribution to journalArticle

Harris, Samantha P. ; Lyons, Ross G. ; Bezold, Kristina L. / In the thick of it : HCM-causing mutations in myosin binding proteins of the thick filament. In: Circulation Research. 2011 ; Vol. 108, No. 6. pp. 751-764.
@article{bb15026f59554077b62f73c80ecb54d1,
title = "In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament",
abstract = "In the 20 years since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM), an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins, including the myosin essential and regulatory light chains and cardiac myosin binding protein (cMyBP)-C. However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM-causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin-driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.",
keywords = "hypertrophic cardiomyopathy, myosin binding protein-C, myosin essential light chain, myosin regulatory light chain",
author = "Harris, {Samantha P.} and Lyons, {Ross G.} and Bezold, {Kristina L.}",
year = "2011",
month = "3",
day = "18",
doi = "10.1161/CIRCRESAHA.110.231670",
language = "English (US)",
volume = "108",
pages = "751--764",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - In the thick of it

T2 - HCM-causing mutations in myosin binding proteins of the thick filament

AU - Harris, Samantha P.

AU - Lyons, Ross G.

AU - Bezold, Kristina L.

PY - 2011/3/18

Y1 - 2011/3/18

N2 - In the 20 years since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM), an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins, including the myosin essential and regulatory light chains and cardiac myosin binding protein (cMyBP)-C. However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM-causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin-driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.

AB - In the 20 years since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM), an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins, including the myosin essential and regulatory light chains and cardiac myosin binding protein (cMyBP)-C. However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM-causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin-driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.

KW - hypertrophic cardiomyopathy

KW - myosin binding protein-C

KW - myosin essential light chain

KW - myosin regulatory light chain

UR - http://www.scopus.com/inward/record.url?scp=79953048882&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953048882&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.110.231670

DO - 10.1161/CIRCRESAHA.110.231670

M3 - Article

C2 - 21415409

AN - SCOPUS:79953048882

VL - 108

SP - 751

EP - 764

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 6

ER -