Functional characterization of human myosin-binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon-specific cardiac phenotypes in zebrafish model

Journal of Cellular Physiology
Sahar I Da'asKhalid A Fakhro

Abstract

Myosin-binding protein C 3 (MYBPC3) variants are the most common cause of hypertrophic cardiomyopathy (HCM). HCM is a complex cardiac disorder due to its significant genetic and clinical heterogeneity. MYBPC3 variants genotype-phenotype associations remain poorly understood. We investigated the impact of two novel human MYBPC3 splice-site variants: V1: c.654+2_654+4dupTGG targeting exon 5 using morpholino MOe5i5; and V2: c.772+1G>A targeting exon 6 using MOe6i6; located within C1 domain of cMyBP-C protein, known to be critical in regulating sarcomere structure and contractility. Zebrafish MOe5i5 and MOe6i6 morphants recapitulated typical characteristics of human HCM with cardiac phenotypes of varying severity, including reduced cardiomyocyte count, thickened ventricular myocardial wall, a drastic reduction in heart rate, stroke volume, and cardiac output. Analysis of all cardiac morphological and functional parameters demonstrated that V2 cardiac phenotype was more severe than V1. Coinjection with synthetic human MYBPC3 messenger RNA (mRNA) partially rescued disparate cardiac phenotypes in each zebrafish morphant. While human MYBPC3 mRNA partially restored the decreased heart rate in V1 morphants and displayed increased percent...Continue Reading

Citations

Oct 4, 2000·Nature Genetics·A Nasevicius, S C Ekker
Mar 23, 2002·Circulation Research·Samantha P HarrisRichard L Moss
Aug 9, 2008·Journal of the American College of Cardiology·Iacopo OlivottoBarry J Maron
Sep 21, 2010·Developmental and Comparative Immunology·Sahar I Da'asJason N Berman
Dec 22, 2010·The Journal of Physiology·Rudi Vennekens
Mar 19, 2011·Circulation Research·Samantha P HarrisKristina L Bezold
Dec 23, 2011·Basic Research in Cardiology·Saskia SchlossarekLucie Carrier
Jan 20, 2012·Journal of Visualized Experiments : JoVE·Jingchun Yang, Xiaolei Xu
Jun 19, 2012·Differentiation; Research in Biological Diversity·Shu Tu, Neil C Chi
Jul 17, 2012·Journal of the American College of Cardiology·Barry J MaronChristopher Semsarian
Sep 18, 2012·Journal of Molecular and Cellular Cardiology·Md Shenuarin BhuiyanJeffrey Robbins
Dec 13, 2012·Journal of Cardiovascular Translational Research·Heba Sh KassemMagdi Yacoub
Mar 26, 2013·PloS One·Poornima GajendraraoMagdi Yacoub
Jan 2, 2014·Journal of Molecular and Cellular Cardiology·Saskia SchlossarekLucie Carrier
Jan 28, 2014·American Journal of Physiology. Heart and Circulatory Physiology·David BarefieldSakthivel Sadayappan
Apr 2, 2014·Metallomics : Integrated Biometal Science·Andrew B NowakowskiDavid H Petering
Jan 1, 2013·Global Cardiology Science & Practice·Kar Lai Poon, Thomas Brand
Apr 23, 2014·Progress in Molecular Biology and Translational Science·Robert N WilkinsonFredericus J M van Eeden
Oct 18, 2014·AJNR. American Journal of Neuroradiology·R Menezes-ReisM H Nogueira-Barbosa
May 15, 2015·Journal of Cardiovascular Translational Research·Poornima GajendraraoMagdi Yacoub
Sep 12, 2015·Gene·Lucie CarrierFriederike Cuello
Feb 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Samantha P HarrisVitold E Galkin
Feb 4, 2016·International Journal of Molecular Sciences·Anja BühlerSteffen Just
Apr 26, 2016·Journal of Molecular and Cellular Cardiology·Paul J M WijnkerLucie Carrier
Jun 9, 2016·Journal of Biomolecular Structure & Dynamics·Navaneethakrishnan T KrishnamoorthyMagdi Yacoub
Aug 10, 2016·Heart Failure Reviews·Despina Bournele, Dimitris Beis
Aug 18, 2016·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Roddy WalshHugh Watkins
Nov 12, 2016·Development·Yu-Huan ShihXiaolei Xu
Mar 2, 2017·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Huseyin C YalcinMagdi Yacoub
May 12, 2017·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Keith NykampScott Topper

Related Concepts

Heart
Binding Protein
Exons
Gene Mutant
Myocytes, Cardiac
Myocardium
Splice Site SNP
Analysis
Cerebrovascular Accident
MYBPC3

Related Feeds

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.