Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.

The Journal of Biological Chemistry
C. Suay-CorrederaJorge J Alegre-Cebollada

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.

References

Jan 1, 2000·Cardiovascular Research·C S RedwoodH Watkins
Jun 25, 2002·Journal of Molecular Biology·Raphael GueroisLuis Serrano
Jul 12, 2002·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Pertti JääskeläinenMarkku Laakso
Oct 9, 2002·Current Protein & Peptide Science·S M Kelly, N C Price
Sep 20, 2005·Journal of Molecular Biology·Peng YueJohn Moult
Aug 8, 2007·Nature Reviews. Genetics·Gert C ScheperChristopher G Proud
Aug 14, 2008·Nature Reviews. Molecular Cell Biology·Tommer Ravid, Mark Hochstrasser
Feb 12, 2011·American Journal of Human Genetics·Daniel M JordanShamil R Sunyaev
Mar 19, 2011·Circulation Research·Samantha P HarrisKristina L Bezold
Oct 25, 2011·The Journal of Molecular Diagnostics : JMD·Felice AmatoRossella Tomaiuolo
Nov 8, 2011·Journal of Muscle Research and Cell Motility·Steven MarstonLucie Carrier
Jul 17, 2012·Journal of the American College of Cardiology·Barry J MaronChristopher Semsarian
Jun 21, 2013·The Journal of Biological Chemistry·Kristina L BezoldSamantha P Harris
Nov 5, 2013·The Journal of Molecular Diagnostics : JMD·Valeria D'ArgenioFrancesco Salvatore
Nov 8, 2013·Pflügers Archiv : European journal of physiology·Sakthivel Sadayappan, Pieter P de Tombe
May 27, 2014·Frontiers in Microbiology·Germán L Rosano, Eduardo A Ceccarelli
Jul 18, 2014·Circulation. Cardiovascular Genetics·Adam S HelmsSharlene M Day
Jan 30, 2015·Cardiovascular Research·Jolanda van der VeldenLucie Carrier
Feb 19, 2015·Protein Engineering, Design & Selection : PEDS·Benjamin T PorebskiAshley M Buckle
Mar 6, 2015·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Sue RichardsUNKNOWN ACMG Laboratory Quality Assurance Committee
Mar 19, 2015·Annual Review of Biochemistry·Yeon Lee, Donald C Rio
Mar 31, 2015·Journal of the American College of Cardiology·Christopher SemsarianBarry J Maron
Mar 31, 2015·The International Journal of Biochemistry & Cell Biology·Vedrana Bali, Zsuzsanna Bebok
Apr 13, 2015·Trends in Cardiovascular Medicine·Elizabeth M McNally, Alfred L George
Jan 19, 2016·Archives of Biochemistry and Biophysics·Sabine J van DijkSamantha P Harris
Jun 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Julian R HomburgerEuan A Ashley
Aug 18, 2016·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Roddy WalshHugh Watkins

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Citations

Sep 2, 2021·Biophysics Reviews·Jorge Alegre-Cebollada
Jun 12, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Carmen Suay-Corredera, Jorge Alegre-Cebollada

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