Variable cardiac myosin binding protein-C expression in the myofilaments due to MYBPC3 mutations in hypertrophic cardiomyopathy

Journal of Molecular and Cellular Cardiology
R Y ParbhudayalD W D Kuster

Abstract

Mutations in MYBPC3 are the most common cause of hypertrophic cardiomyopathy (HCM). These mutations produce dysfunctional protein that is quickly degraded and not incorporated in the myofilaments. Most patients are heterozygous and allelic expression differs between cells. We hypothesized that this would lead to cell-to-cell variation in cardiac myosin binding protein-C (cMyBP-C, encoded by MYBPC3 gene) protein levels. Twelve HCM patients were included (six had no sarcomere mutations (HCMsmn) and served as the control group and six harbored mutations in the MYBPC3 gene (MYBPC3mut). Western blot and RNA sequencing analysis of cardiac tissue lysates were performed to detect overall cMyBP-C protein and mRNA levels. Cellular expression of cMyBP-C and α-actin was obtained by immunofluorescence staining. Quantification of cell-to-cell variation of cMyBP-C expression between cardiomyocytes was measured by determining the ratio of cMyBP-C:α-actin stained area of each cell. Protein and mRNA analysis revealed significantly reduced cMyBP-C levels in MYBPC3mut patients compared with HCMsmn patients (0.73 ± 0.09 vs. 1.0 ± 0.15, p < .05; 162.3 ± 16.4 vs. 326.2 ± 41.9 RPKM, p = .002), without any sign of truncated proteins. Immunofluorescence...Continue Reading

Citations

Aug 12, 2020·Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation·R A de BoerUNKNOWN DOSIS consortium
Feb 12, 2019·Pflügers Archiv : European journal of physiology·Theresia Kraft, Judith Montag
Nov 6, 2020·Journal of Molecular and Cellular Cardiology·Maike SchuldtJolanda van der Velden
Feb 10, 2021·The International Journal of Cardiovascular Imaging·Rahana Y ParbhudayalJolanda van der Velden
Jan 13, 2021·International Journal of Molecular Sciences·Diana CimiottiKornelia Jaquet
Sep 14, 2020·Journal of Molecular and Cellular Cardiology·Thomas G Martin, Jonathan A Kirk
Jul 6, 2021·Frontiers in Cardiovascular Medicine·Graham ChakafanaKaren Sliwa

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