The A31P missense mutation in cardiac myosin binding protein C alters protein structure but does not cause haploinsufficiency

Archives of Biochemistry and Biophysics
Sabine J van DijkSamantha P Harris

Abstract

Mutations in MYBPC3, the gene encoding cardiac myosin binding protein C (cMyBP-C), are a major cause of hypertrophic cardiomyopathy (HCM). While most mutations encode premature stop codons, missense mutations causing single amino acid substitutions are also common. Here we investigated effects of a single proline for alanine substitution at amino acid 31 (A31P) in the C0 domain of cMyBP-C, which was identified as a natural cause of HCM in cats. Results using recombinant proteins showed that the mutation disrupted C0 structure, altered sensitivity to trypsin digestion, and reduced recognition by an antibody that preferentially recognizes N-terminal domains of cMyBP-C. Western blots detecting A31P cMyBP-C in myocardium of cats heterozygous for the mutation showed a reduced amount of A31P mutant protein relative to wild-type cMyBP-C, but the total amount of cMyBP-C was not different in myocardium from cats with or without the A31P mutation indicating altered rates of synthesis/degradation of A31P cMyBP-C. Also, the mutant A31P cMyBP-C was properly localized in cardiac sarcomeres. These results indicate that reduced protein expression (haploinsufficiency) cannot account for effects of the A31P cMyBP-C mutation and instead suggest t...Continue Reading

References

Jun 9, 2004·Lancet·Perry Elliott, William J McKenna
Aug 10, 2012·Lancet·Barry J Maron, Martin S Maron
Sep 12, 2015·Gene·Lucie CarrierFriederike Cuello

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Citations

May 10, 2016·Archives of Biochemistry and Biophysics·Brandon J Biesiadecki
Mar 28, 2020·Clinical Genetics·Cristina Gil-OrtuñoMaría J Fernández Del Palacio
Nov 21, 2018·Pflügers Archiv : European journal of physiology·Amelia A GlazierSharlene M Day
Oct 5, 2018·Pflügers Archiv : European journal of physiology·Joshua A Stern, Yu Ueda
Dec 12, 2020·Frontiers in Physiology·James W McNamaraSakthivel Sadayappan
Jun 8, 2021·The Journal of Biological Chemistry·Carmen Suay-CorrederaJorge Alegre-Cebollada
Oct 26, 2021·Journal of Feline Medicine and Surgery·Mark D Kittleson, Etienne Côté

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