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Your search keyword '"cMyBP-C"' showing total 2 results
Start Over Descriptor "cMyBP-C" Publisher escholarship, university of california
2 results on '"cMyBP-C"'

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

Author

van Dijk, Sabine J, Kooiker, Kristina Bezold, Mazzalupo, Stacy, Yang, Yuanzhang, Kostyukova, Alla S, Mustacich, Debbie J, Hoye, Elaine R, Stern, Joshua A, Kittleson, Mark D, and Harris, Samantha P

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Rare Diseases, Pediatric Cardiomyopathy, Pediatric, Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Alanine, Animals, Cardiomyopathy, Hypertrophic, Carrier Proteins, Cats, Circular Dichroism, Codon, Terminator, Haploinsufficiency, Heart, Immunohistochemistry, Muscle Cells, Mutation, Mutation, Missense, Myocardium, Proline, Protein Conformation, Protein Domains, Protein Structure, Secondary, Recombinant Proteins, Sarcomeres, cMyBP-C, Hypertrophic cardiomyopathy, Missense mutation, Animal models of cardiac disease, Biochemistry & Molecular Biology
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 that the A31P mutation causes HCM through a poison polypeptide mechanism that disrupts cMyBP-C or myocyte function.

Published
2016

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

Author

Mark D Kittleson, Kristina B. Kooiker, Debbie Mustacich, Yuanzhang Yang, Alla S. Kostyukova, Samantha P. Harris, Sabine J. van Dijk, Stacy Mazzalupo, Elaine Hoye, and Joshua A. Stern

Subjects
0301 basic medicine, Secondary, Protein Conformation, Mutant, Haploinsufficiency, medicine.disease_cause, Biochemistry, Protein Structure, Secondary, Mutant protein, Missense mutation, Mutation, Alanine, Circular Dichroism, Heart, Immunohistochemistry, Stop codon, Recombinant Proteins, Hypertrophic cardiomyopathy, Codon, Terminator, Sarcomeres, Protein Structure, Biochemistry & Molecular Biology, cMyBP-C, Proline, Cardiomyopathy, Nonsense mutation, Mutation, Missense, Biophysics, Biology, Article, 03 medical and health sciences, Protein Domains, medicine, Animals, Terminator, Codon, Molecular Biology, Muscle Cells, Binding protein, Myocardium, Cardiomyopathy, Hypertrophic, Molecular biology, 030104 developmental biology, Animal models of cardiac disease, Hypertrophic, Cats, Biochemistry and Cell Biology, Missense, Carrier Proteins
Abstract

© 2016 Elsevier Inc. All rights reserved. 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 that the A31P mutation causes HCM through a poison polypeptide mechanism that disrupts cMyBP-C or myocyte function.

Published
2016
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