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Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy.

ABSTRACT: AIMS:A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-C?C10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-C?C10mutin vivo are unknown. We hypothesized that expression of cMyBP-C?C10mut exerts a poison polypeptide effect leading to improper assembly of cardiac sarcomeres and the development of HCM. METHODS AND RESULTS:To determine whether expression of cMyBP-C?C10mut is sufficient to cause HCM and contractile dysfunction in vivo, we generated transgenic (TG) mice having cardiac-specific protein expression of cMyBP-C?C10mut at approximately half the level of endogenous cMyBP-C. At 12?weeks of age, significant hypertrophy was observed in TG mice expressing cMyBP-C?C10mut (heart weight/body weight ratio: 4.43?±?0.11?mg/g non-transgenic (NTG) vs. 5.34?±?0.25?mg/g cMyBP-C?C10mut, P?

SUBMITTER: Kuster DWD 

PROVIDER: S-EPMC6872972 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy.

Kuster Diederik W D DWD   Lynch Thomas L TL   Barefield David Y DY   Sivaguru Mayandi M   Kuffel Gina G   Zilliox Michael J MJ   Lee Kyoung Hwan KH   Craig Roger R   Namakkal-Soorappan Rajasekaran R   Sadayappan Sakthivel S  

Cardiovascular research 20191201 14

<h4>Aims</h4>A 25-base pair deletion in the cardiac myosin binding protein-C (cMyBP-C) gene (MYBPC3), proposed to skip exon 33, modifies the C10 domain (cMyBP-CΔC10mut) and is associated with hypertrophic cardiomyopathy (HCM) and heart failure, affecting approximately 100 million South Asians. However, the molecular mechanisms underlying the pathogenicity of cMyBP-CΔC10mutin vivo are unknown. We hypothesized that expression of cMyBP-CΔC10mut exerts a poison polypeptide effect leading to improper  ...[more]

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