Asymmetric septal hypertrophy in heterozygous cMyBP-C null mice

Cardiovascular Research
L CarrierKenneth R Chien

Abstract

Cardiac myosin-binding protein C (cMyBP-C) gene mutations are involved in familial hypertrophic cardiomyopathy (FHC). Many of these mutations produce truncated proteins, which are unstable in the cardiac tissue of patients, suggesting that haploinsufficiency could account for the development of the phenotype. However, existing mouse models of cMyBP-C gene mutations have represented hypomorphic alleles without evidence of asymmetric septal hypertrophy, a key FHC phenotypic feature. In the present study, we generated a new model of cMyBP-C null mice and characterized the phenotype in both homozygotes and heterozygotes at different ages. The mouse model was based upon the targeted deletion of exons 1 and 2, which contain the transcription initiation site, and the phenotype was determined by molecular, functional and morphological analyses. Herein, we demonstrate that inactivation of one or two mouse cMyBP-C alleles leads to different cardiac disorders at different post-natal time windows. The homozygous cMyBP-C null mice do not express the cMyBP-C gene, develop eccentric left ventricular hypertrophy with decreased fractional shortening at 3-4 months of age and a markedly impaired relaxation after 9 months. This is associated with ...Continue Reading

Citations

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