• cardiomyopathy

This report describes fly models relevant to cardiomyopathies that are MYBPC3-related. The human gene implicated in these diseases is cardiac myosin-binding protein C (MYBPC3), which is associated with thin filaments of sarcomeres. MYBPC3 is implicated in several forms of heart disease (see MIM:600958), including CMD1MM (FBhh0000158) and CMH4 (FBhh0000414); all are inherited as autosomal dominants. Historically, MYBPC3 has been found to be one of the most common genes associated with hypertrophic cardiomyopathy (HCM); this observation is strongly supported by a large-scale WES analysis, especially for truncated variants of the gene (Walsh, et al., 2016; pubmed:27532257).

No ortholog of MYBPC3 has been identified in flies.

Multiple UAS constructs of the human Hsap\MYBPC3 gene have been introduced into flies, including wild-type MYBPC3 and genes carrying C-terminal deletions. Expression in the developing indirect flight muscle (IFM) results in incorporation of the human proteins into the sarcomeres; in all 3 cases this leads to structural and morphological alterations of the myofibrils and to a progressive flightless phenotype. A large-scale transcription analysis of the IFM in MYBPC3-expressing animals vs. control animals identified 97 genes with changes in transcription levels, most of which have human orthologs. Similar transcription analyses has been conducted using feline Fcat\MYBPC3 constructs carrying missense variants implicated in feline hypertrophic cardiomyopathy.

Variant(s) implicated in human disease tested (as transgenic human gene): truncated variants of Hsap\MYBPC3 have been introduced into flies. These include truncations at approximately amino acid 643 and at approximately amino acid 1219; the full-length protein is 1274 amino acids.

[updated Mar. 2021 by FlyBase; FBrf0222196]