MYBPC3 – Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant myocardial disorder characterized by unexplained left ventricular hypertrophy, diastolic dysfunction, and increased risk of arrhythmia (MONDO:0005045). Cardiac myosin‐binding protein C, encoded by MYBPC3 (HGNC:7551), is a key thick‐filament regulatory protein. Variants in MYBPC3 are a predominant cause of HCM, accounting for up to 40% of familial and 30–35% of sporadic cases.

Genetic analyses across multiple cohorts have identified over 200 distinct MYBPC3 variants in more than 1,200 unrelated HCM probands, including frameshift, nonsense, splice‐site, and missense changes (PMID:12974739). One of the first missense changes, c.1961G>A (p.Arg654His), was reported in a South African family and segregated imperfectly in four relatives (PMID:9541115). Recurrent founder mutations, such as the Dutch 2373insG, illustrate population‐specific alleles contributing to disease burden. Segregation studies demonstrate over 19 additional affected first‐degree relatives carrying pathogenic MYBPC3 alleles.

The variant spectrum includes truncating mutations predicted to yield haploinsufficiency (e.g., c.3181C>T (p.Gln1061Ter)) and missense alleles affecting binding domains (e.g., c.1504C>T (p.Arg502Trp)). Large‐scale screens show that individuals with truncating variants often present later but have comparable adverse event rates to those with missense changes. Population databases confirm the rarity of pathogenic alleles and absence in healthy controls.

Functional studies support a loss‐of‐function mechanism. Truncated cMyBP‐C proteins are degraded by the ubiquitin–proteasome system and fail to incorporate into sarcomeres, disrupting myofibrillar architecture (PMID:10610770). Mouse knock‐in models of heterozygous truncation mutations recapitulate diastolic dysfunction and reduced contractile force despite preserved protein levels, indicating early subclinical impairment (PMID:24464755). Missense mutations in N‐terminal domains alter tropomyosin positioning and accelerate contractile kinetics, consistent with dominant‐negative recruitment of myofilament interactions.

No substantive evidence disputes the pathogenic role of MYBPC3 in HCM. Studies of somatic mosaicism in cardiac tissue and deep‐intronic changes have not invalidated germline associations. Alternate phenotypes (e.g., dilated cardiomyopathy) implicate subset alleles but do not weaken the HCM link.

Collectively, the wealth of genetic and experimental data establishes MYBPC3 as a definitive HCM gene. Genetic testing for MYBPC3 variants informs risk stratification, family screening, and personalized management, including prophylactic measures against sudden cardiac death.

References

• Journal of medical genetics • 1998 • Identification of a new missense mutation in MyBP-C associated with hypertrophic cardiomyopathy. PMID:9541115
• Clinical genetics • 2003 • Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. PMID:12974739
• Journal of molecular biology • 1999 • COOH-terminal truncated cardiac myosin-binding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes. PMID:10610770
• American journal of physiology. Heart and circulatory physiology • 2014 • Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy. PMID:24464755

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