MYH7 – Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by unexplained left ventricular hypertrophy. The beta-myosin heavy chain gene (MYH7; HGNC:7577) encodes the major motor protein of the cardiac sarcomere. Pathogenic missense variants in MYH7 impair myosin motor function, leading to autosomal dominant HCM with variable penetrance and risk of sudden cardiac death.

Autosomal-dominant inheritance of MYH7-related HCM is supported by multiple family studies. In a large referral cohort of 389 unrelated HCM patients, MYH7 variants were detected in 58 probands (PMID:15358028). Segregation analysis in over 10 multigenerational families, including 23 carriers of the Arg723Gly variant with malignant phenotype, demonstrates co-segregation of missense alleles with disease (PMID:11113006).

The MYH7 variant spectrum in HCM is dominated by missense substitutions throughout the head and rod domains. Recurrent hotspot mutations include c.1208G>A (p.Arg403Gln) (PMID:8483915), c.1816G>A (p.Val606Met) (PMID:8788376), and c.2155C>T (p.Arg719Trp) (PMID:10957787). No truncating or loss-of-function variants have been associated with classic HCM, consistent with a dominant-negative or gain-of-function mechanism.

Penetrance and expressivity are variable. In a multigenerational family carrying c.4130C>T (p.Thr1377Met), 19 carriers were identified but only 8 showed clinical HCM (PMID:29343710). Likewise, de novo or compound heterozygous presentations, such as c.2155C>T (p.Arg719Trp) with c.1046T>C (p.Met349Thr), correlate with earlier onset and severe phenotype (PMID:9544842).

Biochemical and cellular studies of HCM-associated variants reveal impaired crossbridge kinetics. The R403Q mutation reduces actin-activated ATPase Vmax by >3.5-fold and motility by ~5-fold (PMID:8294404; PMID:8981935). Mutations such as p.Val606Met show mild ATPase impairment, correlating with variable clinical severity (PMID:9172070).

Transgenic mouse models carrying R403Q in the α- or β-myosin backgrounds demonstrate isoform-dependent alterations in ADP release and force production, recapitulating human HCM phenotypes (PMID:23580644). Conversely, dilated cardiomyopathy-linked MYH7 mutations depress actin motility and ATPase in vitro and produce ventricular dilation in vivo (PMID:16983074).

In summary, autosomal-dominant missense variants in MYH7 cause HCM through altered myosin crossbridge cycling and sarcomeric contractility. The combination of robust genetic segregation, large case–control cohorts, and concordant functional data supports a Strong gene-disease association. MYH7 genetic testing informs clinical management, family screening, and personalized risk stratification.

Key take-home: MYH7-related HCM is a definitive AD disorder driven by missense mutations that impair myosin motor function, warranting gene-based diagnosis and tailored surveillance.

References

• J. Am. Coll. Cardiol. • 2004 • Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy PMID:15358028
• J. Mol. Cell. Cardiol. • 2000 • Malignant hypertrophic cardiomyopathy caused by the Arg723Gly mutation in beta-myosin heavy chain gene PMID:11113006
• Proc. Natl. Acad. Sci. USA • 1993 • Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy PMID:8483915
• Japanese Circ. J. • 1995 • A missense mutation in the beta-myosin heavy chain gene in a Japanese patient with hypertrophic cardiomyopathy PMID:8788376
• Z. Kardiol. • 2000 • Apical hypertrophic cardiomyopathy due to a de novo mutation Arg719Trp of the beta-myosin heavy chain gene PMID:10957787
• Sci. Rep. • 2018 • Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation PMID:29343710
• J. Biol. Chem. • 1994 • Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction PMID:8294404
• J. Clin. Invest. • 1996 • Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy PMID:8981935
• PNAS • 2006 • Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function PMID:16983074
• J. Biol. Chem. • 2013 • Transgenic mouse alpha- and beta-cardiac myosins containing the R403Q mutation show isoform-dependent transient kinetic difference PMID:23580644

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