MYH7 – MYH7-related Skeletal Myopathy

MYH7 encodes the slow/β-cardiac myosin heavy chain, a key sarcomeric motor protein expressed in type I skeletal muscle fibers. Heterozygous mutations in MYH7 cause an autosomal dominant distal myopathy (MONDO:0008050), classically presenting as early‐onset foot dorsiflexor weakness, finger extensor and neck flexor involvement, and Achilles tendon contractures. Onset typically occurs in childhood, with variable progression to proximal involvement and, rarely, cardiomyopathy or respiratory insufficiency.

Clinical validity is categorized as Strong based on over 150 affected individuals from more than 30 unrelated families, including 19 segregations in multi-generation pedigrees (PMID:21279644, PMID:20733148). Multiple kindreds harbor recurrent in-frame deletions, de novo events, and missense changes within the myosin rod, all co-segregating with disease. Segregation in 19 affected relatives underscores robust familial transmission.

Genetically, MYH7-related myopathy exhibits an autosomal dominant inheritance mode. The most common variant is the recurrent c.4522_4524del (p.Glu1508del), observed independently in French, Norwegian, Belgian and Finnish kindreds, and de novo in sporadic cases (PMID:21279644). Additional variants include c.5186_5188del (p.Lys1729del) and c.4850_4852del (p.Lys1617del), with a spectrum of missense and small in-frame deletions clustering in the coiled-coil tail domain.

Functional studies support a dominant-negative mechanism: MPD1-associated R1500P and L1706P mutations impair myosin self-assembly and form cytoplasmic aggregates in muscle cells and nematode models (PMID:22155079). Ultrastructural analyses reveal disrupted antiparallel filament formation and sarcomere-incorporated mutant myosin, consistent with a toxic gain-of-function.

No credible reports dispute the MYH7–Laing distal myopathy association. The concordance of genetic segregation, recurrent variants, and cellular models establishes high clinical validity without conflicting evidence.

In summary, autosomal dominant MYH7 mutations, especially recurrent in-frame deletions like c.4522_4524del (p.Glu1508del), cause a distinctive early-onset distal myopathy. Genetic testing for MYH7 rod domain variants is indicated in patients with tibialis anterior weakness, finger extensor and neck flexor involvement. Accurate molecular diagnosis enables prognosis, family screening, and potential future therapies.

References

• Journal of neurology • 2011 • A novel MYH7 mutation occurring independently in French and Norwegian Laing distal myopathy families and de novo in one Finnish patient. [PMID:21279644]
• Neurology • 2010 • MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. [PMID:20733148]
• Journal of molecular biology • 2012 • Effects of pathogenic proline mutations on myosin assembly. [PMID:22155079]
  

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