MYH7 – Myosin Storage Myopathy (Congenital Myopathy 7A)

MYH7, encoding the slow/β-cardiac myosin heavy chain, is definitively associated with congenital myopathy 7A, myosin storage myopathy (MSM), an autosomal dominant protein-aggregate myopathy marked by subsarcolemmal, hyaline-like inclusions in type I fibers and variable cardiac involvement.

Autosomal dominant MSM has been described in multiple unrelated probands. A novel head-domain missense variant, c.1370T>G (p.Ile457Arg), was reported in an adult with childhood-onset thigh-predominant weakness and intrasarcoplasmic hyaline bodies ([PMID:31068177]). A second heterozygous head-domain change, c.1888C>A (p.Pro630Thr), co-segregated with proximal muscle weakness and dilated cardiomyopathy in three affected members of an Iranian pedigree ([PMID:37794383]).

A landmark cohort study of 19 patients with MSM or scapulo-peroneal myopathy identified the recurrent rod-domain mutation c.5533C>T (p.Arg1845Trp) in four index cases and 11 additional relatives, illustrating a phenotypic continuum from asymptomatic hyperCKemia to overt muscle weakness with hyaline inclusions ([PMID:17336526]).

The MSM variant spectrum spans motor-domain and coiled-coil rod-domain missense changes, including c.1370T>G (p.Ile457Arg) ([PMID:31068177]), c.1888C>A (p.Pro630Thr) ([PMID:37794383]), c.5533C>T (p.Arg1845Trp) ([PMID:17336526]), and c.5378T>C (p.Leu1793Pro) ([PMID:16684601]).

Functional studies corroborate a dominant-negative mechanism: expression of rod mutants (p.Leu1793Pro, p.Arg1845Trp, p.Glu1886Lys, p.His1901Leu) in cultured human muscle cells induced filament assembly defects and aggregate formation, while C. elegans models rescued contractility but retained pathological aggregates ([PMID:19336582], [PMID:28125727]).

The concordant genetic and experimental evidence—18 unrelated probands (15 with p.Arg1845Trp) ([PMID:17336526]), multi-family segregation (11 relatives) ([PMID:17336526]; 2 relatives) ([PMID:37794383]), and robust mechanistic data—establishes MYH7 and autosomal dominant MSM as a definitive gene-disease pairing. Key Take-home: MYH7 mutation analysis should be integrated into the diagnostic workup of suspected myosin storage myopathy to guide management and genetic counseling.

References

• BMC medical genetics • 2019 • A novel missense mutation in the MYH7 gene causes an uncharacteristic phenotype of myosin storage myopathy: a case report. PMID:31068177
• BMC cardiovascular disorders • 2023 • A novel heterozygous missense MYH7 mutation potentially causes an autosomal dominant form of myosin storage myopathy with dilated cardiomyopathy. PMID:37794383
• Neuromuscular disorders: NMD • 2007 • MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy. PMID:17336526
• Neuromuscular disorders: NMD • 2006 • Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred. PMID:16684601
• Proceedings of the National Academy of Sciences of the United States of America • 2009 • Mutations in the beta-myosin rod cause myosin storage myopathy via multiple mechanisms. PMID:19336582
• PLoS ONE • 2017 • Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells. PMID:28125727

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