MYH3 – Sheldon-Hall syndrome

Sheldon-Hall syndrome (SHS) is the most common form of distal arthrogryposis, characterized by congenital non-progressive contractures, triangular facies, prominent nasolabial folds, frequent calcaneovalgus deformity, camptodactyly, ulnar deviation of the fingers, and overlapping digits. Causative heterozygous mutations in MYH3, encoding embryonic myosin heavy chain, underlie approximately one-third of SHS cases and follow an autosomal dominant pattern (PMID:16642020).

In a cohort of 105 distal arthrogryposis type 2B patients, MYH3 variants were found in ~40% of families, corresponding to ~10 unrelated SHS probands, while additional case reports describe at least 2 more probands, for a total of ~12 affected individuals with confirmed MYH3 mutations (PMID:23401156; PMID:29314551). Segregation of novel missense alleles was demonstrated in 6 additional affected relatives in a Chinese family, confirming autosomal dominant transmission (PMID:29625835).

The MYH3 variant spectrum in SHS comprises predominantly missense changes affecting motor and rod domains. Representative alleles include c.859T>G (p.Phe287Val) (PMID:29314551), c.1160A>G (p.Tyr387Cys) (PMID:29625835), a recurrent p.Phe835del and p.Gln1090Pro (PMID:23401156).

Functional studies demonstrate that SHS-associated MYH3 mutations interfere with myosin’s catalytic ATPase activity and force production. Structure–function analyses predict disruption of the active site (PMID:16642020); Drosophila expressing FSS/SHS alleles exhibit sarcomere defects, reduced ATPase activity, and impaired locomotion (PMID:30826400); and a zebrafish smyhc1R673H model recapitulates contractures, vertebral fusions, and motor deficits, which are normalized by a myosin ATPase inhibitor (PMID:33016623).

Pathogenic MYH3 variants exert a dominant-negative effect on embryonic myosin function, leading to prolonged actomyosin binding, reduced step size, and impaired muscle and bone development. The concordance of genetic segregation, variant recurrence, and robust functional concordance supports a strong gene–disease relationship.

The clinical utility of MYH3 testing in SHS includes definitive diagnostic confirmation, informed genetic counseling for autosomal dominant inheritance, and potential exploration of myosin-targeted therapeutic approaches. Key Take-home: MYH3 missense variant analysis is clinically actionable and essential for accurate diagnosis and management of Sheldon-Hall syndrome.

References

• American journal of medical genetics. Part A • 2018 • A novel pathogenic MYH3 mutation in a child with Sheldon-Hall syndrome and vertebral fusions. PMID:29314551
• Neuromuscular disorders : NMD • 2018 • A MYH3 mutation identified for the first time in a Chinese family with Sheldon-Hall syndrome (DA2B). PMID:29625835
• American journal of medical genetics. Part A • 2013 • Spectrum of mutations that cause distal arthrogryposis types 1 and 2B. PMID:23401156
• Nature genetics • 2006 • Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. PMID:16642020
• Developmental biology • 2019 • Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila. PMID:30826400
• EMBO molecular medicine • 2020 • MYH3-associated distal arthrogryposis zebrafish model is normalized with para-aminoblebbistatin. PMID:33016623

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