PIEZO2 – Marden-Walker Syndrome

PIEZO2 encodes a mechanically activated ion channel expressed in proprioceptors and is implicated in a spectrum of autosomal dominant distal arthrogryposis disorders. Heterozygous PIEZO2 variants have been identified in individuals with Gordon syndrome, distal arthrogryposis type 5, and Marden-Walker syndrome, suggesting these phenotypes represent variable expressivity of a single PIEZO2-related condition. In the initial cohort, exome sequencing revealed a PIEZO2 mutation in 1/2 Marden-Walker syndrome cases (PMID:24726473). A subsequent study identified a de novo nonsense variant c.8237G>A (p.Trp2746Ter) in a patient with classic Marden-Walker syndrome and Dandy-Walker malformation (PMID:36588752). To date, two unrelated Marden-Walker syndrome probands harbor heterozygous PIEZO2 variants, with no extended familial segregation reported.

Functional analyses in related distal arthrogryposis disorders demonstrate gain-of-function effects of PIEZO2 channel variants, with increased mechanically activated currents due to altered inactivation kinetics (PMID:23487782). Although direct assays on Marden-Walker syndrome variants are lacking, the established role of PIEZO2 mechanotransduction defects supports a pathogenic mechanism. Collectively, genetic and functional data integrate to position Marden-Walker syndrome at the severe end of the autosomal dominant PIEZO2-related disorder continuum. Inclusion of PIEZO2 in molecular diagnostic panels for Marden-Walker syndrome can facilitate early genetic diagnosis and inform clinical management.

References

• American journal of human genetics • 2014 • Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. PMID:24726473
• Molecular syndromology • 2022 • Further Evidence of a Continuum in the Clinical Spectrum of Dominant PIEZO2-Related Disorders and Implications in Cerebellar Anomalies. PMID:36588752
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. PMID:23487782

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