POMK – Muscular dystrophy-dystroglycanopathy, type A (Walker-Warburg syndrome)

POMK encodes the protein-O-mannose kinase critical for α-dystroglycan glycosylation and extracellular matrix integrity. Autosomal recessive bi-allelic POMK variants have been observed in a pair of male monozygotic twins presenting with congenital muscular dystrophy, hydrocephalus, cortical malformation, cerebellar hypoplasia, occipital meningocele, eye anomalies and markedly elevated creatine kinase (2 probands; PMID:32907597). Both harbored a homozygous nonsense mutation c.640C>T (p.Gln214Ter), confirming POMK’s causal role in Walker-Warburg syndrome. To date, eight pathogenic POMK variants in eight families have been described, of which five presented with the severe WWS phenotype, underscoring phenotypic variability and rarity (PMID:32907597).

Functional inference derives from POMK’s established kinase activity in dystroglycan post-translational modification. A recent Egyptian congenital muscular dystrophy cohort identified an additional homozygous missense variant c.641A>T (p.Gln214Leu) in a patient with brain malformations, supporting diagnostic yield but lacking direct biochemical assays (PMID:38296890). No segregation beyond the twins has been reported, and mechanistic studies of mutant POMK remain limited. Key take-home: POMK screening is warranted in autosomal recessive WWS presentations with classic CNS and ocular malformations.

References

• Orphanet journal of rare diseases • 2020 • Further evidence for POMK as candidate gene for WWS with meningoencephalocele. PMID:32907597
• Neurogenetics • 2024 • Genetic blueprint of congenital muscular dystrophies with brain malformations in Egypt: A report of 11 families. PMID:38296890

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