POMT2 – Muscular dystrophy-dystroglycanopathy, type A

POMT2 encodes protein O-mannosyltransferase 2, one of two catalytic subunits required for O-mannosylation of α-dystroglycan, critical for muscle integrity and neuronal migration. Pathogenic variants in POMT2 cause the severe congenital phenotype Walker-Warburg syndrome, the prototypical form of muscular dystrophy-dystroglycanopathy, type A, with congenital muscular dystrophy, cobblestone lissencephaly, hydrocephalus and ocular malformations.

A candidate gene approach combined with homozygosity mapping in 11 consanguineous Walker-Warburg syndrome families identified homozygous POMT2 mutations in three families and one sporadic patient, establishing POMT2 as the fourth WWS gene (PMID:15894594). Subsequent case series and single‐family reports expanded this to over 30 affected individuals across more than 20 families, confirming autosomal recessive inheritance and broad allelic heterogeneity (PMID:28815891).

Inheritance is autosomal recessive, with segregation demonstrated in multiple sibships including four affected siblings in one family with compound heterozygous variants (PMID:28815891). POMT2 variants encompass missense, loss-of-function and splice‐site changes distributed throughout the gene; recurrent alleles such as p.Tyr666Cys occur in founder contexts, and compound heterozygosity is common.

One representative variant, c.1238G>C (p.Arg413Pro), was identified in a fetus with classic WWS features and cosegregated with disease in a nonconsanguineous family (PMID:36048137). Additional reported variants include c.1484+1G>A and a spectrum of frameshift and nonsense changes, underscoring the gene’s intolerance to loss of function.

Functional studies demonstrate that POMT2 must heterodimerize with POMT1 to catalyze protein O-mannosylation. Coexpression assays in Sf9 cells confirm that neither POMT1 nor POMT2 is active alone, whereas the complex restores enzymatic function; patient muscle biopsies show markedly reduced α-dystroglycan glycosylation (PMID:16698797). Drosophila POMT2 knock-down models phenocopy muscle attachment defects, further supporting a loss-of-function mechanism.

Collectively, the genetic and experimental data support a Strong gene‐disease association and robust genetic evidence for POMT2 in muscular dystrophy-dystroglycanopathy, type A. Functional concordance across biochemical, histological and animal models confirms pathogenicity via defective O-mannosylation. Key take‐home: POMT2 sequencing is essential for molecular diagnosis and genetic counseling in congenital muscular dystrophy with brain and eye anomalies.

References

• Journal of medical genetics • 2005 • POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. PMID:15894594
• American journal of medical genetics. Part A • 2017 • Cystic kidneys in fetal Walker-Warburg syndrome with POMT2 mutation: Intrafamilial phenotypic variability in four siblings and review of literature. PMID:28815891
• Journal of biological chemistry • 2006 • Physical and functional association of human protein O-mannosyltransferases 1 and 2. PMID:16698797
• Fetal and pediatric pathology • 2023 • Fetal Presentation of Walker-Warburg Syndrome with Compound Heterozygous POMT2 Missense Mutations. PMID:36048137

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