POMT2 – Muscle-Eye-Brain Disease

POMT2 encodes protein O-mannosyltransferase 2, an enzyme essential for O-mannosylation of α-dystroglycan. Biallelic loss-of-function variants in POMT2 cause autosomal recessive muscle-eye-brain disease, characterized by congenital muscular dystrophy with severe brain malformations and ocular involvement. The inheritance mode is autosomal recessive, and no extended segregation beyond probands has been reported.

In a fetal series of 47 type II lissencephaly cases, POMT2 mutations were identified in 7% of 41 unrelated families, implicating the gene in severe dystroglycanopathy with prenatal presentation (PMID:17559086). Subsequent screening of congenital muscular dystrophy patients unveiled three novel POMT2 variants, including a founder allele c.1997A>G (p.Tyr666Cys) seen homozygously in two unrelated individuals and in compound heterozygosity in others, confirming POMT2 involvement in muscle-eye-brain–like disease (PMID:17634419).

Patients with POMT2-related muscle-eye-brain disease present with microcephaly (HP:0000252), severe intellectual disability (HP:0010864), cerebral cortical atrophy (HP:0002120), and cerebellar vermis hypoplasia (HP:0001320). Phenotypic spectrum ranges from classic Walker-Warburg syndrome to milder muscle-eye-brain phenotypes without eye malformations.

Functional assays demonstrate that POMT2 must co-express with POMT1 to catalyze O-mannosyltransferase activity. Patient-derived POMT2 mutations lead to hypoglycosylation of α-dystroglycan in muscle and brain tissue, consistent with enzyme loss of function (PMID:15894594, PMID:14699049). Drosophila and mammalian models confirm that disruption of the POMT1–POMT2 complex impairs neuronal migration and muscle integrity.

No studies to date dispute POMT2’s role in muscle-eye-brain disease. Additional genetic modifiers may influence severity, but the core association is robust across independent cohorts and multiple functional assays.

In summary, POMT2 fulfills criteria for a strong gene–disease association: multiple unrelated probands with biallelic pathogenic variants, consistent clinical presentation, and concordant functional loss‐of‐function evidence. Genetic testing for POMT2 should be included in diagnostic panels for congenital muscular dystrophy with brain and eye involvement.

Key Take-home: Biallelic POMT2 variants cause autosomal recessive muscle-eye-brain disease via defective α-dystroglycan O-mannosylation, supporting its clinical utility in diagnosis and genetic counseling.

References

• Human Mutation • 2007 • Molecular heterogeneity in fetal forms of type II lissencephaly. PMID:17559086
• Neurology • 2007 • New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation. PMID:17634419
• Journal of Medical Genetics • 2005 • POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. PMID:15894594
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. PMID:14699049

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