POMGNT2 – Muscular Dystrophy-Dystroglycanopathy Type A

POMGNT2 is an autosomal recessive gene implicated in dystroglycanopathies. To date, there are no reported patients with Walker-Warburg syndrome (type A dystroglycanopathy; MONDO:0000171) carrying POMGNT2 variants, and no segregation data in affected families. However, three unrelated individuals with compound heterozygous or homozygous missense POMGNT2 variants were identified in a cohort of 20 dystroglycanopathy patients presenting with a milder limb-girdle muscular dystrophy without brain malformation (c.494T>C (p.Met165Thr)) [PMID:27066570].

Functional studies using AGO61/POMGNT2-knockout mice demonstrate a loss of laminin-binding α-dystroglycan glycans, abnormal basal lamina formation, and neuronal migration defects consistent with cobblestone lissencephaly (HP:0007260) ([PMID:24256719]). Enzymatic assays confirm that AGO61 acts as a β-1,4-N-acetylglucosaminyltransferase essential for priming functional glycan motifs on α-dystroglycan. These concordant animal and biochemical data support a loss-of-function mechanism.

Overall, clinical genetic evidence for POMGNT2 in Walker-Warburg syndrome remains limited, with no directly affected probands, but functional data are moderate. Additional patient ascertainment and segregation studies are required to establish a definitive gene–disease relationship.

Key Take-home: POMGNT2 loss-of-function leads to defective α-dystroglycan glycosylation and neuronal migration abnormalities, but clinical confirmation in Walker-Warburg syndrome is currently limited.

References

• Scientific Reports • 2013 • AGO61-dependent GlcNAc modification primes the formation of functional glycans on α-dystroglycan PMID:24256719
• Neurology Genetics • 2015 • Milder forms of muscular dystrophy associated with POMGNT2 mutations. PMID:27066570

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