POMT2 – Autosomal recessive limb-girdle muscular dystrophy type 2N

Protein O-mannosyltransferase 2, encoded by POMT2, catalyses O-mannosylation critical for α-dystroglycan glycosylation. Pathogenic variants in POMT2 underlie a spectrum of α-dystroglycanopathies ranging from severe congenital Walker-Warburg syndrome to a milder autosomal recessive limb-girdle muscular dystrophy type 2N.

Inheritance is autosomal recessive. In a 2018 cohort, 12 unrelated probands carried biallelic POMT2 mutations ([PMID:29175898]), and a 2023 exome study identified three additional probands with novel compound heterozygous alleles ([PMID:36217604]). Parental sequencing confirmed trans configuration in all families, supporting consistent AR transmission without dominant effects.

Across these cohorts, 22 pathogenic POMT2 alleles were described, including 11 novel variants affecting missense, splice-site, and frameshift changes. Representative variants include c.557G>A (p.Cys186Tyr) and c.800A>G (p.Asp267Gly) in LGMD2N ([PMID:29175898], [PMID:36217604]). Additional loss-of-function and splice-site mutations have been documented in Walker-Warburg families, encompassing >20 alleles ([PMID:15894594]).

Biochemical assays demonstrate that POMT2 requires coexpression with POMT1 to catalyse O-mannosylation, and POMT2 mutations abolish enzyme activity in systems including Sf9 cells and patient lymphoblasts ([PMID:14699049], [PMID:15894594]). Muscle biopsies show markedly reduced α-dystroglycan glycosylation, confirming pathogenicity in vivo.

LGMD2N presents with proximal muscle weakness, exercise-induced pain, delayed motor milestones, and learning disabilities; all patients exhibited some cognitive impairment and specific muscle group involvement on MRI (hamstrings, paraspinal, gluteal) ([PMID:29175898]). Unlike Walker-Warburg syndrome, LGMD2N lacks severe brain and ocular malformations, defining a distinct clinical-genetic entity.

Integration of genetic and mechanistic data supports a Strong ClinGen association for POMT2 in LGMD2N, with robust AR inheritance and concordant functional evidence. POMT2 testing is clinically useful for diagnosis and prognosis in limb-girdle muscular dystrophy with cognitive features. Key take-home: POMT2 variants are a genetically and functionally validated cause of LGMD2N, guiding targeted diagnostic and management strategies.

References

• Journal of neurology, neurosurgery, and psychiatry • 2018 • Limb girdle muscular dystrophy due to mutations in POMT2. PMID:29175898
• International journal of developmental neuroscience • 2023 • Clinical exome sequencing identifies novel compound heterozygous mutations of the POMT2 gene in patients with limb-girdle muscular dystrophy. PMID:36217604
• 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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