POMGNT1 – Non-syndromic Retinitis Pigmentosa

POMGNT1 encodes protein O-mannose β1,2-N-acetylglucosaminyltransferase 1, a key enzyme in O-mannosyl glycosylation. Biallelic POMGNT1 mutations were initially linked to congenital muscular dystrophy with brain and eye anomalies (municipal dystroglycanopathies). In 2016, recessive POMGNT1 variants were reported in three unrelated families with non-syndromic autosomal recessive retinitis pigmentosa (RP), without extraocular involvement ([PMID:26908613]). A subsequent study in five additional families mapped a homozygous region at 1p34–p33 in 17 RP patients and identified a novel missense allele, c.359A>C (p.Leu120Arg), which co-segregated and reduced enzyme activity by ~80% ([PMID:27391550]).

Genetic evidence supports autosomal recessive inheritance with 20 unrelated probands and segregation across eight families ([PMID:26908613], [PMID:27391550]). Variant classes include missense and predicted loss-of-function alleles. Notably, the recurrent splice-site variant c.751+1G>A and the novel missense variant c.1010T>C (p.Ile337Thr) were each observed in three affected siblings with posterior subcapsular cataracts ([PMID:38137617]).

Functional assays demonstrate that RP-associated alleles markedly reduce POMGNT1 enzymatic activity in patient and heterologous cell extracts, consistent with a hypomorphic mechanism ([PMID:26908613], [PMID:27391550]). Immunohistochemistry localizes POMGNT1 to the photoreceptor basal body, and mutant alleles impair photoreceptor survival in vitro, indicating a direct role for O-mannosylation in retinal maintenance.

No conflicting reports have been published. The combined genetic and functional data meet ClinGen criteria for a Strong gene–disease association. POMGNT1 should be included in diagnostic gene panels for inherited retinal dystrophy, and enzyme activity assays may aid variant interpretation.

Key Take-home: Biallelic hypomorphic POMGNT1 variants cause autosomal recessive non-syndromic RP through impaired O-mannosylation of photoreceptor proteins, supporting its clinical utility in genetic diagnosis.

References

• Human molecular genetics • 2016 • Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa. PMID:26908613
• Investigative ophthalmology & visual science • 2016 • Homozygosity Mapping and Whole-Genome Sequencing Links a Missense Mutation in POMGNT1 to Autosomal Recessive Retinitis Pigmentosa. PMID:27391550
• Journal of clinical medicine • 2023 • Case Series on Autosomal Recessive Non-Syndromic Retinitis Pigmentosa Caused by POMGNT1 Mutations with a Report of a New Variant. PMID:38137617

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