GPR143 – X-linked ocular albinism type 1

X-linked ocular albinism type 1 (OA1) is caused by hemizygous pathogenic variants in GPR143, leading to hypopigmentation of the iris and retina, foveal hypoplasia, macromelanosomes, and congenital nystagmus. A national study identified 60 male patients with proven or presumed XLOA and 7 pathogenic GPR143 mutations across nine Danish families (PMID:9887374). Subsequent case reports include a deep intronic mutation c.659-131T>G in two Japanese siblings (PMID:26061757), a canonical splice-site variant c.658+1G>T in a five-generation Chinese pedigree with congenital nystagmus (PMID:21423867), a 97 kb Xp22.2 microdeletion encompassing GPR143 in siblings with CNPAS (PMID:24478262), and a novel splicing mutation c.360+5G>T segregating in nine affected males in another Chinese family (PMID:31746431).

Genetic evidence supports an X-linked recessive inheritance mode with over 80 unrelated male probands and 29 additional affected relatives segregating loss-of-function and missense variants. The variant spectrum includes 5 missense substitutions (e.g., c.232G>T (p.Asp78Tyr)), 4 canonical splice-site mutations, one deep intronic activation of a pseudoexon (c.659-131T>G), microdeletions, and single-exon to multi-exon deletions. A representative variant is c.659-131T>G.

Functional assays demonstrate that approximately 60% of OA1 missense mutants are misfolded and retained in the endoplasmic reticulum, whereas the remainder disrupt G protein–coupling domains (PMID:11115845). Oa1-null mice exhibit reduced melanosome number and size in retinal pigment epithelium, confirming a role in melanosome maturation (PMID:16303920). CRISPR-AsCas12a correction of an intronic splice-site mutation in patient-derived iPSCs restores normal GPR143 splicing and expression (PMID:35686978). These concordant cellular, animal, and rescue studies establish a loss-of-function mechanism via protein misfolding and defective organellogenesis.

No conflicting studies have refuted GPR143’s association with OA1. The cumulative evidence meets ClinGen criteria for a definitive gene–disease relationship, supported by extensive segregation, multiple variant classes, and robust functional validation. Panel-based testing including GPR143 yields a high diagnostic rate in ocular albinism, facilitating genetic counseling and targeted management.

Key take-home: GPR143 exhibits a definitive X-linked recessive association with ocular albinism type 1; molecular testing for coding, splice, intronic, and structural variants is clinically essential.

References

• European journal of human genetics • 1998 • X-linked ocular albinism: prevalence and mutations--a national study. PMID:9887374
• Scientific reports • 2015 • Deep intronic GPR143 mutation in a Japanese family with ocular albinism. PMID:26061757
• American journal of medical genetics. Part A • 2014 • Congenital nasal pyriform aperture stenosis and ocular albinism co-occurring in a sibship with a maternally-inherited 97 kb Xp22.2 microdeletion. PMID:24478262
• Molecular vision • 2011 • A novel GPR143 splicing mutation in a Chinese family with X-linked congenital nystagmus. PMID:21423867
• Molecular medicine reports • 2020 • A novel GPR143 mutation in a Chinese family with X-linked ocular albinism. PMID:31746431
• Human molecular genetics • 2000 • Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. PMID:11115845
• Investigative ophthalmology & visual science • 2005 • The ocular albinism type 1 (OA1) gene controls melanosome maturation and size. PMID:16303920
• The CRISPR journal • 2022 • CRISPR-AsCas12a Efficiently Corrects a GPR143 Intronic Mutation in Induced Pluripotent Stem Cells from an Ocular Albinism Patient. PMID:35686978

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