GPR143 – X-linked ocular albinism (OA1)

X-linked ocular albinism type 1 (OA1) is an X-linked recessive disorder caused by mutations in the GPR143 gene, which encodes a melanosomal G protein–coupled receptor involved in melanosome biogenesis. Affected hemizygous males present with congenital nystagmus, hypopigmentation of the iris and fundus, foveal hypoplasia, and variable reduction in visual acuity, while obligate female carriers often show subtle iris transillumination and patchy retinal pigmentation due to lyonization (PMID:9457748).

Segregation and linkage studies in multiple pedigrees, including a large family with six affected males and seven carriers, consistently map OA1 to Xp22.3 and co-segregate GPR143 mutations with disease (PMID:9457748). A national register study of 60 male patients estimated a point prevalence of 1 in 60 000 live births and identified pathogenic variants in nine Danish families (PMID:9887374). Across >30 independent families, at least 19 additional affected relatives segregate pathogenic GPR143 alleles, confirming X-linked recessive inheritance.

Over 100 unique variants in GPR143 have been described, including frameshift, nonsense, splice-site, missense, and large intragenic deletions. Loss-of-function mutations predominate, with recurrent alleles such as p.Gly84Asp observed in unrelated families, suggesting founder effects (PMID:8634705). A representative truncating variant is c.943G>T (p.Gly315Ter), identified in a Chinese pedigree and absent in 100 controls, predicted to undergo nonsense-mediated decay (PMID:19123159).

Functional assays support a loss-of-function mechanism: 60% of tested missense mutants are retained in the endoplasmic reticulum with defective glycosylation in COS-7 cells (PMID:11115845), and Oa1–/– mice exhibit reduced melanosome number and aberrant organelle sizing in the retinal pigment epithelium (PMID:16303920). Genome editing using CRISPR-AsCas12a in patient‐derived iPSCs corrects a pathogenic splice defect and restores normal GPR143 expression (PMID:35686978).

No significant conflicting evidence has been reported; phenotypic variability among carriers is attributed to random X-inactivation rather than alternative genetic etiologies. The consistency of genetic, segregation, and experimental data across diverse populations establishes a definitive role for GPR143 in OA1.

Integrating extensive genetic and functional evidence, GPR143 haploinsufficiency and protein misfolding are the primary pathogenic mechanisms in X-linked ocular albinism. Genetic testing of GPR143, including sequencing and deletion analysis, provides a reliable diagnostic tool for affected males and carrier detection in families. Key take-home: GPR143 variant analysis is essential for confirming OA1 diagnosis, guiding genetic counseling, and facilitating carrier screening.

References

• Ophthalmic genetics • 1997 • Clinical and molecular characterization of a family affected with X-linked ocular albinism (OA1) PMID:9457748
• European Journal of Human Genetics • 1998 • X-linked ocular albinism: prevalence and mutations--a national study. PMID:9887374
• Human Molecular Genetics • 1995 • Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism. PMID:8634705
• European Journal of Ophthalmology • 2009 • Identification of a novel mutation in a Chinese family with X-linked ocular albinism. PMID:19123159
• 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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