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ADIPOR1 (HGNC:24040) encodes the adiponectin receptor 1 protein, which is enriched in photoreceptor inner and outer segments. Retinitis pigmentosa (MONDO:0019200) is characterized by nyctalopia, peripheral visual field constriction, and severely reduced visual acuity. Although many genes underlie RP, ADIPOR1 has emerged as a novel locus based on recent genetic and functional studies. Pathogenic variants in ADIPOR1 disrupt receptor folding or abolish function, leading to rod photoreceptor degeneration. Functional assays in zebrafish and mice demonstrate lipid transport defects and photoreceptor loss that mirror the human phenotype. These findings support ADIPOR1 as a clinically actionable RP gene.
A heterozygous missense variant, c.929A>G (p.Tyr310Cys), co-segregates with autosomal dominant RP in a large Chinese pedigree (PMID:27655171). The p.Tyr310Cys substitution affects a conserved transmembrane domain, is absent from population databases, and segregates with disease across multiple generations, providing strong segregation evidence. No other candidate variants were identified in known RP genes, reinforcing ADIPOR1 causality. Penetrance appears complete in observed family members. This establishes a dominant mechanism for ADIPOR1-related RP.
In a syndromic RP case, whole-exome sequencing identified a homozygous frameshift mutation, c.31del (p.Gln11ArgfsTer24), predicting premature truncation of ADIPOR1 (PMID:26662040). The patient presented with retinal dystrophy, obesity, and behavioral abnormalities, phenocopying the Adipor1-null mouse. Immunohistochemistry confirmed retinal ADIPOR1 expression. This variant supports an autosomal recessive inheritance and indicates variable syndromic features.
To date, two pathogenic alleles have been described: the missense p.Tyr310Cys and the truncating p.Gln11ArgfsTer24. Both disrupt receptor structure or stability, leading to loss of function. Neither variant is found at appreciable frequency in control databases (<0.0001). No recurrent or founder alleles have been reported. Additional hypomorphic or deep-intronic variants remain to be characterized.
In vitro, p.Tyr310Cys impairs ADIPOR1 folding and subcellular localization. Morpholino knockdown of adipor1 in zebrafish preferentially reduces rod photoreceptors and is partially rescued by wild-type but not mutant human ADIPOR1 mRNA ([PMID:27655171]). AdipoR1-deficient mice display decreased ω-3 polyunsaturated fatty acids, elevated ceramides, photoreceptor degeneration, and retinal dysfunction—phenotypes ameliorated by inhibitors of ceramide synthesis (PMID:38636661). These concordant models confirm a loss-of-function mechanism via impaired lipid homeostasis and highlight therapeutic targets.
Collectively, genetic and experimental data support a Moderate ClinGen-level association between ADIPOR1 and retinitis pigmentosa, with evidence of both autosomal dominant and recessive inheritance. The mechanistic link involves disrupted protein folding or truncation leading to impaired fatty acid transport and photoreceptor loss. Although only two alleles are described, strong segregation and robust functional concordance justify ADIPOR1 testing in unexplained RP cases. Future studies should define variant spectrum, penetrance, and genotype-phenotype correlations to refine diagnosis and treatment. ADIPOR1 represents a novel diagnostic marker and a potential target for lipid-based therapies in RP.
Gene–Disease AssociationModerateHeterozygous missense variant in one large AD family and homozygous frameshift in one syndromic case with concordant functional models Genetic EvidenceModerateTwo unrelated probands including an AD pedigree and an AR case with co-segregation and predicted loss-of-function variants Functional EvidenceModerateZebrafish knockdown with rescue; mouse knockout with lipidomic defects and pharmacologic rescue |