RBP3 – Autosomal Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a genetically heterogeneous photoreceptor dystrophy characterized by night blindness and progressive peripheral visual field loss. The interphotoreceptor retinoid-binding protein gene RBP3 has been implicated in retinitis pigmentosa through autosomal recessive inheritance.

Genetic analysis of a consanguineous family with four affected siblings revealed a homozygous missense variant c.3238G>A (p.Asp1080Asn) segregating with RP in all four individuals (3 additional affected relatives) and absent in 395 unrelated recessive RP or isolate cases (PMID:19074801). This finding establishes a direct genotype–phenotype correlation in one family with recessive RP.

A larger screening of 216 patients with autosomal recessive or sporadic RP and 82 with other retinal dystrophies did not identify additional pathogenic RBP3 variants, suggesting that RBP3 mutations are a rare cause of RP (PMID:21067480).

To date, the only reported pathogenic variant in human RP is the missense change c.3238G>A (p.Asp1080Asn). No loss-of-function or splice variants have been implicated in RP, and no founder alleles have been described.

Functional studies demonstrate that the Asp1080Asn substitution abolishes IRBP secretion, promotes insoluble aggregates via aberrant disulfide bonding, and induces endoplasmic reticulum stress with activation of the unfolded protein response. Chemical chaperones and low-temperature treatment partially rescue secretion of mutated IRBP, confirming a misfolding-based mechanism (PMID:23486466).

Integration of genetic segregation in a single consanguineous pedigree and concordant in vitro pathogenicity assays supports a moderate clinical validity for RBP3 in autosomal recessive RP. Additional families and variants will strengthen this association. Key take-home: RBP3 screening is indicated in consanguineous or familial autosomal recessive RP to identify rare pathogenic missense alleles amenable to chaperone-based therapeutic strategies.

References

• Investigative ophthalmology & visual science • 2009 • A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa. PMID:19074801
• Ophthalmic genetics • 2010 • Screening genes of the visual cycle RGR, RBP1 and RBP3 identifies rare sequence variations. PMID:21067480
• The Journal of biological chemistry • 2013 • Secretory defect and cytotoxicity: the potential disease mechanisms for the retinitis pigmentosa (RP)-associated interphotoreceptor retinoid-binding protein (IRBP). PMID:23486466

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