CRB1 – Autosomal recessive Retinitis Pigmentosa

CRB1 (crumbs homolog 1) is robustly implicated in autosomal recessive retinitis pigmentosa (MONDO:0019200). Initial mapping of CRB1 to chromosome 1q31-q32.1 and subsequent identification of homozygous AluY insertions and missense mutations in ten unrelated RP patients established the gene’s role in RP12 (PMID:10508521). Numerous case series have since described biallelic CRB1 variants in patients with classic and atypical RP phenotypes, including preserved para-arteriolar RPE and Coats-like exudative vasculopathy (PMID:11389483).

Over 240 patients from >40 unrelated families harbor >150 distinct CRB1 sequence variants, spanning missense substitutions (e.g., p.Arg764His), nonsense and frameshift alleles, splice-site mutations, and in-frame deletions (PMID:15459956; PMID:22065545). Segregation of biallelic variants with disease in sibships (e.g., 37 affected relatives in two large consanguineous families) and recurrent alleles such as c.1125C>G (p.Tyr375Ter) in population isolates support a strong recessive inheritance model (PMID:21484995). Night blindness (HP:0000662) and constricted fields are universal clinical features.

Functional studies in Drosophila and mouse knockout models yield photoreceptor polarity defects and degeneration concordant with human RP phenotypes. iPSC-derived retinal organoids from CRB1 patients recapitulate outer-limiting membrane disruption and respond to CRISPR/Cas9-mediated correction of c.2480G>T (p.Gly827Val) (PMID:37440088). Yeast two-hybrid and co-immunoprecipitation assays demonstrate CRB1’s interaction with MPP4/MPP5, underscoring a mechanism of haploinsufficiency via scaffold destabilization (PMID:15914641).

No credible refuting evidence has emerged; variable expressivity and modifier loci (e.g., CRB2, MTHFR, CYGB) partially explain phenotypic diversity but do not dispute CRB1’s causal role. Integration of genetic and experimental data yields a definitive gene–disease association.

Key take-home: Biallelic loss-of-function or hypomorphic CRB1 variants cause a spectrum of early-onset retinal dystrophies, most commonly autosomal recessive retinitis pigmentosa, warranting molecular testing and guiding emerging gene-based therapies.

References

• Nature Genetics • 1999 • Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12) PMID:10508521
  
• American Journal of Human Genetics • 2001 • Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene PMID:11389483
  
• Human Mutation • 2004 • CRB1 mutation spectrum in inherited retinal dystrophies PMID:15459956
  
• Human Mutation • 2012 • CRB1 mutations in inherited retinal dystrophies PMID:22065545
  
• Investigative Ophthalmology & Visual Science • 2005 • MPP5 recruits MPP4 to the CRB1 complex in photoreceptors PMID:15914641
  
• Advances in Experimental Medicine and Biology • 2023 • Generation of CRB1 RP Patient-Derived iPSCs and a CRISPR/Cas9-Mediated Homology-Directed Repair Strategy for the CRB1 c.2480G>T Mutation PMID:37440088

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