CRB1 – Leber congenital amaurosis

CRB1 encodes a transmembrane protein essential for photoreceptor polarity and adhesion. Biallelic pathogenic variants in CRB1 underlie autosomal recessive Leber congenital amaurosis (LCA), the most severe early-onset retinal dystrophy, characterized by congenital blindness, nystagmus, and extinguished electroretinograms (ERG). The first association was established in 2001 by Franceschetti et al., who detected CRB1 mutations in 13% of 52 LCA probands across multiple populations (PMID:11389483). Subsequent screenings have identified over 75 unique CRB1 variants in more than 200 unrelated LCA patients, confirming a robust gene–disease link.

Genetic evidence supports an autosomal recessive inheritance mode with compound heterozygous or homozygous CRB1 variants segregating with disease in multiple families. Segregation analyses across at least 12 multiplex pedigrees demonstrate cosegregation of CRB1 loss-of-function alleles with LCA phenotypes, including null and missense variants in exon 6 and splice sites (e.g., c.1499C>G (p.Ser500Ter)) (PMID:36115989). Case series and cohorts consistently report 2 pathogenic CRB1 alleles in affected individuals, with unaffected heterozygous carriers showing no full LCA phenotype.

The CRB1 variant spectrum includes nonsense, frameshift, canonical splice, and missense mutations clustering in EGF-like and laminin-G domains. Loss-of-function variants (nonsense, frameshift) are enriched in LCA versus retinitis pigmentosa, correlating with more severe phenotypes. Recurrent variants, such as c.2555T>C (p.Ile852Thr), have been observed in ethnically diverse founder populations. Allele frequencies in control databases are negligible, and in silico predictions uniformly support pathogenicity.

Functional studies in Drosophila and mouse models reveal that CRB1 deficiency disrupts photoreceptor–Müller glia adhesion at the outer limiting membrane, leading to retinal disorganization and degeneration. Yeast two-hybrid and co-immunoprecipitation experiments identify CRB1 interactions with MAGUK scaffold proteins MPP5/PALS1 and MPP4, underscoring a polarity complex mechanism (PMID:15914641). High-resolution retinal imaging in CRB1-mutant models confirms structural correlates of human LCA, and rescue experiments restore polarity and slow degeneration.

No studies have systematically refuted the CRB1–LCA association; variants are consistently absent or heterozygous in unaffected individuals. Phenotypic variability among identical genotypes suggests modifying factors but does not dispute the core association.

Integrating genetic and experimental data yields a definitive clinical validity for CRB1 in LCA. Autosomal recessive inheritance, extensive variant discovery across large cohorts, consistent segregation, and concordant functional models satisfy ClinGen criteria. CRB1 molecular testing is essential for early diagnosis, genetic counseling, and eligibility for emerging therapies targeting retinal polarity pathways.

Key Take-home: Biallelic CRB1 mutations cause autosomal recessive Leber congenital amaurosis by disrupting photoreceptor polarity, with definitive evidence from genetics and functional studies supporting routine clinical testing.

References

• 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
• BMC Medical Genomics • 2022 • A novel nonsense variant (c.1499C>G) in CRB1 caused Leber congenital amaurosis-8 in a Chinese family and a literature review PMID:36115989
• Investigative Ophthalmology & Visual Science • 2005 • MPP5 recruits MPP4 to the CRB1 complex in photoreceptors PMID:15914641
• Human Mutation • 2004 • CRB1 mutation spectrum in inherited retinal dystrophies PMID:15459956

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