CRB1 – Leber congenital amaurosis 8

Leber congenital amaurosis 8 (LCA8) is an autosomal recessive early-onset retinal dystrophy characterized by profound visual impairment, congenital nystagmus (HP:0000639), and extinguished full‐field electroretinography ([PMID:37804373]). Two unrelated affected individuals harbor homozygous CRB1 nonsense variants, c.3057T>A (p.Tyr1019Ter) ([PMID:37804373]) and c.1499C>G (p.Ser500Ter) ([PMID:36115989]), consistent with loss-of-function pathogenicity.

CRB1 encodes a transmembrane polarity protein essential for photoreceptor–Müller glia adhesion. Drosophila models expressing human CRB1 missense alleles display abnormal subcellular localization, impaired rescue of crb null phenotypes, and accelerated photoreceptor degeneration, supporting a haploinsufficiency mechanism ([PMID:28515229]).

Key Take‐home: Limited but consistent genetic and functional data support biallelic CRB1 loss‐of‐function as the cause of LCA8, informing molecular diagnosis and potential gene‐based therapies.

References

• Documenta ophthalmologica. Advances in ophthalmology • 2023 • A novel pathogenic CRB1 variant presenting as Leber Congenital Amaurosis 8 and evaluation of gene editing feasibility. [PMID:37804373]
• 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]
• Journal of cell science • 2017 • Unique cell biological profiles of retinal disease-causing missense mutations in the polarity protein Crumbs. [PMID:28515229]

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