RPGRIP1 – Leber congenital amaurosis 6

RPGRIP1 is a ciliary transition zone protein essential for photoreceptor connecting cilium integrity. Biallelic pathogenic variants in RPGRIP1 underlie autosomal recessive Leber congenital amaurosis 6 (Leber congenital amaurosis 6).

In a Chinese cohort, five unrelated families were molecularly diagnosed with LCA6 due to compound heterozygous or homozygous RPGRIP1 variants presenting congenital night blindness, nystagmus, and early visual defect (PMID:34796026). Subsequent studies identified additional unrelated probands in Thai (n = 1) (PMID:28453600) and Iranian (n = 1) (PMID:29193763) pedigrees with fully co-segregating LoF alleles.

To date, at least seven unrelated probands harbor biallelic loss-of-function variants, including nonsense and frameshift changes. A founder deep intronic variant c.1468-128T>G was shown to account for 13% of RPGRIP1 alleles in a French LCA cohort, with pseudo-exon inclusion confirmed by patient lymphoblast assays (PMID:33670832). The variant spectrum encompasses early truncating (e.g., c.1111C>T (p.Arg371Ter)), splice-site, and deep intronic mutations.

Functionally, RPGRIP1 isoforms interact with the RCC1-homology domain of RPGR, localizing together in rod outer segments and mediating vesicular trafficking in photoreceptors (PMID:10958648). In Rpgrip1 knockout and splice-acceptor mutant mice, rod outer segments fail to elaborate, leading to early photoreceptor degeneration that phenocopies human LCA6 (PMID:19679561). These data support a loss-of-function, haploinsufficiency mechanism.

No studies have refuted the association, although clinical presentations exhibit heterogeneity in fundus morphology and ERG severity, suggesting potential modifier effects or isoform-specific expression.

Integration of robust genetic segregation in multiple families, recurrent alleles including a prevalent deep intronic founder, and concordant in vivo and in vitro functional assays establish a Definitive autosomal recessive association between RPGRIP1 and Leber congenital amaurosis 6. Key Take-home: Molecular diagnosis of RPGRIP1-mediated LCA6 is critical for patient stratification and eligibility for gene-targeted therapies.

References

• Journal of ophthalmology • 2021 • Ocular Characteristics of Patients with Leber Congenital Amaurosis 6 Caused by Pathogenic RPGRIP1 Gene Variation in a Chinese Cohort PMID:34796026
• Investigative ophthalmology & visual science • 2017 • Whole Exome Sequencing in Eight Thai Patients With Leber Congenital Amaurosis Reveals Mutations in the CTNNA1 and CYP4V2 Genes PMID:28453600
• Journal of cellular and molecular medicine • 2018 • Identification of a novel RPGRIP1 mutation in an Iranian family with leber congenital amaurosis by exome sequencing PMID:29193763
• Genes • 2021 • Whole Locus Sequencing Identifies a Prevalent Founder Deep Intronic RPGRIP1 Pathologic Variant in the French Leber Congenital Amaurosis Cohort PMID:33670832
• Human molecular genetics • 2000 • The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors PMID:10958648
• Human molecular genetics • 2009 • RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesis PMID:19679561

Evidence Based Scoring (AI generated)