RPGRIP1 – Cone-Rod Dystrophy

RPGRIP1 encodes a ciliary protein expressed in the photoreceptor connecting cilium. Biallelic RPGRIP1 variants are classically linked to Leber congenital amaurosis but also underlie autosomal recessive cone-rod dystrophy (CORD), characterized by primary cone degeneration followed by rod involvement. Early identification of RPGRIP1-mediated CORD is critical for diagnosis and emerging gene therapies.

In a Chinese cohort of 163 unrelated CORD probands, RPGRIP1 variants were found in 2 individuals (1.2%) (PMID:26992781). In a separate exome study of 47 Chinese CORD families, one family harbored a homozygous nonsense variant c.799C>T (p.Arg267Ter) in RPGRIP1 (PMID:23776498). Molecular diagnosis in 99 Chinese inherited retinal degeneration patients identified three probands with RPGRIP1 mutations—including c.154C>T (p.Arg52Ter)—co-segregating with retinitis pigmentosa and Leber congenital amaurosis (PMID:28456785). A natural history review of 228 RPGRIP1 patients documented 13 CORD cases, with an average onset in early childhood (PMID:34722527).

Segregation analysis demonstrates co-segregation in multiple families. Two affected siblings in one sibship with c.154C>T (p.Arg52Ter) shared the homozygous variant (PMID:28456785). A novel Iranian family recessive frameshift c.2890del (p.Ser964ProfsTer?) showed complete segregation among affected relatives (PMID:29193763). A deep intronic founder variant c.1468-128T>G segregated in 8 of 60 CORD pedigrees in a French cohort (PMID:33670832).

Functional assays confirm the mechanism of pathogenicity. RPGRIP1 interacts with RPGR via its RPGR-interacting domain; LCA- and CORD-associated mutations disrupt this binding in yeast two-hybrid and co-immunoprecipitation assays (PMID:10958648, PMID:15800011). C2 domain mutations abolish interaction with nephrocystin-4, implicating defective vesicular transport in photoreceptors (PMID:16339905).

Animal models recapitulate the human phenotype. Rpgrip1 knockout mice fail to elaborate rod outer segments and exhibit early photoreceptor degeneration, mirroring human CORD (PMID:19679561). In a canine RPGRIP1(-/-) model, oligogenic modifiers on chromosomes 15 and 30 modulate age of onset and severity, illustrating genetic complexity (PMID:22193413).

In summary, autosomal recessive RPGRIP1 loss-of-function causes cone-rod dystrophy with consistent genetic and functional evidence across human cohorts and animal models. Key take-home: genetic testing for RPGRIP1 should be integrated into CORD diagnostic panels to identify candidates for gene therapy.

References

• Experimental Eye Research • 2016 • Molecular genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands. PMID:26992781
• PLoS One • 2013 • Exome sequencing of 47 chinese families with cone-rod dystrophy: mutations in 25 known causative genes. PMID:23776498
• Oncotarget • 2017 • Targeted next generation sequencing identified novel mutations in RPGRIP1 associated with both retinitis pigmentosa and Leber's congenital amaurosis in unrelated Chinese patients. PMID:28456785
• Frontiers in Cell and Developmental Biology • 2021 • Retinal Degeneration Associated With RPGRIP1: A Review of Natural History, Mutation Spectrum, and Genotype-Phenotype Correlation in 228 Patients. PMID:34722527
• 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 • 2005 • Limited proteolysis differentially modulates the stability and subcellular localization of domains of RPGRIP1 that are distinctly affected by mutations in Leber's congenital amaurosis. PMID:15800011
• Proceedings of the National Academy of Sciences • 2005 • Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. PMID:16339905
• Human Molecular Genetics • 2009 • RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesis. PMID:19679561
• Mammalian Genome • 2012 • Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration. PMID:22193413

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