RPGRIP1 – Leber Congenital Amaurosis

RPGRIP1 (HGNC:13436) encodes the retinitis pigmentosa GTPase regulator–interacting protein 1, which localizes to the photoreceptor connecting cilium and anchors RPGR. Biallelic pathogenic variants in RPGRIP1 cause an early-onset, autosomal recessive form of Leber congenital amaurosis (LCA) characterized by congenital blindness and nystagmus (PMID:11283794; PMID:11528500).

Autosomal recessive inheritance is supported by consanguineous pedigrees, including a homozygous 1-bp insertion c.2608_2609insA (p.Leu870TyrfsTer7) in exon 16 in an Emirati family (PMID:23278760) and a homozygous exon 17 deletion c.2710+372_2895+76del1339 in Japanese siblings with LCA (PMID:25096270). Segregation of these variants with disease in multiple families underscores causality.

In a cohort of 57 unrelated LCA patients, recessive null alleles in RPGRIP1 were found in 6% of cases, demonstrating its contribution to LCA across diverse populations (PMID:11283794). A comprehensive survey of 179 LCA patients reported that RPGRIP1 mutations account for 4.5% of cases, confirming recurrent involvement in sporadic and familial presentations (PMID:15024725). Deep-intronic founder variants (e.g., c.1468-128T>G) further expand the mutation spectrum in French cohorts (PMID:33670832).

The variant spectrum includes frameshift, nonsense, splice-site, and deep-intronic alleles leading to loss of function. One representative variant is c.2608_2609insA (p.Leu870TyrfsTer7), confirmed by Sanger sequencing and predicted to truncate the RPGR-interacting domain, triggering mRNA decay (PMID:23278760).

Functional studies demonstrate that RPGRIP1 interacts with RPGR and nephrocystin-4 in the ciliary transport complex, and that disease-associated mutations disrupt these interactions (PMID:10958648; PMID:16339905). Rpgrip1 knockout mice fail to elaborate rod outer segments and undergo rapid photoreceptor degeneration, mirroring human LCA pathology (PMID:19679561).

Collectively, genetic and experimental concordance establish a definitive gene–disease association. Biallelic loss-of-function RPGRIP1 variants disrupt ciliary transport and outer segment morphogenesis, leading to autosomal recessive LCA. This knowledge supports molecular diagnosis, family counseling, and the development of targeted therapies. Key take-home: RPGRIP1 is a definitive LCA gene, and LoF variants should be screened in patients with infantile-onset blindness and nystagmus.

References

• American journal of human genetics • 2001 • Null RPGRIP1 alleles in patients with Leber congenital amaurosis PMID:11283794
• European journal of human genetics : EJHG • 2001 • Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis PMID:11528500
• Ophthalmic genetics • 2013 • Identification of a novel LCA6 mutation in an Emirati family PMID:23278760
• Japanese journal of ophthalmology • 2014 • A novel exon 17 deletion mutation of RPGRIP1 gene in two siblings with Leber congenital amaurosis PMID:25096270
• Human mutation • 2004 • Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis PMID:15024725
• 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
• Proceedings of the National Academy of Sciences of the United States of America • 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

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