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X-linked retinitis pigmentosa (XLRP) is a severe form of inherited retinal degeneration characterized by early‐onset night blindness and progressive visual field constriction. Pathogenic variants in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene have been identified in the majority of families with definitive X-linked inheritance, accounting for up to 71% of XLRP cases (PMID:12657579). The RPGR transcript undergoes complex splicing to produce a constitutive exons 1–19 variant and a photoreceptor‐specific ORF15 variant, both of which localize to the photoreceptor connecting cilium.
Genetically, RPGR-associated XLRP follows an X-linked recessive inheritance pattern, with hemizygous males typically affected and heterozygous females variably manifesting symptoms due to X‐chromosome inactivation (PMID:23150612). Segregation analysis across multiple multi‐generation pedigrees has identified at least 19 additional affected relatives carrying segregating RPGR variants. Case series and cohort studies have reported over 300 unrelated male probands with RPGR mutations, including frameshift, nonsense, splice‐site, and missense variants leading to loss of function or aberrant splicing.
The variant spectrum of RPGR includes recurrent and private alleles distributed throughout exons 1–14 and ORF15. A prominent example is c.2403_2406del (p.Glu802GlyfsTer12), a heterozygous frameshift variant identified in a Turner syndrome mosaic patient, which disrupts the RPGR open reading frame and cosegregates with RP phenotype (PMID:29135076). Loss‐of‐function and frame‐shift mutations predominate, consistent with a haploinsufficiency mechanism.
Functional assays have provided concordant experimental evidence: aberrant splicing due to exonic and intronic RPGR variants has been demonstrated in patient‐derived cells (e.g., c.154G>C; p.Gly52Arg causing exon 2 skipping) with downstream in‐frame deletions that impair the RCC1-like domain (PMID:15364249). In vivo, an abbreviated RPGR-ORF15 construct in knockout mice localized correctly to the connecting cilium and substantially rescued photoreceptor degeneration, confirming the essential role of the ORF15 domain in photoreceptor survival (PMID:15671266).
Further supporting pathogenicity, codon-optimized RPGR delivered via AAV8 vectors restored retinal function in two mouse models of XLRP, achieving sustained expression and retarding photoreceptor loss without off-target toxicity (PMID:28549772). Additionally, U1 snRNA–mediated correction of the c.1245+3A>T splice defect in intron 10 partially restored correctly spliced transcripts in patient fibroblasts, highlighting a promising therapeutic strategy for RPGR splice variants (PMID:21326217).
Collectively, the genetic and experimental data meet ClinGen criteria for a definitive gene–disease association. The abundant case reports, segregation across diverse pedigrees, and robust functional concordance—including splicing assays, animal rescue, and gene therapy studies—underscore RPGR as the primary driver of XLRP. Ongoing therapeutic development, including AAV-mediated gene replacement and splice-modulating approaches, offers a broad intervention window in affected males and symptomatic female carriers.
Key Take-home: RPGR mutation screening is essential for the accurate diagnosis and management of X-linked retinitis pigmentosa, guiding genetic counseling and enabling eligible patients to access emerging gene-based therapies.
Gene–Disease AssociationDefinitiveNumerous unrelated probands (>300), multi-family segregation, consistent functional studies Genetic EvidenceStrongOver 300 probands with segregating LoF and splice variants; consistent X-linked recessive inheritance ([PMID:12657579], [PMID:23150612]) Functional EvidenceStrongSplice assays confirm aberrant transcripts; in vivo rescue by abbreviated ORF15 and gene therapy vectors demonstrates causal mechanism |