CRX – Retinitis Pigmentosa

Autosomal dominant mutations in the cone-rod homeobox gene (CRX) underlie a subset of retinitis pigmentosa cases, with both missense and truncating variants reported in unrelated families. Early studies screened 294 unrelated RP probands and identified CRX mutations in four families, including late-onset RP and congenital Leber congenital amaurosis ([PMID:9792858]). Subsequent reports described novel heterozygous nonsense and frameshift variants such as c.292C>T (p.Arg98Ter) in a Chinese family and c.425A>G (p.Tyr142Cys) in two Italian patients, each segregating with atypical or mild RP phenotypes ([PMID:30460480]; [PMID:38792980]).

Inheritance is autosomal dominant with incomplete penetrance noted in some pedigrees. Segregation analysis across five families revealed at least four additional affected relatives harboring segregating CRX variants despite variable expressivity ([PMID:9792858]). In a Japanese cohort of 1,204 RP patients, CRX accounted for ~0.8% of cases, with recurrent p.Arg41Trp observed in ≥4 patients ([PMID:31213501]). Overall, eleven pathogenic CRX variants have been reported in RP, including six missense and five protein-truncating changes, with no founder alleles reported to date.

Functional assays demonstrate that homeodomain missense mutations impair DNA binding and transactivation of photoreceptor promoters. Deletion mapping defined critical DNA-binding and transactivation domains, showing that variants such as p.Arg41Gln and p.Arg90Trp reduce rhodopsin-promoter activation and synergy with NRL ([PMID:10984472]; [PMID:11971869]). Nonsense mutations truncating the homeodomain abrogate protein expression, consistent with haploinsufficiency in RP ([PMID:30460480]).

No studies have convincingly refuted the CRX–RP association; however, variable penetrance and asymptomatic carriers complicate genetic counseling. Some variants originally classified as pathogenic have been re-evaluated as likely benign based on population frequency and lack of segregation, highlighting the need for careful variant interpretation.

In conclusion, CRX variants contribute a moderate proportion of autosomal dominant RP. Genetic testing of CRX should include both sequencing and copy-number assessment, with functional data informing pathogenicity. The presence of CRX mutations supports a clinical diagnosis of RP and guides family screening and potential future gene-targeted therapies.

Key Take-home: Autosomal dominant CRX mutations reliably cause retinitis pigmentosa via impaired transcriptional regulation of photoreceptor genes, warranting inclusion in diagnostic panels.

References

• American journal of human genetics • 1998 • A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. PMID:9792858
• Genes & genomics • 2019 • A novel CRX variant (p.R98X) is identified in a Chinese family of Retinitis pigmentosa with atypical and mild manifestations. PMID:30460480
• Medicina (Kaunas, Lithuania) • 2024 • Atypic Retinitis Pigmentosa Clinical Features Associated with a Peculiar CRX Gene Mutation in Italian Patients. PMID:38792980
• The Journal of biological chemistry • 2000 • Functional domains of the cone-rod homeobox (CRX) transcription factor. PMID:10984472
• Human molecular genetics • 2002 • Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy. PMID:11971869
• Journal of medical genetics • 2019 • Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients. PMID:31213501

Evidence Based Scoring (AI generated)