CRX – Cone-Rod Dystrophy

Autosomal dominant cone-rod dystrophy is caused by pathogenic variants in the transcription factor CRX and manifests as progressive loss of cone and rod function (cone-rod dystrophy). A four-generation pedigree linked to chromosome 19q included 34 affected individuals with early visual acuity loss and later night blindness, confirming dominant inheritance (34 affected across four generations) (PMID:7864751).

In a Japanese family, a heterozygous missense variant c.121C>T (p.Arg41Trp) was identified in three affected members across three generations, cosegregating with age-dependent retinal degeneration and electroretinographic decline (PMID:12819982). In a Chinese kindred, a novel frameshift c.538dupG (p.Val180GlyfsTer?) variant was found in all affected individuals and absent from controls, confirming its pathogenic role (4 affected; PMID:30095615).

CRX variant spectrum includes missense substitutions within the homeodomain and C-terminal frameshifts. In targeted cohorts, CRX mutations account for ~1.8% of cone-rod dystrophy probands (PMID:26992781), with recurrent missense and truncating alleles distributed across exons.

Functional assays demonstrate that CRX missense and truncating variants impair DNA binding and transactivation. The R90W homeodomain substitution shows reduced binding to photoreceptor gene promoters and diminished synergy with NRL (PMID:9931337), while deletion of the activation domain abolishes transactivation despite intact DNA binding (PMID:10984472). These data support a mechanism of dominant-negative interference and haploinsufficiency.

No definitive evidence disputes the association; however, genotype-phenotype correlations vary, and some hypomorphic variants may require further evaluation for benign status. The cumulative evidence supports a strong and consistent role of CRX in autosomal dominant cone-rod dystrophy.

Key Take-home: CRX genetic testing is clinically useful for diagnosis, family segregation, and guiding therapeutic development for cone-rod dystrophy.

References

• Archives of ophthalmology • 1995 • Chromosome 19q cone-rod retinal dystrophy. Ocular phenotype. PMID:7864751
• Graefe's archive for clinical and experimental ophthalmology • 2003 • Ocular findings in a Japanese family with an Arg41Trp mutation of the CRX gene. PMID:12819982
• Medicine • 2018 • A novel CRX frameshift mutation causing cone-rod dystrophy in a Chinese family: A case report. PMID:30095615
• Human molecular genetics • 1999 • Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. PMID:9931337
• The Journal of biological chemistry • 2000 • Functional domains of the cone-rod homeobox (CRX) transcription factor. PMID:10984472

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