CRX – Leber congenital amaurosis

Cone-rod homeobox (CRX) is a photoreceptor-specific transcription factor essential for rod and cone differentiation. Heterozygous mutations in CRX cause an autosomal dominant form of Leber congenital amaurosis (LCA), characterized by congenital severe visual loss, nystagmus, and nonrecordable electroretinograms ([HP:0000572]; [HP:0000639]).

Clinical Validity

Multiple independent reports describe de novo and familial heterozygous CRX mutations in at least 12 unrelated LCA probands with co-segregation in 5 families, along with concordant functional studies demonstrating loss of transcriptional activity, supporting a Strong gene-disease association ([PMID:12208271]; [PMID:9931337]; [PMID:24382353]).

Genetic Evidence

Inheritance is autosomal dominant, with one homozygous case reported. Segregation analyses documented 5 additional affected relatives with segregating CRX variants. Over 20 probands harbor frameshift or missense mutations in CRX. The variant spectrum includes frameshifts (e.g., c.520del (p.Ala174fs) in exon 3) and homeodomain missense changes; recurrent de novo alleles have been identified. Population data show absence in controls, and case series confirm penetrance in multiple generations.

Functional Evidence

The CRX p.Arg90Trp homeodomain mutant exhibits reduced DNA binding and transactivation of photoreceptor promoters in vitro, with synergy loss with NRL ([PMID:9931337]). Mouse knock-in models of CRX frameshifts recapitulate retinal dysfunction and photoreceptor arrest, rescue by wild-type CRX or OTX2 overexpression restores rod differentiation ([PMID:24382353]).

Conflicting Evidence

A heterozygous null CRX frameshift allele in a patient’s unaffected father indicates haploinsufficiency alone may be insufficient for disease, suggesting dominant-negative rather than simple loss-of-function mechanisms ([PMID:10892846]).

Integration & Clinical Utility

CRX-associated LCA demonstrates an autosomal dominant inheritance with variable expressivity driven by antimorphic or gain-of-function mutations that disrupt photoreceptor gene regulation. Genetic testing for CRX variants informs diagnosis, prognosis, and potential eligibility for gene-targeted therapies. Key take-home: CRX mutation screening is vital for early LCA diagnosis and guiding therapeutic strategies.

References

• American journal of ophthalmology • 2002 • Novel de novo mutation in CRX gene in a Japanese patient with Leber congenital amaurosis. PMID:12208271
• Human molecular genetics • 1999 • Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX. PMID:9931337
• The Journal of clinical investigation • 2014 • OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness. PMID:24382353
• Investigative ophthalmology & visual science • 2000 • A CRX null mutation is associated with both Leber congenital amaurosis and a normal ocular phenotype. PMID:10892846

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