Analysis of Developmental Genes in LCA Patients with CRX Mutations and Genotype-Phenotype Correlation

Abstract

Abstract: : Purpose:Leber congenital amaurosis (LCA) is a clinically and genetically heterogenous disorder presenting in infancy with profound visual loss. Six causative genes, GUCY2D, RPE-65, CRX, AIPL1, CRB1 and RPGRIP1 have been identified. The cone-rod homeobox gene encodes a 299 amino acid protein involved in photoreceptor-specific transcription. We investigated the relationship between genotype and phenotype in patients with mutations in CRX, which account for 4% of all LCA mutations. Analysis of retina-expressed homeobox genes OTX2 and RX were undertaken in an effort to identify a second mutation in another developmental gene as the phenotype of patients with CRX mutations vary considerably, suggesting the existence of a second mutation in another gene. Methods:Mutation screening was performed using direct sequencing in a cohort of 172 LCA patients of worldwide distribution. Clinical diagnosis was based on ocular findings of reduced vision, nystagmus, sluggish pupils, normal or retinal pigmentary changes and markedly reduced ERG. Results:Mutations in CRX were detected in 11patients, four unaffected first degree relatives and absent in 150 controls. Only heterozygote mutations in CRX were identified suggesting autosomal dominant inheritance with reduced penetrance. No mutations were detected in OTX2 and RX. Phenotype consisted of vision ranging from LP to HM, nystagmus, sluggish pupillary reaction, optic disc pallor, markedly attenuated retinal vessels, atrophic changes and stippling in the macula and varying degrees of peripheral retinal mottling. Keratoconus and cataracts were identified in one proband (G248ins23bp). Cataracts were detected in older patients in whom an elongated protein was predicted. Macular changes were noted in half the patients. ERG of one patient (A177del1bp) showed residual cone function. Conclusion:Most mutations causing LCA occured in exon three. Eight novel mutations were detected. The phenotype of LCA patients with CRX mutations ranges from mild to severe and appears to be associated with macular changes in most patients. Analysis of OTX2 and RX were undertaken based on the hypothesis of transcriptional homeodomain activity of CRX influencing other ocular developmental genes, however further investigation is necessary. Evidently CRX is essential for normal photoreceptor structure and function.

Keywords: 562 retinal degenerations: hereditary • 420 genetics • 480 mutations