Disease relevance of CRX

• Our results suggest that CRX transcription interference accounts for the retinal degeneration in SCA7 and thus may provide an explanation for how cell-type specificity is achieved in this polyglutamine repeat disease [1].
• In human cell lines, PNR expression was observed in Y79 retinoblastoma along with other photoreceptor marker genes such as CRX [2].
• Because loss of CRX function could alter the expression of a number of other retinal proteins, we screened for mutations in the CRX gene in probands with a range of degenerative retinal diseases [3].
• Of the 294 unrelated individuals screened, we identified four CRX mutations in families with clinical diagnoses of autosomal dominant cone-rod dystrophy, late-onset dominant retinitis pigmentosa, or dominant congenital Leber amaurosis (early-onset retinitis pigmentosa), and we identified four additional benign sequence variants [3].
• Three patients (16.7%) developed a hydropneumothorax due to U-GCTP which was detected by sonography but was missed by postero-anterior CRX in one patient [4].

Psychiatry related information on CRX

• Dominant CRX mutations have not been associated with mental retardation or developmental delay that has sometimes been found in Leber congenital amaurosis caused by other genes [5].

High impact information on CRX

• De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis [6].
• Mutations in the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative effect and demonstrate that CRX is essential for the maintenance of mammalian photoreceptors [7].
• Here we show that mutations in a novel photoreceptor-specific homeodomain transcription factor gene (CRX) cause an autosomal dominant form of cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13 [7].
• Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor [7].
• In affected members of a CORD2-linked family, the highly conserved glutamic acid at the first position of the recognition helix is replaced by alanine (E80A) [7].

Biological context of CRX

• We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation [1].
• These data suggest that the R90W mutation results in a CRX protein with reduced DNA binding and transcriptional regulatory activity and that the subsequent changes in photoreceptor gene expression lead to the very early onset severe visual impairment in LCA [8].
• These mice reproduced features of infantile SCA7 (ataxia, visual impairments, and premature death) and showed impaired short-term synaptic potentiation; downregulation of photoreceptor-specific genes, despite apparently normal CRX activity, led to shortening of photoreceptor outer segments [9].
• The goal of this study is to better understand the molecular basis of CRX function and to provide insight into how mutations in CRX cause such a variety of clinical phenotypes [10].
• Genomic DNA was screened for mutations by means of single-strand conformational polymorphism (SSCP) analysis in exons of the RPE65 and CRX genes [11].

Anatomical context of CRX

• The CRX (cone-rod homeobox) gene is specifically expressed in developing and mature photoreceptors and encodes an otd/Otx-like paired homeodomain protein [8].
• If any discrepancy between TS, the clinical presentation and the CRX became apparent, either a lateral CRX or a computed tomography (CT) of the thorax was performed [4].
• The patients were divided into four angiographic groups: (I) lesions at the left anterior descending (LAD), n = 35; (II) stenosis at the circumflex (CRX), n = 35; (III) stenosis at the right coronary artery (RCA), n = 35; and (IV) another group of 35 normal subjects serving as controls [12].
• The tissue-specific gene expression within the pineal gland and retina derives, in part, from a pineal/retina-specific transcription factor, cone-rod homeobox protein, which binds to a pineal regulatory element [13].
• Immunoglobulin deposition observed in sural nerve biopsies and abnormal immunoglobulin patterns in the "CSF in some cases suggest a dysimmune pathogenesis; thus the term chronic relapsing (dysimmune) polyneuropathy (CRDP) is preferred [14].

Associations of CRX with chemical compounds

• A homozygous substitution of arginine (R) at codon 90 by tryptophan (W) was identified in the CRX homeodomain of one of the probands who was nearly blind from birth [8].
• Deletion analysis revealed that the CRX homeodomain (CRX-HD) plays an important role in the interaction with the NRL leucine zipper [15].
• However, CRX is a transcription factor for several retinal genes, including the opsins and the gene for interphotoreceptor retinoid binding protein [3].
• When the copper-resistant methanogen Methanobacterium bryantii BKYH was exposed to 1 mM Cu(II), it secreted approximately fourfold increased levels of three proteins, copper response extracellular (CRX) proteins [16].
• The promoter elements, common to both the X-arrestin and S-antigen genes, include the Ret-1/PCE-1 (PCE-1-like in X-arrestin), CRX, and the thyroid hormone/retinoic acid-responsive sequences, the former two being present in a number of photoreceptor-expressed genes [17].

Physical interactions of CRX

• In addition, alignment of 5'-flanking sequences upstream of the human and mouse RS1 translation initiation sites identified putative binding sites for several transcription factors including CRX, a homeodomain transcription factor known to activate the transcription of several photoreceptor-specific genes [18].

Regulatory relationships of CRX

• Interestingly, the mapped CRX transactivation domains were also critical when coexpressed with NRL [10].
• (2001) provide insight into the cell specificity of pathology for a polyglutamine disease by relating SCA7-induced retinal degeneration to a disruption of the photoreceptor-specific transcription factor CRX [19].

Other interactions of CRX

• The clinical presentation was variable; however, the visual evolution in patients with mutations in GUCY2D and CRX remained stable, while individuals with mutations in the RPE65 gene showed progressive visual loss [20].
• Mutant alleles of the CRX gene have recently been associated with autosomal dominant cone-rod dystrophy (CORD) as well as dominant Leber congenital amaurosis (LCA) [8].
• With the PDE6B promoter, FIZ1 synergized with NRL alone, and the inclusion of CRX decreased this synergy [21].
• PCR-SSCP mutation analysis revealed no mutations in the screened RPE65 and CRX genes [11].
• Our method was applied to three retina-specific TFs, CRX, NRL and NR2E3, and a number of potential targets were predicted [22].

Analytical, diagnostic and therapeutic context of CRX

• In SCA7 transgenic mice, electrophoretic mobility shift assays indicated reduced CRX binding activity, while RT-PCR analysis detected reductions in CRX-regulated genes [1].
• Consistent with these results, chromatin immunoprecipitation assays document retinal-specific association of CRX, GCN5, and acetylated histone H3 with CRX target genes [23].
• Previous data had shown CRX expression in the adult human retina to be photoreceptor-specific; however, we demonstrate that this gene is also expressed in the inner nuclear layer (INL) of the human and mouse retina by in situ hybridization and immunocytochemistry [24].
• Binding assay and cell culture studies indicate that both PCE-1 and OTX elements and at least two different regulatory factors RX and CRX are necessary for high level, photoreceptor cell-restricted gene expression [25].
• Real-time PCR and/or Northern blot analysis confirmed the expression changes of a subset of genes including the upregulation of a pineal- and retina-specific transcription factor, CRX [26].

References