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Gene Review

CRX  -  cone-rod homeobox

Homo sapiens

Synonyms: CORD2, CRD, Cone-rod homeobox protein, LCA7, OTX3
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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


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


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


  1. Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. La Spada, A.R., Fu, Y.H., Sopher, B.L., Libby, R.T., Wang, X., Li, L.Y., Einum, D.D., Huang, J., Possin, D.E., Smith, A.C., Martinez, R.A., Koszdin, K.L., Treuting, P.M., Ware, C.B., Hurley, J.B., Ptácek, L.J., Chen, S. Neuron (2001) [Pubmed]
  2. Identification of a photoreceptor cell-specific nuclear receptor. Kobayashi, M., Takezawa, S., Hara, K., Yu, R.T., Umesono, Y., Agata, K., Taniwaki, M., Yasuda, K., Umesono, K. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. Sohocki, M.M., Sullivan, L.S., Mintz-Hittner, H.A., Birch, D., Heckenlively, J.R., Freund, C.L., McInnes, R.R., Daiger, S.P. Am. J. Hum. Genet. (1998) [Pubmed]
  4. Accuracy of transthoracic sonography in excluding post-interventional pneumothorax and hydropneumothorax. Comparison to chest radiography. Reissig, A., Kroegel, C. European journal of radiology. (2005) [Pubmed]
  5. Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX. Rivolta, C., Berson, E.L., Dryja, T.P. Hum. Mutat. (2001) [Pubmed]
  6. De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis. Freund, C.L., Wang, Q.L., Chen, S., Muskat, B.L., Wiles, C.D., Sheffield, V.C., Jacobson, S.G., McInnes, R.R., Zack, D.J., Stone, E.M. Nat. Genet. (1998) [Pubmed]
  7. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Freund, C.L., Gregory-Evans, C.Y., Furukawa, T., Papaioannou, M., Looser, J., Ploder, L., Bellingham, J., Ng, D., Herbrick, J.A., Duncan, A., Scherer, S.W., Tsui, L.C., Loutradis-Anagnostou, A., Jacobson, S.G., Cepko, C.L., Bhattacharya, S.S., McInnes, R.R. Cell (1997) [Pubmed]
  8. 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. Swaroop, A., Wang, Q.L., Wu, W., Cook, J., Coats, C., Xu, S., Chen, S., Zack, D.J., Sieving, P.A. Hum. Mol. Genet. (1999) [Pubmed]
  9. SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Yoo, S.Y., Pennesi, M.E., Weeber, E.J., Xu, B., Atkinson, R., Chen, S., Armstrong, D.L., Wu, S.M., Sweatt, J.D., Zoghbi, H.Y. Neuron (2003) [Pubmed]
  10. Functional domains of the cone-rod homeobox (CRX) transcription factor. Chau, K.Y., Chen, S., Zack, D.J., Ono, S.J. J. Biol. Chem. (2000) [Pubmed]
  11. Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA. Ozgül, R.K., Bozkurt, B., Kiratli, H., Oğüş, A. Eye (London, England) (2006) [Pubmed]
  12. Increased lung uptake during myocardial scintigraphy improves the detection and localization of coronary artery disease. Papadopoulos, C.L., Doumas, A.S., Koliakos, G., Gitsios, C., Sakadamis, G. Angiology. (1995) [Pubmed]
  13. Molecular rhythms in the pineal gland. Li, X., Borjigin, J., Snyder, S.H. Curr. Opin. Neurobiol. (1998) [Pubmed]
  14. Chronic relapsing (dysimmune) polyneuropathy: pathogenesis and treatment. Dalakas, M.C., Engel, W.K. Ann. Neurol. (1981) [Pubmed]
  15. The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation. Mitton, K.P., Swain, P.K., Chen, S., Xu, S., Zack, D.J., Swaroop, A. J. Biol. Chem. (2000) [Pubmed]
  16. Purification of the copper response extracellular proteins secreted by the copper-resistant methanogen Methanobacterium bryantii BKYH and cloning, sequencing, and transcription of the gene encoding these proteins. Kim, B.K., Pihl, T.D., Reeve, J.N., Daniels, L. J. Bacteriol. (1995) [Pubmed]
  17. Isolation and characterization of the human X-arrestin gene. Sakuma, H., Murakami, A., Fujimaki, T., Inana, G. Gene (1998) [Pubmed]
  18. Isolation and characterization of the murine X-linked juvenile retinoschisis (Rs1h) gene. Gehrig, A.E., Warneke-Wittstock, R., Sauer, C.G., Weber, B.H. Mamm. Genome (1999) [Pubmed]
  19. Qs in the nucleus. Orr, H.T. Neuron (2001) [Pubmed]
  20. Mutational analysis and clinical correlation in Leber congenital amaurosis. Dharmaraj, S.R., Silva, E.R., Pina, A.L., Li, Y.Y., Yang, J.M., Carter, C.R., Loyer, M.K., El-Hilali, H.K., Traboulsi, E.K., Sundin, O.K., Zhu, D.K., Koenekoop, R.K., Maumenee, I.H. Ophthalmic Genet. (2000) [Pubmed]
  21. FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod-specific promoters in vitro. Mali, R.S., Zhang, X., Hoerauf, W., Doyle, D., Devitt, J., Loffreda-Wren, J., Mitton, K.P. Exp. Eye Res. (2007) [Pubmed]
  22. Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation. Qian, J., Esumi, N., Chen, Y., Wang, Q., Chowers, I., Zack, D.J. Nucleic Acids Res. (2005) [Pubmed]
  23. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Palhan, V.B., Chen, S., Peng, G.H., Tjernberg, A., Gamper, A.M., Fan, Y., Chait, B.T., La Spada, A.R., Roeder, R.G. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  24. Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development. Bibb, L.C., Holt, J.K., Tarttelin, E.E., Hodges, M.D., Gregory-Evans, K., Rutherford, A., Lucas, R.J., Sowden, J.C., Gregory-Evans, C.Y. Hum. Mol. Genet. (2001) [Pubmed]
  25. Both PCE-1/RX and OTX/CRX interactions are necessary for photoreceptor-specific gene expression. Kimura, A., Singh, D., Wawrousek, E.F., Kikuchi, M., Nakamura, M., Shinohara, T. J. Biol. Chem. (2000) [Pubmed]
  26. Gene expression networks underlying retinoic acid-induced differentiation of human retinoblastoma cells. Li, A., Zhu, X., Brown, B., Craft, C.M. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
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