CRX (gene) explained

Cone-rod homeobox protein is a protein that in humans is encoded by the CRX gene.^{[1] [2] [3]}

Function

The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber's congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined.

Mammalian CRX encodes a 299 amino acid protein containing a DNA binding homeodomain (HD) near its N-terminus followed by glutamine rich (Gln), and basic amino acid regions, then a C-terminal transactivation domain (AD).^[4] While structural biochemistry has demonstrated that the CRX HD adopts a canonical homeodomain protein fold, the AD is predicted to be flexible and disordered. The structural attributes of the CRX AD have yet to be solved.^[5]

Evolution

CRX is a divergent duplicate of OTX produced during the 2 rounds of vertebrate whole genome duplication.^[6]

In the eutherian mammals, CRX has again duplicated by tandem gene duplication, with six ancestral duplicates, which are collectively referred to as ETCHbox genes.^[7]

Further reading

• Paunescu K, Preising MN, Janke B, Wissinger B, Lorenz B . Genotype-phenotype correlation in a German family with a novel complex CRX mutation extending the open reading frame . Ophthalmology . 114 . 7 . 1348–1357.e1 . Jul 2007 . 17320181 . 10.1016/j.ophtha.2006.10.034 .
• Evans K, Fryer A, Inglehearn C, Duvall-Young J, Whittaker JL, Gregory CY, Butler R, Ebenezer N, Hunt DM, Bhattacharya S . Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion . Nature Genetics . 6 . 2 . 210–3 . Feb 1994 . 8162077 . 10.1038/ng0294-210 . 333926 .
• Chen S, Wang QL, Nie Z, Sun H, Lennon G, Copeland NG, Gilbert DJ, Jenkins NA, Zack DJ . Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes . Neuron . 19 . 5 . 1017–30 . Nov 1997 . 9390516 . 10.1016/S0896-6273(00)80394-3 . 18485264 . free .
• Swain PK, Chen S, Wang QL, Affatigato LM, Coats CL, Brady KD, Fishman GA, Jacobson SG, Swaroop A, Stone E, Sieving PA, Zack DJ . Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration . Neuron . 19 . 6 . 1329–36 . Dec 1997 . 9427255 . 10.1016/S0896-6273(00)80423-7 . 409482 . free .
• Sohocki MM, Sullivan LS, Mintz-Hittner HA, Birch D, Heckenlively JR, Freund CL, McInnes RR, Daiger SP . A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene . American Journal of Human Genetics . 63 . 5 . 1307–15 . Nov 1998 . 9792858 . 1377541 . 10.1086/302101 .
• Swaroop A, Wang QL, Wu W, Cook J, Coats C, Xu S, Chen S, Zack DJ, Sieving PA . 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 . Human Molecular Genetics . 8 . 2 . 299–305 . Feb 1999 . 9931337 . 10.1093/hmg/8.2.299 . free .
• Bessant DA, Payne AM, Mitton KP, Wang QL, Swain PK, Plant C, Bird AC, Zack DJ, Swaroop A, Bhattacharya SS . A mutation in NRL is associated with autosomal dominant retinitis pigmentosa . Nature Genetics . 21 . 4 . 355–6 . Apr 1999 . 10192380 . 10.1038/7678 . 28621258 .
• Yanagi Y, Masuhiro Y, Mori M, Yanagisawa J, Kato S . p300/CBP acts as a coactivator of the cone-rod homeobox transcription factor . Biochemical and Biophysical Research Communications . 269 . 2 . 410–4 . Mar 2000 . 10708567 . 10.1006/bbrc.2000.2304 .
• Zhu X, Craft CM . Modulation of CRX transactivation activity by phosducin isoforms . Molecular and Cellular Biology . 20 . 14 . 5216–26 . Jul 2000 . 10866677 . 85970 . 10.1128/MCB.20.14.5216-5226.2000 .
• Mitton KP, Swain PK, Chen S, Xu S, Zack DJ, Swaroop A . The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation . The Journal of Biological Chemistry . 275 . 38 . 29794–9 . Sep 2000 . 10887186 . 10.1074/jbc.M003658200 . free .
• Bibb LC, Holt JK, Tarttelin EE, Hodges MD, Gregory-Evans K, Rutherford A, Lucas RJ, Sowden JC, Gregory-Evans CY . Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development . Human Molecular Genetics . 10 . 15 . 1571–9 . Jul 2001 . 11468275 . 10.1093/hmg/10.15.1571 . free .
• La Spada AR, Fu YH, Sopher BL, Libby RT, Wang X, Li LY, Einum DD, Huang J, Possin DE, Smith AC, Martinez RA, Koszdin KL, Treuting PM, Ware CB, Hurley JB, Ptácek LJ, Chen S . Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7 . Neuron . 31 . 6 . 913–27 . Sep 2001 . 11580893 . 10.1016/S0896-6273(01)00422-6 . 51784415 . free .
• Rivolta C, Peck NE, Fulton AB, Fishman GA, Berson EL, Dryja TP . Novel frameshift mutations in CRX associated with Leber congenital amaurosis . Human Mutation . 18 . 6 . 550–1 . Dec 2001 . 11748859 . 10.1002/humu.1243 . 37801650 . free .
• Koenekoop RK, Loyer M, Dembinska O, Beneish R . Visual improvement in Leber congenital amaurosis and the CRX genotype . Ophthalmic Genetics . 23 . 1 . 49–59 . Mar 2002 . 11910559 . 10.1076/opge.23.1.49.2200 . 21536673 .
• Chen S, Wang QL, Xu S, Liu I, Li LY, Wang Y, Zack DJ . Functional analysis of cone-rod homeobox (CRX) mutations associated with retinal dystrophy . Human Molecular Genetics . 11 . 8 . 873–84 . Apr 2002 . 11971869 . 10.1093/hmg/11.8.873 . free .
• Nakamura M, Ito S, Miyake Y . Novel de novo mutation in CRX gene in a Japanese patient with leber congenital amaurosis . American Journal of Ophthalmology . 134 . 3 . 465–7 . Sep 2002 . 12208271 . 10.1016/S0002-9394(02)01542-8 .
• Lines MA, Hébert M, McTaggart KE, Flynn SJ, Tennant MT, MacDonald IM . Electrophysiologic and phenotypic features of an autosomal cone-rod dystrophy caused by a novel CRX mutation . Ophthalmology . 109 . 10 . 1862–70 . Oct 2002 . 12359607 . 10.1016/S0161-6420(02)01187-9 .
• Hodges MD, Vieira H, Gregory-Evans K, Gregory-Evans CY . Characterization of the genomic and transcriptional structure of the CRX gene: substantial differences between human and mouse . Genomics . 80 . 5 . 531–42 . Nov 2002 . 12408971 . 10.1016/S0888-7543(02)96854-0 .

External links

• GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview

Notes and References

1. Freund CL, Gregory-Evans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, Bellingham J, Ng D, Herbrick JA, Duncan A, Scherer SW, Tsui LC, Loutradis-Anagnostou A, Jacobson SG, Cepko CL, Bhattacharya SS, McInnes RR . Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor . Cell . 91 . 4 . 543–53 . Nov 1997 . 9390563 . 10.1016/S0092-8674(00)80440-7 . 5755412 . free . 10261/270606 . free .
2. Freund CL, Wang QL, Chen S, Muskat BL, Wiles CD, Sheffield VC, Jacobson SG, McInnes RR, Zack DJ, Stone EM . De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis . Nature Genetics . 18 . 4 . 311–2 . Apr 1998 . 9537410 . 10.1038/ng0498-311 . 22131800 .
3. Web site: Entrez Gene: CRX cone-rod homeobox.
4. Tran NM, Zhang A, Zhang X, Huecker JB, Hennig AK, Chen S . Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy . PLOS Genet . Feb 6, 2014 . 10 . 2 . e1004111 . 24516401 . 10.1371/journal.pgen.1004111 . 3916252 . free .
5. Clanor PB, Buchholz CN, Hayes JE, Friedman MA, White AM, Enke RA, Berndsen CE . Structural and functional analysis of the human cone-rod homeobox transcription factor . Proteins . March 23, 2022 . 90 . 8 . 1584–1593 . 35255174 . 10.1002/prot.26332 . 9271546 . free .
6. Germot A, Lecointre G, Plouhinec JL, Le Mentec C, Girardot F, Mazan S . Structural evolution of Otx genes in craniates . Molecular Biology and Evolution . 18 . 9 . 1668–78 . September 2001 . 11504847 . 10.1093/oxfordjournals.molbev.a003955 . free .
7. Maeso I, Dunwell TL, Wyatt CD, Marlétaz F, Vető B, Bernal JA, Quah S, Irimia M, Holland PW . Evolutionary origin and functional divergence of totipotent cell homeobox genes in eutherian mammals . BMC Biology . 14 . 1 . 45 . June 2016 . 27296695 . 4904359 . 10.1186/s12915-016-0267-0 . free .