IRX1

IRX1
Identifiers
Aliases	IRX1 , IRX-5, IRXA1, iroquois homeobox 1
External IDs	OMIM: 606197; MGI: 1197515; HomoloGene: 19065; GeneCards: IRX1; OMA:IRX1 - orthologs
Gene location (Human) Chr. Chromosome 5 (human) [1] Band 5p15.33 Start 3,595,832 bp [1] End 3,601,403 bp [1]
Gene location (Mouse) Chr. Chromosome 13 (mouse) [2] Band 13 C1|13 38.43 cM Start 72,106,040 bp [2] End 72,111,842 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in parotid gland epithelium of lactiferous gland lactiferous duct renal medulla skin of arm minor salivary glands gonad human kidney skin of leg subcutaneous adipose tissue Top expressed in vestibular membrane of cochlear duct digit right lung left lung parotid gland right lung lobe incisor otic placode interventricular septum lip More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding DNA-binding transcription repressor activity, RNA polymerase II-specific sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component nucleus Biological process specification of loop of Henle identity metanephros development regulation of transcription, DNA-templated proximal/distal pattern formation involved in metanephric nephron development negative regulation of transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 79192 16371 Ensembl ENSG00000170549 ENSMUSG00000060969 UniProt P78414 P81068 RefSeq (mRNA) NM_024337 NM_010573 RefSeq (protein) NP_077313 NP_034703 Location (UCSC) Chr 5: 3.6 – 3.6 Mb Chr 13: 72.11 – 72.11 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Iroquois-class homeodomain protein IRX-1, also known as Iroquois homeobox protein 1, is a protein that in humans is encoded by the IRX1 gene. ^{[5] [6]} All members of the Iroquois (IRO) family of proteins share two highly conserved features, encoding both a homeodomain and a characteristic IRO sequence motif. ^[7] Members of this family are known to play numerous roles in early embryo patterning. ^[5] IRX1 has also been shown to act as a tumor suppressor gene in several forms of cancer. ^{[8] [9] [10] [11]}

Role in development

IRX1 is a member of the Iroquois homeobox gene family. Members of this family play multiple roles during pattern formation in embryos of numerous vertebrate and invertebrate species. ^{[5] [12]} IRO genes are thought to function early in development to define large territories, and again later in development for further patterning specification. ^[7] Experimental data suggest roles for IRX1 in vertebrates may include development and patterning of lungs, limbs, heart, eyes, and nervous system. ^{[13] [14] [15] [16] [17] [18]}

Gene

Overview

IRX1 is located on the forward DNA strand (see Sense (molecular biology)) of chromosome 5, from position 3596054 - 3601403 at the 5p15.3 location. ^[5] The human gene product is a 1858 base pair mRNA with 4 predicted exons in humans. ^[19] Promoter analysis was performed using El Dorado through the Genomatix software page. ^[20] The predicted promoter region spans 1040 base pairs from position 3595468 through 3595468 on the forward strand of chromosome 5.

Gene neighborhood

IRX1 is relatively isolated, with no other protein coding genes found from position 3177835 – 5070004. ^[5]

Expression

Microarray and RNA seq data suggest that IRX1 is ubiquitously expressed at low levels in adult tissues, with the highest relative levels of expression occurring in the heart, adipose, kidney, and breast tissues. ^{[21] [22]} Moderate to high levels are also indicated in the lung, prostate and stomach. ^{[22] [23]} Promoter analysis with the El Dorado program from Genomatix predicted that IRX1 expression is regulated by factors that include E2F cell cycle regulators, NRF1, and ZF5, ^[24] and brachyury. ^[20] Expression data from human, mouse, and developing mouse brains are available though the Allen Brain Atlas. ^[25]

Protein

Properties and characteristics

The mature IRX1 protein has 480 amino acid residues, with a molecular mass of 49,600 daltons and an isoelectric point of 5.7. A BLAST search revealed that IRX1 contains two highly conserved domains: a homeodomain and a characteristic IRO motif of unknown function. ^[26] The homeodomain belongs to the TALE (three amino acid loop extension) class of homeodomains, and is characterized by the addition of three extra amino acids between the first and second helix of three alpha helices that comprise the domain. ^[27] The presence of this well characterized homeodomain strongly suggests that IRX1 acts as a transcription factor. This is further supported by the predicted localization of IRX1 to the nucleus. ^[28] The IRO motif is a region downstream of the homeodomain that is found only in members of the Iroquois-class homeodomain proteins, though its function is poorly understood. However, its similarity to an internal region of the Notch receptor protein suggests that it may be involved with protein-protein interaction. ^[7] In addition to these two characteristic domains, IRX1 contains a third domain from the HARE-HTH superfamily ^[29] fused to the C-terminal end of the homeodomain. ^[30] This domain adopts a winged helix-turn-helix fold predicted to bind DNA, and is thought to play a role in recruiting effector activities to DNA. ^[29] Several forms of post-translational modification are predicted, including SUMOylation, C-mannosylation, and phosphorylation, using bioinformatics tools from ExPASy. ^[31] Bioinformatic analysis of IRX1 with the NetPhos tool predicted 71 potential phosphorylation sites throughout the protein. ^[32]

Protein Interactions

Potential protein interacting partners for IRX1 were found using computational tools. The STRING database lists nine putative interacting partners supported by text mining evidence, though closer analysis of the results shows little support for most of these predicted interactions. ^[33] However, it is possible that one of these proteins, CDKN1A, is involved in the predicted regulation of IRX1 by E2F cell cycle regulators. ^{[20] [33]}

Conservation

Orthologs

IRX1 has a high degree of conservation across vertebrate and invertebrate species. The entire protein is more fully conserved through vertebrate species, while only the homeodomain and IRO motif are conserved in more distant homologs. ^[12] Homologous sequences were found in species as distantly related to humans as the pig roundworm Ascaris suum, from the family Ascarididae, using BLAST and the ALIGN tool through the San Diego Super Computer Biology Workbench. ^[26] The following is a table describing the evolutionary conservation of IRX1.

Genus Species	Organism Common Name	Divergence from Humans (MYA) [34]	NCBI Protein Accession Number	Sequence Identity [26]	Protein Length	Common Gene Name
Homo sapiens [30]	Humans	--	NP_077313	100%	480	IRX-1
Pongo abelii [35]	Sumatran Orangutan	15.7	XP_002815448	99%	480	IRX-1
Bos taurus [36]	Cattle	94.2	XP_002696496	92.3%	476	IRX-1
Mus musculus [37]	House Mouse	92.3	NP_034703	91.5%	480	IRX-1
Rattus norvegicus [38]	Brown rat	92.3	NP_001100801	90.4%	480	IRX-1
Gallus gallus [39]	Red Junglefowl	296	NP_001025509	72.9%	467	IRX-1
Xenopus tropicalis [40]	Western clawed frog	371.2	NP_001188351	68%	467	IRX-1
Latimeria chalumnae [41]	West Indian Ocean coelacanth	441.9	XP_006002089	65.1%	460	Irx-1-A-like isoform X1
Danio rerio [42]	Zebrafish	400.1	NP_997067	61.1%	426	Irx-1 isoform 1
Taeniopygia guttata [43]	Zebra finch	296	XP_002189063	59.7%	400	Irx-1-A-like
Astyanax mexicanus [44]	Mexican tetra	400.1	XP_007254591.1	58%	450	IRX-1
Ophiophagus hannah [45]	King cobra	296	ETE68928	54.5%	387	Irx-1-A partial
Ovis aries [46]	Sheep	94.2	XP_004017207	43.3%	260	IRX-1
Condylura cristata [47]	Star-nosed mole	94.2	XP_004678440	41.7%	342	IRX-1
Branchiostoma floridae [48]	Lancelet	713.2	ACF10237.1	35.5%	461	Iroquois A isoform 1
Strongylocentrotus purpuratus [49]	Purple sea urchin	742.9	NP_001123285	31.7%	605	Iroquois homeobox A
Ascaris suum [50]	Pig roundworm	937.5	F1KXE6	29%	444	IRX-1
Caenorhabditis elegans [51]	Nematode roundworm	937.5	NP_492533.2	28.6%	377	IRX-1
Drosophila melanogaster [52]	Fruit fly	782.7	NP_524045	27%	717	Araucan isoform A

Paralogs

IRX1 is one of six members of the Iroquois-class homeodomain proteins found in humans: IRX2 , IRX3 , IRX4 , IRX5 , and IRX6 . IRX1, IRX2, and IRX4 are found on human chromosome 5, and their orientation corresponds to that of IRX3, IRX5, and IRX6 found on human chromosome 16. ^[7] It is thought that the genomic organization of IRO genes in conserved gene clusters allows for coregulation and enhancer sharing during development.

References

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14. Cheng CW, Yan CH, Choy SW, Hui MN, Hui CC, Cheng SH (September 2007). "Zebrafish homologue irx1a is required for the differentiation of serotonergic neurons". Developmental Dynamics. 236 (9): 2661–2667. doi: 10.1002/dvdy.21272 . PMID   17685478. S2CID   142831.
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20. "El Dorado". Genomatix. Retrieved May 17, 2014.^{[ permanent dead link ‍]}
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24. Numoto M, Yokoro K, Koshi J (March 1999). "ZF5, which is a Kruppel-type transcriptional repressor, requires the zinc finger domain for self-association". Biochemical and Biophysical Research Communications. 256 (3): 573–578. doi:10.1006/bbrc.1999.0375. PMID   10080939.
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48. "NCBI Nucleotide: ACF10237.1" . Retrieved 18 May 2014.
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51. "NCBI Nucleotide: NP_492533.2" . Retrieved 18 May 2014.
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Further reading

• Lam CY, Tam PO, Fan DS, Fan BJ, Wang DY, Lee CW, et al. (September 2008). "A genome-wide scan maps a novel high myopia locus to 5p15". Investigative Ophthalmology & Visual Science. 49 (9): 3768–3778. doi:10.1167/iovs.07-1126. PMID   18421076.
• Cirulli ET, Kasperaviciūte D, Attix DK, Need AC, Ge D, Gibson G, et al. (July 2010). "Common genetic variation and performance on standardized cognitive tests". European Journal of Human Genetics. 18 (7): 815–820. doi:10.1038/ejhg.2010.2. PMC   2987367 . PMID   20125193.
• Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, et al. (August 2009). "Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling". Gut. 58 (8): 1078–1083. doi:10.1136/gut.2008.169052. PMID   19240061. S2CID   17111427.
• Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi: 10.1101/gr.6.9.791 . PMID   8889548.
• Lewis MT, Ross S, Strickland PA, Snyder CJ, Daniel CW (June 1999). "Regulated expression patterns of IRX-2, an Iroquois-class homeobox gene, in the human breast". Cell and Tissue Research. 296 (3): 549–554. doi:10.1007/s004410051316. PMID   10370142. S2CID   37046813.
• Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, et al. (June 2008). "Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma". Cancer Research. 68 (12): 4494–4499. doi: 10.1158/0008-5472.CAN-07-6509 . PMID   18559491.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.