Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

NKX2-3 (NK2 homeobox 3)

Written2014-11Zhenwu Lin, John P Hegarty, Joanna Floros, Andre Franke
Pennsylvania State University College of Medicine PA USA (ZL); Division of Colon, Rectal Surgery Department of Surgery Pennsylvania State University College of Medicine PA USA (JPH); Departments of Pediatrics, Obstetrics, Gynecology, CHILD Research Center, Pennsylvania State University College of Medicine PA USA (JF); Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany (AF)

Abstract NKX2-3 gene is a member of the homeobox, NKX family. The gene encodes a homeodomain-containing transcription factor. GO (gene ontology) annotations related to this gene include sequence-specific DNA binding and gene-specific transcription factor activity. NKX2-3 is essential for normal development and functions of the small intestine and spleen of embryonic and adult mice. Disruption of Nkx2-3 in mice results in postnatal lethality and abnormal development of the small intestine and the spleen. Villus formation in the small intestine appears considerably delayed in Nkx2-3(null) fetuses due to reduced proliferation of the epithelium, while massively increased growth of crypt cells follows in surviving adults. A complex intestinal malabsorption phenotype and striking abnormalities of gut-associated lymphoid tissue and spleen suggest deranged leukocyte homing. RT-PCR and immunohistochemistry revealed that NKX2-3 controls regional expression of leukocyte homing coreceptor mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in specialized endothelial cells of the viscera. This indicates a potential role for NXK2-3 in establishing the developmental and positional cues in endothelia that regulate leukocyte homing through local control of cellular adhesion. Studies of disease association indicated that NKX2-3 is associated with IBD (both Crohn's disease and ulcerative colitis), intestinal fibrosis, colon rectal cancer, and dental caries.

Keywords NKX2-3, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative disease (UC), homeodomain-containing transcription factor

(Note : for Links provided by Atlas : click)

Identity

Alias_namesNKX2C
NK-2 (Drosophila) homolog C
NK2 transcription factor related, locus 3 (Drosophila)
Alias_symbol (synonym)NKX2.3
CSX3
NKX4-3
Other aliasNK2.3
HGNC (Hugo) NKX2-3
LocusID (NCBI) 159296
Atlas_Id 51779
Location 10q24.2  [Link to chromosome band 10q24]
Location_base_pair Starts at 99532933 and ends at 99536523 bp from pter ( according to hg19-Feb_2009)  [Mapping NKX2-3.png]
 
  Chromosomal location of human NKX2-3 gene. NKX2-3 gene is located on chr 10q24.2, size 3592 bp, starting at 101292690 bp and ending at 101296281 bp from the pter (the end of short arm) of the chromosome 10. The gene orientation is on the plus strand. The NKX2-3 gene consists of 2 exons 527 bp (101292690-101293248 nt) and 1540 bp (101294742-101298281 nt) respectively, an intron 1496 bp (101293248-101294742 nt). GOT1: glutamic-oxaloacetric transaminase 1 soluble; SLC25A28: solute carrier family 25 (mitochondrial iron transporter) member 28; ENTP7: ectonucleoside triphosphate diphophohydrolase 7.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Note The human NKX2-3 gene has two transcripts. NKX2-3-001, ENST00000344586, 2097 nt mRNA encoding a protein of 364 amino acids; NKX2-3-201, ENST00000622383, 1986 nt mRNA encoding a protein of 296 amino acids.
 
  Human NKX2-3 mRNA. The gene for NKX2-3 consists of two exons of 527 and 1540 bp, respectively. The intron is 1496 bp. Positions of start (cDNA 179 nt) and stop (cDNA 1534 nt) codons are indicated. These data refer to ENSEMBL transcript.
Description The gene has two exons and one intron.
Transcription The transcription takes place in a centromere --> telomere orientation. The length of the processed mRNA is about 2094 nucleotides.
Pseudogene Not known.

Protein

Note The NKX2-3 protein is a 364-amino acid (molecular weight 38405.63g/mol) protein.
 
  Human NKX2-3 protein. The NKX2-3 protein is a 364-amino acid (molecular weight 38405.63g/mol) protein including a TN domain (tinman domain; transcription repressor domain), HD domain (homeodomain, 60 aa), SD domain (NK2 specific domain), and TAD domain (transcriptional activation domain).
Description The NKX2-3 protein (364 amino acids) translated from the long transcript contains a TN domain (residues 10-19), HD domain (residues 148-207), SD domain (residues 222-238) and TAD domain (residues 239-364).
Expression Expression is mainly observed in pharynx, small intestine, liver, spleen, heart, lymph node, thyroid, adrenal gland, breast, skin, ovary, prostate, testis, and retina.
Localisation Nucleus, but also observed outside the nucleus.
Function NKX2-3 is a nuclear transcription factor that plays an important role in the regulation of gene transcription. Studies from siRNA knockdown followed by cDNA profiling indicate that many genes are regulated by NKX2-3. This indicates involvement of NKX2-3 in the regulation of transcription, of immune and inflammatory response, cell growth and proliferation, cell adhesion, metabolic processes, angiogenesis, lymph-angiogenesis, and others (Yu et al., 2011).
Results from NKX2-3 deficient mice and other studies demonstrate that NKX2-3 is essential for intestine and spleen development (Pabst et al., 1999; Pabst et al., 2000). NKX2-3 is required for heart formation (Fu et al., 1998) and salivary gland and tooth morphogenesis and plays a role during pharyngeal organogenesis (Biben et al., 2002). NKX2-3 is essential for B cell maturation and T cell dependent immune response (Shaffer et al., 2013), and regulates leukocyte homing through local control of cellular adhesion molecules including MADCAM-1 and VCAM in mice (Wang et al., 2000) and IBD patients (our unpublished data).
Nkx2-3 and regulation of the arteriovenous endothelial profile
Individual transcription factors interact in a complex network to regulate the arteriovenous profile. Aranguren et al. 2013 examined the expression of 64 known arterial and 12 known venous genes from freshly isolated arterial and venous endothelial cells from human umbilical cord. The expression of approximately 36% of the examined arterial genes was found to be regulated by NKX2-3 (Aranguren et al., 2013).
Nkx2-3 and lymphoid tissue development
It remains to be determined whether the formation of enteric lymphatic capillaries is affected by the absence of Nkx2-3, similar to the observed reduction of Peyer's patches. In contrast to the leukocyte homing in pLNs and Peyer's patches, the spleen lacks high endothelial venules (HEVs) and requires no L-selectin binding for subsequent leukocyte extravasation. Evidence indicated that the integrity of the marginal sinus and the proper vascular segregation of the red pulp was controlled by NKX2-3 (Balogh et al., 2007).
Czömpöly et al. 2011 found that the disruption of Nkx2-3 expression in mice, the spleen develops a peripheral lymph node (pLN)-like mRNA expression signature, coupled with the appearance of HEVs. These HEV-like vessels undergo postnatal maturation and progressively replace MAdCAM-1 by pLN addressin together with the display of CCL21 arrest chemokine, reminiscent of HEV formation in pLNs (Czömpöly et al., 2011). This transformation of splenic vasculature into pLN-like vessels emphasizes the importance of Nkx2-3 in correct vessel formation for spleen ontogeny in mammals.
Kellermayer et al. 2011 reported that Nkx2.3-deficient mice develop splenic and gut-associated vascular and lymphoid tissue abnormalities with disordered segregation of T- and B- cells. Splenic defects include absence of the marginal sinus vasculature and an atrophic red pulp sinus network with an extensive network of lymphocyte-filled endothelial sacs lined by cells expressing LYVE-1, a marker associated with lymphatic endothelium cells (Kellermayer et al., 2011). This raises the possibility that endothelial differentiation and maturation may be affected by altered expression of Nkx2-3.
Homology NKX2-3 is a homeodomain protein belonging to the NK2 family. The other NK2 family members are Nkx2-1 (at 14q13), Nkx2-2 (at 20p11), Nkx2-3 (at 10q24.2), Nkx2-4 (at 20p11), Nkx2-5, Nkx2-6, Nkx2-8, Nkx2-9 (at 14q13), and Nkx2-10.
Orthologs of NKX2-3 show a high similarity with the homologues in other species, such as 88.46% (nt) and 90.86% (aa) with mouse, 60% (aa) with chicken, 79% (nt) with Xenopus laevis, 76.29% (nt) with zebrafish, 20% (aa) with fruit fly, and 33% (aa) with worm.

Mutations

Note A total of 304 genetic variants are documented, including 128 upstream and 87 downstream of the gene, 5 variants in the 5' prime and 15 in the 3' primer untranslated regions, 26 missense and 17 synonymous variants in exons, 23 variants in introns, and 2 in-frame deletions.
 
  Mutations in human NKX2-3 gene. A. The base number at the beginning and the end of each exon is shown. Genetic variations rs10883365 and rs11190140 in 5'-prime upstream are the most used for genetic association study, and rs888208 in 3'UTR is used for allele specific expression. TMP_ESP_10_101294794-101294796 GAA/- in Exon 2 is an in-frame deletion. Of the 26 missense genetic variants only three, rs201429667 (p.A49T), rs79873574 (p.P145T, and rs15105391 (p.L358W) have been observed in multiple studies. Of the 17 synonymous variants five have been observed in multiple studies with high MAF (minor allele frequency): rs41290504 (MAF: 0.483), rs145887258 (MAF: 0.001), rs184601313 (MAF: 0.001), rs113459553 (MAF: 0.039), and rs78122843 (MAF: 0.006) in amino acid residue 49, 80, 156, 185, and 194 respectively. B.The base number at the beginning and the end of each exon is shown. The somatic mutations are shown from left to right: COSM71840 p.T10I, COSM1345223 p.D35G, COSM913762 p.A43V, COSM426905 p.A49A, COSM124757 p.G52E, COSM1217392 p.L70S, COSM3686464 p.S102R, COSM2057374 p.S102S, COSM1638416 p.E109Q, COSM465162 p.R165H, COSM1345224 pA216T, COSM404952 C817_837del21 in-frame, and COSM1217393 p.R362L.
Somatic A total of 13 somatic mutations have been reported: one is a 21 bp deletion, two are synonymous variants, and 10 missense variants.
Histological examination showed all the mutations are observed in carcinoma.

Implicated in

Note
  
Entity Colorectal cancer (CRC)
Note Loss of heterozygosity on chromosome 10 where IL10 is located was observed in sporadic CRC. RT-PCR results indicated that the NKX2-3 gene is down regulated (Wang et al., 2008). A high expression of NKX2-3 was found in the CRC experimental group compared to the control group (Li et al., 2012).
  
  
Entity CRC with synchronous liver metastasis
Note NKX2-3 with other 6 genes was incorporated into a genetic model for estimating chemotherapy sensitivity. The result from 30 ACC (advanced colorectal cancer) patients (13 were assigned to experimental group and 17 to the control group) showed an overall accurate prediction rate of 99.3% (Lu et al., 2013).
  
  
Entity Liver metastases
Note NKX2-3 is expressed to a low level in liver metastases than in primary tumors and normal enterochromaffin cells (Leja et al., 2009).
  
  
Entity Inflammatory bowel disease (IBD)
Note NKX2-3 was first identified as IBD susceptibility gene from a GWAS study in 2006 (Wellcome Trust Case Control, 2007) and then it was replicated in several cohorts in both CD and US (Parkes et al., 2007; Franke et al., 2008; Barrett et al., 2008). The association is widely studied with genetic variations rs10883365 and rs11190140, in different IBD populations, including Japanese population (484 CD and 470 controls (Yamazaki et al., 2009), Dutch-Belgian (2731IBD: 1656 CD and 1075UC) (Weersma et al., 2009), Eastern European IBD patients (810 CD and 428 UC) (Meggyesi et al., 2010), Central Pennsylvania population in US (Yu et al., 2009), Italian cohort (both CD and UC, adult and pediatric IBD) (Latiano et al., 2011), and Lithuanian-Latvian population (444 UC and 1154 controls) (Skieceviciene et al., 2013). A specific association of NKX2-3 rs1088365 with smoking CD patients has been observed (310 CD and 976 controls) (van der Heide et al., 2010). These studies have been reviewed (Cho and Brant, 2011; Van Limbergen et al., 2014).
A recent comprehensive meta-analysis of 17 studies involving 17329 patients and 18029 controls showed a significantly increased CD or UC risk in persons carrying a G allele at rs10883365 polymorphism (A/G) compared with those with an A allele. (OR = 1.226, 95%CI: 1.177-1.277 and OR = 1.274, 95%CI: 1.175-1.382 respectively). In the subgroup analysis, a significantly increased CD risk was found in both Europeans and Asians. For rs11190140 polymorphism (C/T) and CD risk, the risk estimate for the allele contrast was OR = 1.201 (1.136-1.269) (Lu et al., 2014).
Prognosis Results from a study in 572 CD, 328 UC patients, 437 non-IBD, and 137 healthy controls using 29 biomarkers, 4 genetic markers including NKX2-3, 8 serological markers, and 17 inflammatory markers, indicated that these markers can differentiate non-IBD from CD and UC patients (Plevy et al., 2013).
 
Studies on genetic association of Nkx2-3 gene with IBD.
  
  
Entity Intestinal fibrosis
Note Intestinal fibrosis is among the most common complications of IBD, and is usually defined as an excessive accumulation of scar tissue in the intestinal wall. Severe fibrosis is seen in up to 30% of patients with CD, a high proportion of them require surgery. In addition, endothelial-to-mesenchymal transition (EndoMT) results in the trans-differentiation of intestinal mucosal microvascular cells (HIMEC) into mesenchymal cells. This indicates that the intestinal microvasculature may also contribute to IBD-associated fibrosis (Rieder et al., 2011).
Nkx2-3 is highly expressed in the gut mesenchyme, such as myofibroblasts and the smooth muscle cells of the muscularis mucosae. Myofibroblasts are known to play key roles in wound healing and fibrosis. Known Nkx2-3 regulation of genes mediating fibrogenesis and wound healing, such as endothelins, angiotensin converting enzyme, and angiotensin-II, and nitric oxide, may result in active deposition of ECM resulting in the characteristic fibrosis of CD (Yu et al., 2011).
Interestingly, related Nkx2.5 is a known repressor of myofibroblast α-smooth muscle actin (α-SMA) gene transcription in the lung (Hu et al., 2010). Similarly, aberrant Nkx2-3 expression in the gut may result in increased intestinal myofibroblast differentiation intestinal fibrosis. We note that the Nkx2-3-regulated transcription factor KLF-4 (gut-enriched Krüppel-like factor) represses α-SMA gene expression by interacting with Smad3 (TGF-β signaling) to prevent Smad3 binding, resulting in reduced myofibroblast differentiation (Hu et al., 2007).
  
  
Entity Dental caries
Note Dental caries, also known as tooth decay or a cavity, is an infection, bacterial in origin. It causes demineralization and destruction of the hard tissues of the teeth (enamel, dentin and cementum) as a result of the production of acid by bacterial fermentation of food debris accumulated on the tooth surface. In a GWAS study with 518987 genetic variations NKX2-3 was shown to be a suggestive genetic association with dental caries pattern in the permanent dentition (Shaffer et al., 2013).
  

Breakpoints

 
  Schematic representation of 10q24 and 12p13 regions implicated in the t(10;12). Genomic representation of t(10;12) ETV6 (exon 3)-GOT1 (exon 12) fusion is in frame. The fusion transcript was identified by RT-PCR with primers located in the exon 6 of ETV6 and the exon 3 of GOT1 followed by sequence analysis. The sterile alpha motif (SAM) domain (exons 2 to 4) responsible for hetero- and homodimerization with other ETV6 protein and possibly other ETS family members, are indicated.
Note A ETV6-GOT1 fusion contains a chimeric transcript containing ETV6 sequence fused to genomic sequences located at 22961 bp 3' to GOT1 and 79407 bp 5' to NK2 transcription factor related, locus 3 (NKX2-3). This may result in the dysregulation of NKX2-3, which lies adjacent to the breakpoint (Struski et al., 2008).

To be noted

miRNAs targeting human Nkx2-3
The top miRNAs binding the 3'-UTR of the human NKX2-3 transcript were identified using TargetScan v6.2 (Lewis et al., 2005) and Miranda algorithm v4.0 (Betel et al., 2006) with parameters of >8-mer matches with mirSVR scores <= -1 and PhastCons score >= 0.6 BP. Identified miRNAs included members of the miR-92a microRNA precursor family of highly conserved miRNAs (miR-25, miR-92a, miR-92b and miR-363). The miR-92a family plays an important role in regulating mammalian organs including heart and lungs, and immune system, formation of blood vessels, and development of endothelial cells. Inhibition of miR-92a can enhance angiogenesis and viability of endothelial cells (Zhang et al., 2014). miRNA92a family and miRNA-32 affect expression of endothelial Kruppel-like factors KLF2 and KLF-4, possibly though regulation of Nkx2-3 expression (Loyer et al., 2014).
Epigenetic modification of genetic variant
Rs11190140 is a C/T variation followed by G. The C allele is in a CG dinucleotide. The C is subjected to methylation. The genetic variation and epigenetic modification affect the NFAT transcription factor binding to the DNA, T< nonmethylated C< methylated C (John et al., 2011).
Nkx2-3 allelic expression imbalance in human IBD colonic mucosa
Arai et al. 2011 (Arai et al., 2011) examined the expression of Nkx2-3 mRNA from colonic mucosa from Japanese patients with IBD. Allelic expression ratios of NKX2.3 mRNA transcribed from risk haplotype to the non-risk haplotype in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195) (Arai et al., 2011). This observed allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa.

Bibliography

Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa.
Arai T, Kakuta Y, Kinouchi Y, Kimura T, Negoro K, Aihara H, Endo K, Shiga H, Kanazawa Y, Kuroha M, Moroi R, Nagasawa H, Shimodaira Y, Takahashi S, Shimosegawa T.
Hum Immunol. 2011 Jul;72(7):587-91. doi: 10.1016/j.humimm.2011.03.023. Epub 2011 Apr 8.
PMID 21514341
 
Unraveling a novel transcription factor code determining the human arterial-specific endothelial cell signature.
Aranguren XL, Agirre X, Beerens M, Coppiello G, Uriz M, Vandersmissen I, Benkheil M, Panadero J, Aguado N, Pascual-Montano A, Segura V, Prosper F, Luttun A.
Blood. 2013 Dec 5;122(24):3982-92. doi: 10.1182/blood-2013-02-483255. Epub 2013 Oct 9.
PMID 24108462
 
Distinct roles of lymphotoxin-beta signaling and the homeodomain transcription factor Nkx2.3 in the ontogeny of endothelial compartments in spleen.
Balogh P, Balazs M, Czompoly T, Weih DS, Arnold HH, Weih F.
Cell Tissue Res. 2007 Jun;328(3):473-86. Epub 2007 Feb 21.
PMID 17318587
 
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ; NIDDK IBD Genetics Consortium, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E; Belgian-French IBD Consortium; Wellcome Trust Case Control Consortium, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ.
Nat Genet. 2008 Aug;40(8):955-62. doi: 10.1038/ng.175. Epub 2008 Jun 29.
PMID 18587394
 
The microRNA.org resource: targets and expression.
Betel D, Wilson M, Gabow A, Marks DS, Sander C.
Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53. Epub 2007 Dec 23.
PMID 18158296
 
NK-2 class homeobox genes and pharyngeal/oral patterning: Nkx2-3 is required for salivary gland and tooth morphogenesis.
Biben C, Wang CC, Harvey RP.
Int J Dev Biol. 2002;46(4):415-22.
PMID 12141427
 
Recent insights into the genetics of inflammatory bowel disease.
Cho JH, Brant SR.
Gastroenterology. 2011 May;140(6):1704-12. doi: 10.1053/j.gastro.2011.02.046.
PMID 21530736
 
Transcription factor Nkx2-3 controls the vascular identity and lymphocyte homing in the spleen.
Czompoly T, Labadi A, Kellermayer Z, Olasz K, Arnold HH, Balogh P.
J Immunol. 2011 Jun 15;186(12):6981-9. doi: 10.4049/jimmunol.1003770. Epub 2011 May 18.
PMID 21593383
 
Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis.
Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, Schuldt D, Nikolaus S, Rosenstiel P, Krawczak M, Schreiber S.
Nat Genet. 2008 Jun;40(6):713-5. doi: 10.1038/ng.148. Epub 2008 Apr 27.
PMID 18438405
 
Vertebrate tinman homologues XNkx2-3 and XNkx2-5 are required for heart formation in a functionally redundant manner.
Fu Y, Yan W, Mohun TJ, Evans SM.
Development. 1998 Nov;125(22):4439-49.
PMID 9778503
 
Nkx2.5/Csx represses myofibroblast differentiation.
Hu B, Wu YM, Wu Z, Phan SH.
Am J Respir Cell Mol Biol. 2010 Feb;42(2):218-26. doi: 10.1165/rcmb.2008-0404OC. Epub 2009 Apr 24.
PMID 19395679
 
Gut-enriched Krüppel-like factor interaction with Smad3 inhibits myofibroblast differentiation.
Hu B, Wu Z, Liu T, Ullenbruch MR, Jin H, Phan SH.
Am J Respir Cell Mol Biol. 2007 Jan;36(1):78-84. Epub 2006 Jul 20.
PMID 16858008
 
NKX2-3 variant rs11190140 is associated with IBD and alters binding of NFAT.
John G, Hegarty JP, Yu W, Berg A, Pastor DM, Kelly AA, Wang Y, Poritz LS, Schreiber S, Koltun WA, Lin Z.
Mol Genet Metab. 2011 Sep-Oct;104(1-2):174-9. doi: 10.1016/j.ymgme.2011.06.023. Epub 2011 Jul 6.
PMID 21803625
 
Absence of Nkx2-3 homeodomain transcription factor induces the formation of LYVE-1-positive endothelial cysts without lymphatic commitment in the spleen.
Kellermayer Z, Labadi A, Czompoly T, Arnold HH, Balogh P.
J Histochem Cytochem. 2011 Jul;59(7):690-700. doi: 10.1369/0022155411410061.
PMID 21705651
 
Investigation of multiple susceptibility loci for inflammatory bowel disease in an Italian cohort of patients.
Latiano A, Palmieri O, Latiano T, Corritore G, Bossa F, Martino G, Biscaglia G, Scimeca D, Valvano MR, Pastore M, Marseglia A, D'Inca R, Andriulli A, Annese V.
PLoS One. 2011;6(7):e22688. doi: 10.1371/journal.pone.0022688. Epub 2011 Jul 27.
PMID 21818367
 
Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas.
Leja J, Essaghir A, Essand M, Wester K, Oberg K, Totterman TH, Lloyd R, Vasmatzis G, Demoulin JB, Giandomenico V.
Mod Pathol. 2009 Feb;22(2):261-72. doi: 10.1038/modpathol.2008.174. Epub 2008 Oct 24.
PMID 18953328
 
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
Lewis BP, Burge CB, Bartel DP.
Cell. 2005 Jan 14;120(1):15-20.
PMID 15652477
 
Identification of Nkx2-3 and TGFB1I1 expression levels as potential biomarkers to predict the effects of FOLFOX4 chemotherapy.
Li S, Lu X, Chi P, Pan J.
Cancer Biol Ther. 2012 Apr;13(6):443-9. doi: 10.4161/cbt.19298. Epub 2012 Apr 1.
PMID 22313639
 
Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice.
Loyer X, Potteaux S, Vion AC, Guerin CL, Boulkroun S, Rautou PE, Ramkhelawon B, Esposito B, Dalloz M, Paul JL, Julia P, Maccario J, Boulanger CM, Mallat Z, Tedgui A.
Circ Res. 2014 Jan 31;114(3):434-43. doi: 10.1161/CIRCRESAHA.114.302213. Epub 2013 Nov 19.
PMID 24255059
 
Establishment of a predictive genetic model for estimating chemotherapy sensitivity of colorectal cancer with synchronous liver metastasis.
Lu X, Pan J, Li S, Shen S, Chi P, Lin H, Huang Y, Xu Z, Huang S.
Cancer Biother Radiopharm. 2013 Sep;28(7):552-8. doi: 10.1089/cbr.2012.1431. Epub 2013 May 30.
PMID 23721165
 
Contribution of NKX2-3 polymorphisms to inflammatory bowel diseases: a meta-analysis of 35358 subjects.
Lu X, Tang L, Li K, Zheng J, Zhao P, Tao Y, Li LX.
Sci Rep. 2014 Jan 29;4:3924. doi: 10.1038/srep03924.
PMID 24473197
 
NKX2-3 and IRGM variants are associated with disease susceptibility to IBD in Eastern European patients.
Meggyesi N, Kiss LS, Koszarska M, Bortlik M, Duricova D, Lakatos L, Molnar T, Lenicek M, Vitek L, Altorjay I, Papp M, Tulassay Z, Miheller P, Papp J, Tordai A, Andrikovics H, Lukas M, Lakatos PL.
World J Gastroenterol. 2010 Nov 7;16(41):5233-40.
PMID 21049557
 
NKX2.3 is required for MAdCAM-1 expression and homing of lymphocytes in spleen and mucosa-associated lymphoid tissue.
Pabst O, Forster R, Lipp M, Engel H, Arnold HH.
EMBO J. 2000 May 2;19(9):2015-23.
PMID 10790368
 
Targeted disruption of the homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small intestine and spleen.
Pabst O, Zweigerdt R, Arnold HH.
Development. 1999 May;126(10):2215-25.
PMID 10207146
 
Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.
Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D, Drummond H, Lees CW, Khawaja SA, Bagnall R, Burke DA, Todhunter CE, Ahmad T, Onnie CM, McArdle W, Strachan D, Bethel G, Bryan C, Lewis CM, Deloukas P, Forbes A, Sanderson J, Jewell DP, Satsangi J, Mansfield JC; Wellcome Trust Case Control Consortium, Cardon L, Mathew CG.
Nat Genet. 2007 Jul;39(7):830-2. Epub 2007 Jun 6.
PMID 17554261
 
Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn's disease, and ulcerative colitis patients.
Plevy S, Silverberg MS, Lockton S, Stockfisch T, Croner L, Stachelski J, Brown M, Triggs C, Chuang E, Princen F, Singh S.
Inflamm Bowel Dis. 2013 May;19(6):1139-48. doi: 10.1097/MIB.0b013e318280b19e.
PMID 23518807
 
Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis.
Rieder F, Kessler SP, West GA, Bhilocha S, de la Motte C, Sadler TM, Gopalan B, Stylianou E, Fiocchi C.
Am J Pathol. 2011 Nov;179(5):2660-73. doi: 10.1016/j.ajpath.2011.07.042. Epub 2011 Sep 21.
PMID 21945322
 
GWAS of dental caries patterns in the permanent dentition.
Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, Weeks DE, Weyant RJ, Crout R, McNeil DW, Marazita ML.
J Dent Res. 2013 Jan;92(1):38-44. doi: 10.1177/0022034512463579. Epub 2012 Oct 11.
PMID 23064961
 
Replication study of ulcerative colitis risk loci in a Lithuanian-Latvian case-control sample.
Skieceviciene J, Kiudelis G, Ellinghaus E, Balschun T, Jonaitis LV, Zvirbliene A, Denapiene G, Leja M, Pranculiene G, Kalibatas V, Saadati H, Ellinghaus D, Andersen V, Valantinas J, Irnius A, Derovs A, Tamelis A, Schreiber S, Kupcinskas L, Franke A.
Inflamm Bowel Dis. 2013 Oct;19(11):2349-55. doi: 10.1097/MIB.0b013e3182a3eaeb.
PMID 23974994
 
ETV6/GOT1 fusion in a case of t(10;12)(q24;p13)-positive myelodysplastic syndrome.
Struski S, Mauvieux L, Gervais C, Helias C, Liu KL, Lessard M.
Haematologica. 2008 Mar;93(3):467-8. doi: 10.3324/haematol.11988.
PMID 18310541
 
Advances in IBD genetics.
Van Limbergen J, Radford-Smith G, Satsangi J.
Nat Rev Gastroenterol Hepatol. 2014 Jun;11(6):372-85. doi: 10.1038/nrgastro.2014.27. Epub 2014 Mar 11. (REVIEW)
PMID 24614343
 
Homeodomain factor Nkx2-3 controls regional expression of leukocyte homing coreceptor MAdCAM-1 in specialized endothelial cells of the viscera.
Wang CC, Biben C, Robb L, Nassir F, Barnett L, Davidson NO, Koentgen F, Tarlinton D, Harvey RP.
Dev Biol. 2000 Aug 15;224(2):152-67.
PMID 10926756
 
Screening of new tumor suppressor genes in sporadic colorectal cancer patients.
Wang X, Zbou C, Qiu G, Fan J, Tang H, Peng Z.
Hepatogastroenterology. 2008 Nov-Dec;55(88):2039-44.
PMID 19260473
 
Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort.
Weersma RK, Stokkers PC, Cleynen I, Wolfkamp SC, Henckaerts L, Schreiber S, Dijkstra G, Franke A, Nolte IM, Rutgeerts P, Wijmenga C, Vermeire S.
Am J Gastroenterol. 2009 Mar;104(3):630-8. doi: 10.1038/ajg.2008.112. Epub 2009 Jan 27.
PMID 19174780
 
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
Wellcome Trust Case Control Consortium.
Nature. 2007 Jun 7;447(7145):661-78.
PMID 17554300
 
Positive association of genetic variants in the upstream region of NKX2-3 with Crohn's disease in Japanese patients.
Yamazaki K, Takahashi A, Takazoe M, Kubo M, Onouchi Y, Fujino A, Kamatani N, Nakamura Y, Hata A.
Gut. 2009 Feb;58(2):228-32. doi: 10.1136/gut.2007.140764. Epub 2008 Oct 20.
PMID 18936107
 
NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells.
Yu W, Hegarty JP, Berg A, Chen X, West G, Kelly AA, Wang Y, Poritz LS, Koltun WA, Lin Z.
PLoS One. 2011;6(5):e20454. doi: 10.1371/journal.pone.0020454. Epub 2011 May 26.
PMID 21637825
 
Association of a Nkx2-3 polymorphism with Crohn's disease and expression of Nkx2-3 is up-regulated in B cell lines and intestinal tissues with Crohn's disease.
Yu W, Lin Z, Kelly AA, Hegarty JP, Poritz LS, Wang Y, Li T, Schreiber S, Koltun WA.
J Crohns Colitis. 2009 Sep;3(3):189-95. doi: 10.1016/j.crohns.2009.04.003. Epub 2009 Jun 10.
PMID 21172269
 
MiR-92a regulates viability and angiogenesis of endothelial cells under oxidative stress.
Zhang L, Zhou M, Qin G, Weintraub NL, Tang Y.
Biochem Biophys Res Commun. 2014 Apr 18;446(4):952-8. doi: 10.1016/j.bbrc.2014.03.035. Epub 2014 Mar 17.
PMID 24650666
 
Differences in genetic background between active smokers, passive smokers, and non-smokers with Crohn's disease.
van der Heide F, Nolte IM, Kleibeuker JH, Wijmenga C, Dijkstra G, Weersma RK.
Am J Gastroenterol. 2010 May;105(5):1165-72. doi: 10.1038/ajg.2009.659. Epub 2009 Dec 1.
PMID 19953089
 

Citation

This paper should be referenced as such :
Zhenwu Lin, John P Hegarty, Joanna Floros, Andre Franke
NKX2-3 (NK2 homeobox 3)
Atlas Genet Cytogenet Oncol Haematol. 2016;20(1):18-25.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NKX2-3ID51779ch10q24.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(6;11)(q27;q23) KMT2A/AFDN


External links

Nomenclature
HGNC (Hugo)NKX2-3   7836
Cards
AtlasNKX2-3ID51779ch10q24
Entrez_Gene (NCBI)NKX2-3  159296  NK2 homeobox 3
AliasesCSX3; NK2.3; NKX2.3; NKX2C; 
NKX4-3
GeneCards (Weizmann)NKX2-3
Ensembl hg19 (Hinxton)ENSG00000119919 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000119919 [Gene_View]  chr10:99532933-99536523 [Contig_View]  NKX2-3 [Vega]
ICGC DataPortalENSG00000119919
TCGA cBioPortalNKX2-3
AceView (NCBI)NKX2-3
Genatlas (Paris)NKX2-3
WikiGenes159296
SOURCE (Princeton)NKX2-3
Genetics Home Reference (NIH)NKX2-3
Genomic and cartography
GoldenPath hg38 (UCSC)NKX2-3  -     chr10:99532933-99536523 +  10q24.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NKX2-3  -     10q24.2   [Description]    (hg19-Feb_2009)
EnsemblNKX2-3 - 10q24.2 [CytoView hg19]  NKX2-3 - 10q24.2 [CytoView hg38]
Mapping of homologs : NCBINKX2-3 [Mapview hg19]  NKX2-3 [Mapview hg38]
OMIM606727   
Gene and transcription
Genbank (Entrez)AK300856 AK313485 BC025788 BI764885
RefSeq transcript (Entrez)NM_145285
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NKX2-3
Cluster EST : UnigeneHs.243272 [ NCBI ]
CGAP (NCI)Hs.243272
Alternative Splicing GalleryENSG00000119919
Gene ExpressionNKX2-3 [ NCBI-GEO ]   NKX2-3 [ EBI - ARRAY_EXPRESS ]   NKX2-3 [ SEEK ]   NKX2-3 [ MEM ]
Gene Expression Viewer (FireBrowse)NKX2-3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)159296
GTEX Portal (Tissue expression)NKX2-3
Human Protein AtlasENSG00000119919-NKX2-3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8TAU0   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8TAU0  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8TAU0
Splice isoforms : SwissVarQ8TAU0
PhosPhoSitePlusQ8TAU0
Domaine pattern : Prosite (Expaxy)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (EBI)Homeobox-like    Homeobox_CS    Homeobox_dom    Homeobox_metazoa   
Domain families : Pfam (Sanger)Homeobox (PF00046)   
Domain families : Pfam (NCBI)pfam00046   
Domain families : Smart (EMBL)HOX (SM00389)  
Conserved Domain (NCBI)NKX2-3
DMDM Disease mutations159296
Blocks (Seattle)NKX2-3
SuperfamilyQ8TAU0
Human Protein Atlas [tissue]ENSG00000119919-NKX2-3 [tissue]
Peptide AtlasQ8TAU0
HPRD05992
IPIIPI00152116   
Protein Interaction databases
DIP (DOE-UCLA)Q8TAU0
IntAct (EBI)Q8TAU0
FunCoupENSG00000119919
BioGRIDNKX2-3
STRING (EMBL)NKX2-3
ZODIACNKX2-3
Ontologies - Pathways
QuickGOQ8TAU0
Ontology : AmiGOleukocyte homeostasis  plasma cell differentiation  molecular_function  cellular_component  nucleus  transcription, DNA-templated  triglyceride metabolic process  biological_process  gland morphogenesis  macrophage differentiation  regulation of cell proliferation  odontogenesis of dentin-containing tooth  CD4-positive, alpha-beta T cell differentiation  sequence-specific DNA binding  positive regulation of transcription from RNA polymerase II promoter  lymph node development  spleen development  Peyer's patch development  post-embryonic digestive tract morphogenesis  leukocyte migration  
Ontology : EGO-EBIleukocyte homeostasis  plasma cell differentiation  molecular_function  cellular_component  nucleus  transcription, DNA-templated  triglyceride metabolic process  biological_process  gland morphogenesis  macrophage differentiation  regulation of cell proliferation  odontogenesis of dentin-containing tooth  CD4-positive, alpha-beta T cell differentiation  sequence-specific DNA binding  positive regulation of transcription from RNA polymerase II promoter  lymph node development  spleen development  Peyer's patch development  post-embryonic digestive tract morphogenesis  leukocyte migration  
NDEx NetworkNKX2-3
Atlas of Cancer Signalling NetworkNKX2-3
Wikipedia pathwaysNKX2-3
Orthology - Evolution
OrthoDB159296
GeneTree (enSembl)ENSG00000119919
Phylogenetic Trees/Animal Genes : TreeFamNKX2-3
HOVERGENQ8TAU0
HOGENOMQ8TAU0
Homologs : HomoloGeneNKX2-3
Homology/Alignments : Family Browser (UCSC)NKX2-3
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNKX2-3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NKX2-3
dbVarNKX2-3
ClinVarNKX2-3
1000_GenomesNKX2-3 
Exome Variant ServerNKX2-3
ExAC (Exome Aggregation Consortium)ENSG00000119919
GNOMAD BrowserENSG00000119919
Genetic variants : HAPMAP159296
Genomic Variants (DGV)NKX2-3 [DGVbeta]
DECIPHERNKX2-3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNKX2-3 
Mutations
ICGC Data PortalNKX2-3 
TCGA Data PortalNKX2-3 
Broad Tumor PortalNKX2-3
OASIS PortalNKX2-3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNKX2-3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNKX2-3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NKX2-3
DgiDB (Drug Gene Interaction Database)NKX2-3
DoCM (Curated mutations)NKX2-3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NKX2-3 (select a term)
intoGenNKX2-3
NCG5 (London)NKX2-3
Cancer3DNKX2-3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606727   
Orphanet
MedgenNKX2-3
Genetic Testing Registry NKX2-3
NextProtQ8TAU0 [Medical]
TSGene159296
GENETestsNKX2-3
Target ValidationNKX2-3
Huge Navigator NKX2-3 [HugePedia]
snp3D : Map Gene to Disease159296
BioCentury BCIQNKX2-3
ClinGenNKX2-3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD159296
Chemical/Pharm GKB GenePA31643
Clinical trialNKX2-3
Miscellaneous
canSAR (ICR)NKX2-3 (select the gene name)
Probes
Litterature
PubMed41 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNKX2-3
EVEXNKX2-3
GoPubMedNKX2-3
iHOPNKX2-3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 12 16:28:48 CEST 2017

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggewtionq r contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.