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Gene Review

NKX2-5  -  NK2 homeobox 5

Homo sapiens

Synonyms: CHNG5, CSX, CSX1, Cardiac-specific homeobox, HLHS2, ...
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Disease relevance of NKX2-5


High impact information on NKX2-5

  • Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation [5].
  • The cardiac homeobox protein Nkx2-5 is essential in cardiac development, and mutations in Csx (which encodes Nkx2-5) cause various congenital heart diseases [5].
  • Co-transfection of Nkx2-5 and Tbx5 into COS-7 cells showed that they also associate with each other in mammalian cells [5].
  • A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located [1].
  • These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life [1].

Biological context of NKX2-5

  • None of the VSD patients had this mutation; yet 14/29 had at least one mutation in the third helix leading to either inactivation or reduction of NKX2-5 transactivation [6].
  • To address the functional consequences of single and multiple mutations of NKX2-5, we developed a functional assay in the budding yeast Saccharomyces cerevisiae, which could determine transactivation capacity and specificity of expressed NKX2-5 alleles towards targeted response element (RE) sequences [6].
  • We studied the pathology and molecular genetics of NKX2-5 in diseased heart tissues of 68 patients with complex congenital heart disease (CHD), particularly atrial (ASD), ventricular (VSD), and atrioventricular septal defects (AVSD) [7].
  • We found one previously documented NKX2-5 missense mutation, T178M, in members of a family with ASD without AV conduction block [3].
  • RESULTS: Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis and that NKX2-5 mutations contribute to TD [8].

Anatomical context of NKX2-5

  • Human heart development requires an orderly coordination of transcriptional programs, with the homeodomain protein NKX2-5 being one of the key transcription factors required for the differentiation of mesodermal progenitor cells [6].
  • Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis [8].
  • Furthermore, overexpression of NKX2.5 in C2C12 cells and primary cultures of human fetal myoblasts led to differentiation of myoblasts into neuron-like cells and expression of neuronal markers [9].
  • The expression of NKX2.5 in terminally differentiated C2C12 myotubes resulted in a change in morphology and breakdown into smaller myotubes [9].
  • High NKX2-5 expression was also found in the T-cell lines PEER and CCRF-CEM, which harbor an NKX2-5-BCL11B rearrangement, and in the embryonic kidney cell line 293 [10].

Associations of NKX2-5 with chemical compounds

  • Mutational analysis and in vitro kinase assays suggested that this 40-kDa Csx/Nkx2.5 kinase is a catalytic subunit of casein kinase II (CKII) that phosphorylates the serine residue between the first and second helix of the homeodomain [11].
  • Furthermore, nested reverse transcriptase-polymerase chain reaction from formalin-fixed, paraffin-embedded tissue was performed and demonstrated that the Nkx2.5/Csx and eHAND gene product to be detected in all cases, and in three of six cases, respectively [12].
  • We have genetically defined a novel conserved tyrosine-rich domain (YRD) within Nkx2-5 that has co-evolved with its homeodomain [13].
  • Furthermore, heterozygous mutation of all nine tyrosines to alanine created an allele with a strong dominant-negative-like activity in vivo: ES cell<-->embryo chimaeras bearing the heterozygous mutation died before term with cardiac malformations similar to the more severe anomalies seen in NKX2.5 mutant families [13].
  • The detection of beta amyloid by CSX was nullified by formic acid pretreatment of the tissue section [14].
  • Knockdown of PU.1, known to be trichostatin A responsive and which potentially binds TLX3/NKX2-5 promoters, effected down-regulation of both homeobox genes [15].

Enzymatic interactions of NKX2-5

  • SUMO-2 linkage to Nkx2.5 was catalyzed only by PIASx and not by other PIAS proteins [16].

Regulatory relationships of NKX2-5

  • In this t(5;14) variant, NKX2-5 is expressed instead of TLX3 at both RNA and protein levels [2].
  • As a result of this recombination NKX2-5 was placed under influence of the TRD enhancer, resulting in strong ectopic NKX2-5 expression [10].
  • Humans with heterozygous mutations in the NKX2.5 gene generally have a disorder involving progressive atrio-ventricular conduction block and atrial septal defect, although sometimes other abnormalities including tetralogy of Fallot [17].

Other interactions of NKX2-5

  • Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1 [18].
  • Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease [1].
  • The coding region of the NKX2-5 locus was amplified by polymerase chain reaction and sequenced [3].
  • GATA-6 cannot substitute for GATA-4 for interaction with Nkx2-5 [19].
  • Adipose tissue-derived stem cells (ADSCs) were transduced with two different lentiviral vectors simultaneously: (1) a lentiviral vector expressing eGFP controlled by the Nkx2.5 promoter and (2) a lentiviral vector expressing DsRed2 controlled by the myosin light chain-2v promoter (MLC-2v) [20].

Analytical, diagnostic and therapeutic context of NKX2-5


  1. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Schott, J.J., Benson, D.W., Basson, C.T., Pease, W., Silberbach, G.M., Moak, J.P., Maron, B.J., Seidman, C.E., Seidman, J.G. Science (1998) [Pubmed]
  2. The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Nagel, S., Kaufmann, M., Drexler, H.G., MacLeod, R.A. Cancer Res. (2003) [Pubmed]
  3. Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome. Elliott, D.A., Kirk, E.P., Yeoh, T., Chandar, S., McKenzie, F., Taylor, P., Grossfeld, P., Fatkin, D., Jones, O., Hayes, P., Feneley, M., Harvey, R.P. J. Am. Coll. Cardiol. (2003) [Pubmed]
  4. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. Benson, D.W., Silberbach, G.M., Kavanaugh-McHugh, A., Cottrill, C., Zhang, Y., Riggs, S., Smalls, O., Johnson, M.C., Watson, M.S., Seidman, J.G., Seidman, C.E., Plowden, J., Kugler, J.D. J. Clin. Invest. (1999) [Pubmed]
  5. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Hiroi, Y., Kudoh, S., Monzen, K., Ikeda, Y., Yazaki, Y., Nagai, R., Komuro, I. Nat. Genet. (2001) [Pubmed]
  6. Functional dissection of sequence-specific NKX2-5 DNA binding domain mutations associated with human heart septation defects using a yeast-based system. Inga, A., Reamon-Buettner, S.M., Borlak, J., Resnick, M.A. Hum. Mol. Genet. (2005) [Pubmed]
  7. Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations. Reamon-Buettner, S.M., Hecker, H., Spanel-Borowski, K., Craatz, S., Kuenzel, E., Borlak, J. Am. J. Pathol. (2004) [Pubmed]
  8. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. Dentice, M., Cordeddu, V., Rosica, A., Ferrara, A.M., Santarpia, L., Salvatore, D., Chiovato, L., Perri, A., Moschini, L., Fazzini, C., Olivieri, A., Costa, P., Stoppioni, V., Baserga, M., De Felice, M., Sorcini, M., Fenzi, G., Di Lauro, R., Tartaglia, M., Macchia, P.E. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  9. CSX/Nkx2.5 modulates differentiation of skeletal myoblasts and promotes differentiation into neuronal cells in vitro. Riazi, A.M., Lee, H., Hsu, C., Van Arsdell, G. J. Biol. Chem. (2005) [Pubmed]
  10. The effect of a novel recombination between the homeobox gene NKX2-5 and the TRD locus in T-cell acute lymphoblastic leukemia on activation of the NKX2-5 gene. Przybylski, G.K., Dik, W.A., Grabarczyk, P., Wanzeck, J., Chudobska, P., Jankowski, K., von Bergh, A., van Dongen, J.J., Schmidt, C.A., Langerak, A.W. Haematologica (2006) [Pubmed]
  11. Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5. Kasahara, H., Izumo, S. Mol. Cell. Biol. (1999) [Pubmed]
  12. Cardiomyogenic differentiation in cardiac myxoma expressing lineage-specific transcription factors. Kodama, H., Hirotani, T., Suzuki, Y., Ogawa, S., Yamazaki, K. Am. J. Pathol. (2002) [Pubmed]
  13. A tyrosine-rich domain within homeodomain transcription factor Nkx2-5 is an essential element in the early cardiac transcriptional regulatory machinery. Elliott, D.A., Solloway, M.J., Wise, N., Biben, C., Costa, M.W., Furtado, M.B., Lange, M., Dunwoodie, S., Harvey, R.P. Development (2006) [Pubmed]
  14. The presence of a novel protein in calf serum that recognizes beta amyloid in the formalin-fixed section. Kanemaru, K., Hasegawa, M., Shimada, H., Ihara, Y. Am. J. Pathol. (1990) [Pubmed]
  15. Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3'-BCL11B enhancers and coregulation by PU.1 and HMGA1. Nagel, S., Scherr, M., Kel, A., Hornischer, K., Crawford, G.E., Kaufmann, M., Meyer, C., Drexler, H.G., MacLeod, R.A. Cancer Res. (2007) [Pubmed]
  16. Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier. Wang, J., Zhang, H., Iyer, D., Feng, X.H., Schwartz, R.J. J. Biol. Chem. (2008) [Pubmed]
  17. Developmental paradigms in heart disease: insights from tinman. Prall, O.W., Elliott, D.A., Harvey, R.P. Ann. Med. (2002) [Pubmed]
  18. GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Pehlivan, T., Pober, B.R., Brueckner, M., Garrett, S., Slaugh, R., Van Rheeden, R., Wilson, D.B., Watson, M.S., Hing, A.V. Am. J. Med. Genet. (1999) [Pubmed]
  19. The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. Durocher, D., Charron, F., Warren, R., Schwartz, R.J., Nemer, M. EMBO J. (1997) [Pubmed]
  20. Genetically selected stem cells from human adipose tissue express cardiac markers. Bai, X., Pinkernell, K., Song, Y.H., Nabzdyk, C., Reiser, J., Alt, E. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  21. Assignment of cardiac homeobox gene CSX to human chromosome 5q34. Shiojima, I., Komuro, I., Inazawa, J., Nakahori, Y., Matsushita, I., Abe, T., Nagai, R., Yazaki, Y. Genomics (1995) [Pubmed]
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