NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila).

2005-03-01   Roderick MacLeod , Stefan Nagel 

DSMZ-Deutsche Sammlung von, Mikroorganismen und Zellkulturen, Inhoffenstr. 7B, D-38124 Braunschweig, Germany




Atlas Image
The gene for NKX2-5 comprizes two exons of 510 and 1075 bp, respectively. The length of the intron is 1540 bp. Positions of start and stop codons are indicated. These data refer to ENSEMBL transcript


The gene has two exons and one intron.


Transcription takes place in a telomere --> centromere orientation. The length of the processed mRNA is about 1500 bp.


Not known


Atlas Image
Figure shows mutations causing various cardiac anomalies. NKX2-5 contains two exons encoding a 324-amino acid protein including a tinman domain (TN), homeodomain (black) and an NK2 domain. Truncation mutations are shown above, missense mutations below. ? indicates deletion of the intron 1 splice donor site. Note clustering of mutations within the homeobox itself.


324 amino acids; 35-38 kDa, depending on phosphorylation status; contains one TN domain (residues 10-21), one homeodomain (residues 138-197), and one NK2 domain (residues 212-234).


Expression is mainly restricted to the heart. But during embryogenesis NKX2-5 expression has also been detected in spleen-precursor cells.


Cytoplasmatic and nuclear, probably depending on phosphorylation status


Involved in differentiation processes in heart development and in homeostasis and survival of cardiac myocytes.


Homeodomain protein with membership of the NK2 / NKX family.



Among vertebrates, NKX2-5 is the most highly conserved of the Drosophila tinman homologs and subject to transcriptional control via complex series of cis-regulatory elements both proximal and distal of the transcription unit.


Haploinsufficiency due to loss-of-function mutations is associated with atrioventricular conduction defects and tetralogy of Fallot


Recently identified in cardiac disease.

Implicated in

Entity name
t(5;14)(q35;q32) in acute lymphoblastic leukaemia (ALL) and t(5;14)(q35;q11) in chronic lymphocytic leukaemia
NKX2-5 lies circa 2 Mbp telomeric of TLX3 which is recurrently targeted for juxtaposition with BCL11B by t(5;14)(q35;q32) in a subset of patients (both pediatric and adult) in T-cell ALL. Studies performed on pediatric T-ALL cell lines have shown that visually identical t(5;14) rearrangements may target NKX2-5 or TLX3 . Initial data suggest that the t(5;14) variant targeting NKX2-5 is clinically rare . The clinical involvement t(5;14)/NKX2-5 has only been recently identified but has yet to be published.
In addition to T-ALL, NKX2-5 rearrangement has been reported in a case of chronic lymphocytic leukaemia (CLL) with t(5;14)(q35;q11) where the activating partner at 14q11 is TCRA/TCRD.
The t(5;14) rearrangements respectively targeting NKX2-5 and TLX3 which lies about 2Mbp centromeric are cytogenetically indistinguishable in both conventionally banded and chromosome painting preparations. In addition, both sets of rearrangements are cryptic as equal and similarly banded material from chromosomes 5 and 14 are exchanged. Thus, analysis using sets of BAC clones covering both TLX3 and NKX2-5 loci is necessary to distinguish these rearrangements.
Hybrid gene
Atlas Image
Figure shows FISH analysis of t(5;14) in the pediatric T-ALL cell line PEER using three RP11 library clones located immediately centromeric (779o18, labelled red), spanning (466h21, green) and telomeric (45g21, yellow) of NKX2-5. (See below for map.) The rearrangement may be a simple insertion or, a double translocation whereby chromosome 14 material is first translocated onto the der(5) and then returned by a non-reciprocal copying process to the der(14) accompanied by genomic material surrounding NKX2-5.
Fusion protein
NKX2-5 is developmentally silenced in thymocytes. Formation of t(5;14) juxtaposes NKX2-5 with enhancer elements probably cognate with T-cell specific DNaseI hypersensitive sites present in the downstream regulatory region of BCL11B which plays a central role in thymic maturation. It is believed that both TLX3 and NKX2-5 are reactivated by similar mechanisms involving juxtaposition with T-cell specific regulatory regions. Structural similarities shared by NKX2-5, TLX1 and TLX3 add weight to this hypothesis.


Atlas Image
Figure shows breakpoints described in ALL cell lines with t(5;14)(q35.2;q32) which juxtaposes NKX2-5 with the downstream region of BCL11B - outer breakpoints; and in a case of CLL with t(5;14)(q35.2;q11) where the activating locus was TRD - middle breakpoint. Completion of sequencing data at the NKX2-5 locus has repositioned some of the BAC clones, allowing further refinement of the breakpoint assignments. It is now clear that known breakpoints tightly flank NKX2-5 without disrupting the transcription unit itself. Thus, NKX2-5 translocations may also involve disruption of cis-regulatory elements as has been shown for TLX1(HOX11) in t(10;14)(q24;q11) in T-ALL.


Pubmed IDLast YearTitleAuthors
129707862003t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Français de Cytogénétique Hématologique (GFCH).Berger R et al
115872052001A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia.Bernard OA et al
146841642004The functional mapping of long-range transcription control elements of the HOX11 proto-oncogene.Brake RL et al
147326882004Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites.Crawford GE et al
88121231996NK-2 homeobox genes and heart development.Harvey RP et al
114280012000Atrial form and function: lessons from human molecular genetics.Hatcher CJ et al
153683432004Function follows form: cardiac conduction system defects in Nkx2-5 mutation.Jay PY et al
98585761999Identification 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 et al
79045571993Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants.Lints TJ et al
153251042004BCL11B rearrangements probably target T-cell neoplasia rather than acute myelocytic leukemia.MacLeod RA et al
145003642003The 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 et al
106546102000Embryonic origins of spleen asymmetry.Patterson KD et al
151616462004Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations.Reamon-Buettner SM et al
104772871999Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription.Schwartz RJ et al
96214311998Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development.Tanaka M et al
127174332003Bcl11b is required for differentiation and survival of alphabeta T lymphocytes.Wakabayashi Y et al
151945342004Two dual-color split signal fluorescence in situ hybridization assays to detect t(5;14) involving HOX11L2 or CSX in T-cell acute lymphoblastic leukemia.van Zutven LJ et al

Other Information

Locus ID:

NCBI: 1482
MIM: 600584
HGNC: 2488
Ensembl: ENSG00000183072


dbSNP: 1482
ClinVar: 1482
TCGA: ENSG00000183072


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
YAP1- and WWTR1 (TAZ)-stimulated gene expressionREACTOMER-HSA-2032785
Muscle contractionREACTOMER-HSA-397014
Cardiac conductionREACTOMER-HSA-5576891
Physiological factorsREACTOMER-HSA-5578768


Pubmed IDYearTitleCitations
200620602010Genome-wide association study of PR interval.185
146074542003NKX2.5 mutations in patients with congenital heart disease.86
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
127985842003Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome.68
127985842003Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome.68
206060362010Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian men.51
186895732008Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects.38
199485352010Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.36
164182142006Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis.35
175847352007Transcriptional repression by the T-box proteins Tbx18 and Tbx15 depends on Groucho corepressors.35


Roderick MacLeod ; Stefan Nagel

NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila).

Atlas Genet Cytogenet Oncol Haematol. 2005-03-01

Online version: http://atlasgeneticsoncology.org/gene/42958/nkx2-5-(nk2-transcription-factor-related-locus-5-(drosophila)