Atlas of Genetics and Cytogenetics in Oncology and Haematology


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

Identity

Other namesCSX
CSX1
NKX2E
Hs.54473
NM_004387
cardiac-specific homeobox
HGNC NKX2-5
Location 5q35.2
Local_order cen--- BNIP1---NKX2-5--- STC2---tel

DNA/RNA

 
  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
Description The gene has two exons and one intron.
Transcription Transcription takes place in a telomere --> centromere orientation. The length of the processed mRNA is about 1500 bp.
Pseudogene Not known

Protein

 
  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.
Description 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 Expression is mainly restricted to the heart. But during embryogenesis NKX2-5 expression has also been detected in spleen-precursor cells.
Localisation Cytoplasmatic and nuclear, probably depending on phosphorylation status
Function Involved in differentiation processes in heart development and in homeostasis and survival of cardiac myocytes.
Homology Homeodomain protein with membership of the NK2 / NKX family.

Mutations

Note 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.
Germinal Haploinsufficiency due to loss-of-function mutations is associated with atrioventricular conduction defects and tetralogy of Fallot
Somatic Recently identified in cardiac disease.

Implicated in

Entity t(5;14)(q35;q32) in acute lymphoblastic leukaemia (ALL) and t(5;14)(q35;q11) in chronic lymphocytic leukaemia
Note 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.
Prognosis Unknown
Cytogenetics 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.
 
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.
Hybrid/Mutated Gene No
Abnormal Protein No
Oncogenesis 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.
  

Breakpoints

 
  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.

External links

Nomenclature
HGNCNKX2-5   2488
Entrez_GeneNKX2-5  1482  NK2 transcription factor related, locus 5 (Drosophila)
Cards
AtlasNKX25ID42958ch5q35
GeneCardsNKX2-5
EnsemblNKX2-5 [Search_View]   ENSG00000183072 [Gene_View]
GenatlasNKX2-5
GeneLynxNKX2-5
eGenomeNKX2-5
euGene1482
Genomic and cartography
GoldenPathNKX2-5  -  5q35.2   chr5:172591744-172594868 -  5q34   [Description]    (hg18-Mar_2006)
EnsemblNKX2-5 - 5q34 [CytoView]
NCBIMapview
OMIMDisease map [OMIM]
HomoloGeneNKX2-5
Gene and transcription
GenbankAB021133 [ ENTREZ ]
GenbankAK290615 [ ENTREZ ]
GenbankBC025711 [ ENTREZ ]
GenbankDQ893313 [ ENTREZ ]
GenbankDQ894104 [ ENTREZ ]
RefSeqNM_004387 [ SRS ]    NM_004387 [ ENTREZ ]
RefSeqAC_000048 [ SRS ]    AC_000048 [ ENTREZ ]
RefSeqAC_000137 [ SRS ]    AC_000137 [ ENTREZ ]
RefSeqNC_000005 [ SRS ]    NC_000005 [ ENTREZ ]
RefSeqNT_023133 [ SRS ]    NT_023133 [ ENTREZ ]
RefSeqNW_001838954 [ SRS ]    NW_001838954 [ ENTREZ ]
RefSeqNW_922784 [ SRS ]    NW_922784 [ ENTREZ ]
AceViewNKX2-5 AceView - NCBI
UnigeneHs.54473 [ SRS ]    Hs.54473 [ NCBI ]     HS54473 [ spliceNest ]
Fast-db13215 (alternative variants)
Protein : pattern, domain, 3D structure
SwissProtP52952 [ SRS]    P52952 [ EXPASY ]     P52952 [ INTERPRO ]     P52952 [ UNIPROT ]
PrositePS00027 HOMEOBOX_1 [ SRS ]    PS00027 HOMEOBOX_1 [ Expasy ]
PrositePS50071 HOMEOBOX_2 [ SRS ]    PS50071 HOMEOBOX_2 [ Expasy ]
InterproIPR001356 Homeobox [ SRS ]    IPR001356 Homeobox [ EBI ]
InterproIPR012287 Homeodomain-rel [ SRS ]    IPR012287 Homeodomain-rel [ EBI ]
CluSTrP52952
PfamPF00046 Homeobox [ SRS ]    PF00046 Homeobox [ Sanger ]    pfam00046 [ NCBI-CDD ]
SmartSM00389 HOX [EMBL]
ProdomPD000010 Homeobox[INRA-Toulouse]
ProdomP52952 NKX25_HUMAN [ Domain structure ]   P52952 NKX25_HUMAN  [ sequences sharing at least 1 domain ]
BlocksP52952
HPRD02787
Protein Interaction databases
DIPP52952
IntActP52952
Polymorphism : SNP, mutations, diseases
OMIM108900;187500;600584    [ map ]   
GENECLINICS108900;187500;600584
SNPNKX2-5 [dbSNP-NCBI]  
SNPNM_004387 [SNP-NCI]  
SNPNKX2-5 [GeneSNPs - Utah]  NKX2-5] [HGBASE - SRS]
HAPMAPNKX2-5 [HAPMAP]  
HGMDNKX2-5
General knowledge
Family BrowserNKX2-5 [UCSC Family Browser]
SOURCENM_004387
SMDHs.54473
SAGEHs.54473
GOnegative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter
GOvasculogenesis [Amigo]  vasculogenesis
GOheart looping [Amigo]  heart looping
GOtranscription factor activity [Amigo]  transcription factor activity
GOprotein binding [Amigo]  protein binding
GOprotein binding [Amigo]  protein binding
GOnucleus [Amigo]  nucleus
GOtranscription factor complex [Amigo]  transcription factor complex
GOmulticellular organismal development [Amigo]  multicellular organismal development
GOadult heart development [Amigo]  adult heart development
GOtranscription activator activity [Amigo]  transcription activator activity
GOtranscription repressor activity [Amigo]  transcription repressor activity
GOhemopoiesis [Amigo]  hemopoiesis
GOembryonic heart tube development [Amigo]  embryonic heart tube development
GOsequence-specific DNA binding [Amigo]  sequence-specific DNA binding
GOpositive regulation of transcription from RNA polymerase II promoter [Amigo]  positive regulation of transcription from RNA polymerase II promoter
GOprotein heterodimerization activity [Amigo]  protein heterodimerization activity
GOcardiac muscle development [Amigo]  cardiac muscle development
GOcardiac muscle cell differentiation [Amigo]  cardiac muscle cell differentiation
BIOCARTAALK in cardiac myocytes    [Genes]
BIOCARTAHop Pathway in Cardiac Development    [Genes]
BIOCARTANFAT and Hypertrophy of the heart (Transcription in the broken heart)    [Genes]
PubGeneNKX2-5
TreeFamNKX2-5
CTD1482 [Comparative ToxicoGenomics Database]
Other databases
Probes
ProbeNKX2-5 Related clones (RZPD - Berlin)
PubMed
PubMed49 Pubmed reference(s) in LocusLink

Bibliography

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Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2).
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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).
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Bcl11b is required for differentiation and survival of alphabeta T lymphocytes.
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PMID 14684164
 
Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites.
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PMID 14732688
 
Function follows form: cardiac conduction system defects in Nkx2-5 mutation.
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The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology. 2004 ; 280 (2) : 966-972.
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BCL11B rearrangements probably target T-cell neoplasia rather than acute myelocytic leukemia.
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Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations.
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Contributor(s)

Written03-2005Roderick MacLeod, Stefan Nagel

Citation

This paper should be referenced as such :
MacLeod RAF, Nagel S . NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila).. Atlas Genet Cytogenet Oncol Haematol. March 2005 .
URL : http://AtlasGeneticsOncology.org/Genes/NKX25ID42958ch5q35.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Aug 11 21:15:53 2008


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