Atlas of Genetics and Cytogenetics in Oncology and Haematology
NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila).
| Identity |
| Other names | CSX |
| 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 |
| Bibliography |
| Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. |
| Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP |
| Development (Cambridge, England). 1993 ; 119 (2) : 419-431. |
| PMID 7904557 |
| NK-2 homeobox genes and heart development. |
| Harvey RP |
| Developmental biology. 1996 ; 178 (2) : 203-216. |
| PMID 8812123 |
| Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. |
| Tanaka M, Kasahara H, Bartunkova S, Schinke M, Komuro I, Inagaki H, Lee Y, Lyons GE, Izumo S |
| Developmental genetics. 1998 ; 22 (3) : 239-249. |
| PMID 9621431 |
| 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 |
| Molecular and cellular biology. 1999 ; 19 (1) : 526-536. |
| PMID 9858576 |
| Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription. |
| Schwartz RJ, Olson EN |
| Development (Cambridge, England). 1999 ; 126 (19) : 4187-4192. |
| PMID 10477287 |
| Atrial form and function: lessons from human molecular genetics. |
| Hatcher CJ, Kim MS, Basson CT |
| Trends in cardiovascular medicine. 2000 ; 10 (3) : 93-101. |
| PMID 11428001 |
| Embryonic origins of spleen asymmetry. |
| Patterson KD, Drysdale TA, Krieg PA |
| Development (Cambridge, England). 2000 ; 127 (1) : 167-175. |
| PMID 10654610 |
| A 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, Busson-LeConiat M, Ballerini P, Mauchauffˆ© M, Della Valle V, Monni R, Nguyen Khac F, Mercher T, Penard-Lacronique V, Pasturaud P, Gressin L, Heilig R, Daniel MT, Lessard M, Berger R |
| Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 ; 15 (10) : 1495-1504. |
| PMID 11587205 |
| t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Franˆßais de Cytogˆ©nˆ©tique Hˆ©matologique (GFCH). |
| Berger R, Dastugue N, Busson M, Van Den Akker J, Pˆ©rot C, Ballerini P, Hagemeijer A, Michaux L, Charrin C, Pages MP, Mugneret F, Andrieux J, Talmant P, Hˆ©lias C, Mauvieux L, Lafage-Pochitaloff M, Mozziconacci MJ, Cornillet-Lefebvre P, Radford I, Asnafi V, Bilhou-Nabera C, Nguyen Khac F, Lˆ©onard C, Speleman F, Poppe B, Bastard C, Taviaux S, Quilichini B, Herens C, Grˆ©goire MJ, Cavˆ© H, Groupe Franˆßais de Cytogˆ©nˆ©tique Hˆ©matologique (GFCH), Bernard OA |
| Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 ; 17 (9) : 1851-1857. |
| PMID 12970786 |
| Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). |
| MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG |
| Genes, chromosomes & cancer. 2003 ; 37 (1) : 84-91. |
| PMID 12661009 |
| 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 HG, MacLeod RA |
| Cancer research. 2003 ; 63 (17) : 5329-5334. |
| PMID 14500364 |
| Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. |
| Wakabayashi Y, Watanabe H, Inoue J, Takeda N, Sakata J, Mishima Y, Hitomi J, Yamamoto T, Utsuyama M, Niwa O, Aizawa S, Kominami R |
| Nature immunology. 2003 ; 4 (6) : 533-539. |
| PMID 12717433 |
| The functional mapping of long-range transcription control elements of the HOX11 proto-oncogene. |
| Brake RL, Chatterjee PK, Kees UR, Watt PM |
| Biochemical and biophysical research communications. 2004 ; 313 (2) : 327-335. |
| PMID 14684164 |
| Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites. |
| Crawford GE, Holt IE, Mullikin JC, Tai D, Blakesley R, Bouffard G, Young A, Masiello C, Green ED, Wolfsberg TG, National Institutes Of Health Intramural Sequencing Center, Collins FS |
| Proceedings of the National Academy of Sciences of the United States of America. 2004 ; 101 (4) : 992-997. |
| PMID 14732688 |
| Function follows form: cardiac conduction system defects in Nkx2-5 mutation. |
| Jay PY, Harris BS, Buerger A, Rozhitskaya O, Maguire CT, Barbosky LA, McCusty E, Berul CI, O'brien TX, Gourdie RG, Izumo S |
| The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology. 2004 ; 280 (2) : 966-972. |
| PMID 15368343 |
| BCL11B rearrangements probably target T-cell neoplasia rather than acute myelocytic leukemia. |
| MacLeod RA, Nagel S, Drexler HG |
| Cancer genetics and cytogenetics. 2004 ; 153 (1) : 88-89. |
| PMID 15325104 |
| Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations. |
| Reamon-Buettner SM, Hecker H, Spanel-Borowski K, Craatz S, Kuenzel E, Borlak J |
| The American journal of pathology. 2004 ; 164 (6) : 2117-2125. |
| PMID 15161646 |
| Transcriptional activation of the cardiac homeobox gene CSX1/NKX2-5. |
| Su X, Busson M, Delabessee E, Azgui Z, Berger R, Beral HM, Bernard OA |
| Blood. 2004 ; 104 : page 152. |
| Two 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, Velthuizen SC, Wolvers-Tettero IL, van Dongen JJ, Poulsen TS, MacLeod RA, Beverloo HB, Langerak AW |
| Haematologica. 2004 ; 89 (6) : 671-678. |
| PMID 15194534 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 03-2005 | Roderick 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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