Reviewed, UniProtKB/Swiss-Prot P52952 (NKX25_HUMAN)

Names and origin

Protein names

Recommended name:
    Homeobox protein Nkx-2.5
Alternative name(s):
    Homeobox protein NK-2 homolog E
    Cardiac-specific homeobox
    Homeobox protein CSX

Gene names

Name:	NKX2-5
Synonyms:	CSX, NKX2.5, NKX2E

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	324 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Implicated in commitment to and/or differentiation of the myocardial lineage. Acts as a transcriptional activator of ANF in cooperation with GATA4 By similarity.
Subunit structure	Interacts with HIPK1 and HIPK2, but not HIPK3. Interacts with the C-terminal zinc finger of GATA4 through its homeobox domain. Also interacts with JARID2 which represses its ability to activate transcription of ANF. Interacts with FBLIM1 By similarity.
Subcellular location	Nucleus Probable.
Tissue specificity	Expressed only in the heart.
Involvement in disease	Defects in NKX2-5 are the cause of atrial septal defect with atrioventricular conduction defects (ASD-AVCD) [MIM:108900]. ASD-AVCD is a congenital heart malformation characterized by atrioventricular conduction defects and incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. Ref.4 Ref.5 Ref.7 Ref.8 Defects in NKX2-5 are a cause of tetralogy of Fallot (TOF) [MIM:187500]. TOF is a congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. This condition results in a blue baby at birth due to inadequate oxygenation. Surgical correction is emergent. Ref.5 Ref.6 Defects in NKX2-5 are the cause of congenital hypothyroidism non-goitrous type 5 (CHNG5) [MIM:225250]. CHNG5 is a non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. CHNG5 presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland. Ref.9
Sequence similarities	Belongs to the NK-2 homeobox family. Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Atrial septal defect Disease mutation
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Developmental protein
Gene Ontology (GO)
Biological process	adult heart development Ref.4 Inferred from mutant phenotype. Source: UniProtKB atrial cardiac muscle cell development Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB cardiac muscle tissue development Ref.1 Inferred from expression pattern. Source: UniProtKB cardiac muscle tissue morphogenesis Inferred from mutant phenotype. Source: UniProtKB embryonic heart tube development Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB heart looping Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB hemopoiesis Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of cardiac muscle cell apoptosis Inferred from mutant phenotype. Source: UniProtKB negative regulation of myotube differentiation Inferred from mutant phenotype. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB pharyngeal system development Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of calcium ion transport via voltage-gated calcium channel activity Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cardioblast differentiation Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell proliferation Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of heart contraction Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of neuron differentiation Inferred from mutant phenotype. Source: UniProtKB positive regulation of sodium ion transport Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of survival gene product expression Inferred from mutant phenotype. Source: UniProtKB positive regulation of transcription initiation from RNA polymerase II promoter Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of transcription via serum response element binding Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB regulation of cardiac muscle contraction Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB spleen development Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB thyroid gland development Ref.9 Inferred from mutant phenotype. Source: UniProtKB tongue development Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB vasculogenesis Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB ventricular cardiac muscle cell development Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	transcription factor complex Inferred by curator. Source: UniProtKB
Molecular function	SUMO binding Inferred from physical interaction. Source: UniProtKB phosphate binding Inferred from direct assay. Source: UniProtKB protein heterodimerization activity Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB protein homodimerization activity Inferred from physical interaction. Source: UniProtKB serum response element binding Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB transcription activator activity Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB transcription factor activity Inferred from direct assay. Source: UniProtKB transcription factor binding Inferred from physical interaction. Source: UniProtKB transcription repressor activity Ref.1 Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TBX5	Q99593-1	2	EBI-936601,EBI-304423

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 324	324	Homeobox protein Nkx-2.5		PRO_0000048937
Regions
	DNA binding	138 – 197	60	Homeobox
	Compositional bias	42 – 108	67	Ala/Pro-rich
	Compositional bias	208 – 282	75	Ala/Pro-rich
Natural variations
	Natural variant	7	1	L → P in ASD-AVCD; somatic mutation. Ref.7		VAR_038212
	Natural variant	15	1	K → I in ASD-AVCD. Ref.8		VAR_038213
	Natural variant	16	1	D → A: dbSNP rs17052019.		VAR_049581
	Natural variant	19	1	N → S in ASD-AVCD; somatic mutation. Ref.7		VAR_038214
	Natural variant	21	1	E → Q in TOF and ASD-AVCD.		VAR_038215
	Natural variant	22	1	Q → P in ASD-AVCD. Ref.8		VAR_038216
	Natural variant	25	1	R → C in ASD-AVCD, TOF and CHNG5; exhibits significant functional impairment with reduction of transactivation properties and dominant-negative effect; the mutant protein activity on the DIO2, TG and TPO promoters is significantly impaired.		VAR_010116
	Natural variant	45	1	S → P in ASD-AVCD; somatic mutation. Ref.7		VAR_038217
	Natural variant	51	1	F → L in ASD-AVCD; somatic mutation. Ref.7		VAR_038218
	Natural variant	63	1	A → V in ASD-AVCD. Ref.8		VAR_038219
	Natural variant	69	1	L → P in ASD-AVCD; somatic mutation. Ref.7		VAR_038220
	Natural variant	77	1	P → L in ASD-AVCD; somatic mutation. Ref.7		VAR_038221
	Natural variant	114	1	C → R in ASD-AVCD; somatic mutation. Ref.7		VAR_038222
	Natural variant	114	1	C → S in ASD-AVCD; somatic mutation. Ref.7		VAR_038223
	Natural variant	118	1	K → R in ASD-AVCD; somatic mutation. Ref.7		VAR_038224
	Natural variant	119	1	A → S in CHNG5; exhibits a significant functional impairment with reduction of transactivation properties and dominant-negative effect which was associated with reduced DNA binding. Ref.9		VAR_047869
	Natural variant	124	1	K → R in ASD-AVCD; somatic mutation. Ref.7		VAR_038225
	Natural variant	126	1	E → V in ASD-AVCD; somatic mutation. Ref.7		VAR_038226
	Natural variant	127	1	A → E in ASD-AVCD. Ref.8		VAR_038227
	Natural variant	133	1	P → S in ASD-AVCD; somatic mutation. Ref.7		VAR_038228
	Natural variant	135	1	A → T in ASD-AVCD; somatic mutation. Ref.7		VAR_038229
	Natural variant	142	1	R → C in ASD-AVCD. Ref.8		VAR_038230
	Natural variant	144	1	L → P in ASD-AVCD; somatic mutation. Ref.7		VAR_038231
	Natural variant	161	1	R → P in CHNG5; exhibits a significant functional impairment with reduction of transactivation properties and dominant-negative effect which was associated with reduced DNA binding. Ref.9		VAR_047870
	Natural variant	178	1	T → M in ASD-AVCD. Ref.4 Ref.7 Ref.8		VAR_003752
	Natural variant	183	1	K → E in ASD-AVCD; somatic mutation. Ref.7		VAR_038232
	Natural variant	187	1	Q → H in ASD-AVCD. Ref.8		VAR_038233
	Natural variant	188	1	N → K in ASD-AVCD. Ref.5 Ref.8		VAR_010117
	Natural variant	189	1	R → G in ASD-AVCD. Ref.5 Ref.8		VAR_010118
	Natural variant	190	1	R → C in ASD-AVCD. Ref.8		VAR_038234
	Natural variant	191	1	Y → C in ASD-AVCD. Ref.5 Ref.8		VAR_010119
	Natural variant	192	1	K → R in ASD-AVCD; somatic mutation. Ref.7		VAR_038235
	Natural variant	192	1	K → T in ASD-AVCD; somatic mutation. Ref.7		VAR_038236
	Natural variant	194	1	K → R in ASD-AVCD; somatic mutation. Ref.7		VAR_038237
	Natural variant	205	1	V → E in ASD-AVCD; somatic mutation. Ref.7		VAR_038238
	Natural variant	216	1	R → C in TOF and ASD-AVCD.		VAR_038239
	Natural variant	219	1	A → V in ASD-AVCD and TOF; somatic mutation.		VAR_038240
	Natural variant	226	1	D → N in ASD-AVCD; somatic mutation. Ref.7		VAR_038241
	Natural variant	248	1	Y → H in ASD-AVCD; somatic mutation. Ref.7		VAR_038242
	Natural variant	275	1	P → T in ASD-AVCD. Ref.8		VAR_038243
	Natural variant	279	1	S → F in ASD-AVCD; somatic mutation. Ref.7		VAR_038244
	Natural variant	279	1	S → P in ASD-AVCD; somatic mutation. Ref.7		VAR_038245
	Natural variant	281	1	A → V in ASD-AVCD; somatic mutation. Ref.7		VAR_038246
	Natural variant	286	1	A → V in ASD-AVCD; somatic mutation. Ref.7		VAR_038247
	Natural variant	294	1	N → H in ASD-AVCD; somatic mutation. Ref.7		VAR_038248
	Natural variant	299	1	D → G in ASD-AVCD; somatic mutation. Ref.7		VAR_038249
	Natural variant	305	1	S → G in ASD-AVCD; somatic mutation. Ref.7		VAR_038250
	Natural variant	320	1	G → S in ASD-AVCD; somatic mutation. Ref.7		VAR_038251
	Natural variant	322	1	R → Q in ASD-AVCD; somatic mutation. Ref.7		VAR_038252
	Natural variant	323	1	A → T in ASD-AVCD. Ref.8		VAR_038253

Sequences

	Sequence		Length	Mass (Da)
	P52952-1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: ACCC9C2F9C292586	FASTA	324	34,918
	10 20 30 40 50 60 MFPSPALTPT PFSVKDILNL EQQQRSLAAA GELSARLEAT LAPSSCMLAA FKPEAYAGPE 70 80 90 100 110 120 AAAPGLPELR AELGRAPSPA KCASAFPAAP AFYPRAYSDP DPAKDPRAEK KELCALQKAV 130 140 150 160 170 180 ELEKTEADNA ERPRARRRRK PRVLFSQAQV YELERRFKQQ RYLSAPERDQ LASVLKLTST 190 200 210 220 230 240 QVKIWFQNRR YKCKRQRQDQ TLELVGLPPP PPPPARRIAV PVLVRDGKPC LGDSAPYAPA 250 260 270 280 290 300 YGVGLNPYGY NAYPAYPGYG GAACSPGYSC TAAYPAGPSP AQPATAAANN NFVNFGVGDL 310 320 NAVQSPGIPQ SNSGVSTLHG IRAW

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx." Turbay D., Wechsler S.B., Blanchard K.M., Izumo S. Mol. Med. 2:86-96(1996) [PubMed: 8900537] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Heart.
[2]	"Human Nkx-2.5 gene." Tate G., Mitsuya T. Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal lung.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas and Spleen.
[4]	"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 281:108-111(1998) [PubMed: 9651244] [Abstract] Cited for: VARIANT ASD-AVCD MET-178.
[5]	"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. 104:1567-1573(1999) [PubMed: 10587520] [Abstract] Cited for: VARIANT TOF CYS-25, VARIANTS ASD-AVCD LYS-188; GLY-189 AND CYS-191.
[6]	"NKX2.5 mutations in patients with tetralogy of fallot." Goldmuntz E., Geiger E., Benson D.W. Circulation 104:2565-2568(2001) [PubMed: 11714651] [Abstract] Cited for: VARIANTS TOF GLN-21; CYS-25; CYS-216 AND VAL-219.
[7]	"Somatic NKX2-5 mutations as a novel mechanism of disease in complex congenital heart disease." Reamon-Buettner S.M., Borlak J. J. Med. Genet. 41:684-690(2004) [PubMed: 15342699] [Abstract] Cited for: VARIANTS ASD-AVCD PRO-7; SER-19; CYS-25; PRO-45; LEU-51; PRO-69; LEU-77; SER-114; ARG-114; ARG-118; ARG-124; VAL-126; SER-133; THR-135; PRO-144; MET-178; GLU-183; THR-192; ARG-192; ARG-194; GLU-205; VAL-219; ASN-226; HIS-248; PRO-279; PHE-279; VAL-281; VAL-286; HIS-294; GLY-299; GLY-305; SER-320 AND GLN-322.
[8]	"Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect." Hirayama-Yamada K., Kamisago M., Akimoto K., Aotsuka H., Nakamura Y., Tomita H., Furutani M., Imamura S., Takao A., Nakazawa M., Matsuoka R. Am. J. Med. Genet. A 135:47-52(2005) [PubMed: 15810002] [Abstract] Cited for: VARIANTS ASD-AVCD ILE-15; GLN-21; PRO-22; CYS-25; VAL-63; GLU-127; CYS-142; MET-178; HIS-187; LYS-188; GLY-189; CYS-190; CYS-191; CYS-216; VAL-219; THR-275 AND THR-323.
[9]	"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. 91:1428-1433(2006) [PubMed: 16418214] [Abstract] Cited for: VARIANTS CHNG5 CYS-25; SER-119 AND PRO-161, CHARACTERIZATION OF VARIANTS CHNG5 CYS-25; SER-119 AND PRO-161.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneDis

Congenital heart disease website

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	U34962 mRNA. Translation: AAC50470.1. AB021133 mRNA. Translation: BAA35181.1. BC025711 mRNA. Translation: AAH25711.1.
IPI	IPI00006055.
RefSeq	NP_004378.1.
UniGene	Hs.54473
3D structure databases
HSSP	HSSP built from PDB template 1FTT based on UniProtKB P23441.
SMR	P52952. Positions 138-203.
ModBase	Search...
Protein-protein interaction databases
IntAct	P52952. 3 interactions.
PTM databases
PhosphoSite	P52952.
Proteomic databases
PRIDE	P52952.
Genome annotation databases
Ensembl	ENSG00000183072. Homo sapiens. [Contig view]
GeneID	1482.
KEGG	hsa:1482.
Organism-specific databases
GeneCards	GC05M172591.
H-InvDB	HIX0005426.
HGNC	HGNC:2488. NKX2-5.
MIM	108900. phenotype. 187500. phenotype. 225250. phenotype. 600584. gene.
Orphanet	1479. Atrial septal defect - atrioventricular conduction defects. 871. Cardiac conduction defect, familial. 1478. Interauricular communication. 3303. Tetralogy of Fallot.
PharmGKB	PA24202.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P52952.
HOVERGEN	P52952.
OMA	P52952. YGGAACS.
Enzyme and pathway databases
Pathway_Interaction_DB	smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
Gene expression databases
ArrayExpress	P52952.
Bgee	P52952.
CleanEx	HS_NKX2-5.
GermOnline	ENSG00000183072. Homo sapiens.
Family and domain databases
InterPro	IPR001356. Homeobox. IPR017970. Homeobox_CS. IPR012287. Homeodomain-rel. [Graphical view]
Gene3D	G3DSA:1.10.10.60. Homeodomain-rel. 1 hit.
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
ProDom	PD000010. Homeobox. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00389. HOX. 1 hit. [Graphical view]
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	6089.
SOURCE	Search...

Entry information

Entry name

NKX25_HUMAN

Accession

Primary (citable) accession number: P52952

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	June 16, 2009
This is version 96 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)