NKX2-5 NK2 homeobox 5 [Homo sapiens (human)] - Gene

Summary

Official Symbol: NKX2-5provided by HGNC
Official Full Name: NK2 homeobox 5provided by HGNC
Primary source: HGNC:HGNC:2488
See related: Ensembl:ENSG00000183072 MIM:600584
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: CSX; CSX1; VSD3; CHNG5; HLHS2; NKX2E; NKX2.5; NKX4-1
Summary: This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
Expression: Restricted expression toward heart (RPKM 9.4) See more
Orthologs: mouse all

Genomic context

Location:: 5q35.1

Exon count:: 3

Annotation release	Status	Assembly	Chr	Location
109.20200815	current	GRCh38.p13 (GCF_000001405.39)	5	NC_000005.10 (173232109..173235321, complement)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	5	NC_000005.9 (172659107..172662315, complement)

Chromosome 5 - NC_000005.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

pacemaker cardiomyocytes derive from a subset of Nkx2.5+ mesoderm that responds to canonical Wnt5b signaling to initiate the cardiac pacemaker program
Title: Canonical Wnt5b Signaling Directs Outlying Nkx2.5+ Mesoderm into Pacemaker Cardiomyocytes.
Nkx2.5 acts upstream of GDF1 and the genetic variants in GDF1 promoter may confer genetic susceptibility to sporadic CHD potentially by altering its expression.
Title: Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5.
Differential NKX2-5 binding at numerous regulatory variants across the genome contributes to atrial fibrillations.
Title: Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits.
Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.
Title: Oligogenic inheritance of a human heart disease involving a genetic modifier.
NKX2.5 mutations are highly rare in Congenital heart disease patients. However, in silico analysis proves that c.95 A > T missense mutation in NKX2.5 gene is probably pathogenic and may be contributing to the risk of sporadic CHD in the Iranian population
Title: Novel Point Mutations in the <i>NKX2.5</i> Gene in Pediatric Patients with Non-Familial Congenital Heart Disease.
Two rare variants in NKX2-5 and FLNC, carried by 1 in 2400 Icelanders, cause familial Dilated Cardiomyopathy (DCM) in Iceland. These genes have recently been associated with DCM. Given the serious consequences of these variants, we suggest screening for them in individuals with DCM and their family members, with subsequent monitoring of carriers, offering early intervention.
Title: Variants in NKX2-5 and FLNC Cause Dilated Cardiomyopathy and Sudden Cardiac Death.
Single nucleotide variations are the prominent genetic variations of NKX2-5 in Chinese patients with sporadic atrial septal defect. The SNPs rs2277923 and rs3729753 are prominent single nucleotide variations (SNVs) in Chinese patients with sporadic atrial septal defect.
Title: Analysis of NKX2-5 in 439 Chinese Patients with Sporadic Atrial Septal Defect.
Data indicate that Sspn is an Nkx2-5 modifier gene. Complete loss of Sspn function does not cause heart defects but does increase the incidence of muscular ventricular septal defects (VSDs) in combination with an Nkx2-5 mutation.
Title: Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart.
NKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in pulmonary artery smooth muscle cells through the interaction of an upstream promoter and a novel downstream enhancer.
Title: Molecular Basis for Dysregulated Activation of NKX2-5 in the Vascular Remodeling of Systemic Sclerosis.
Two SNPs of NKX2-5 (rs2277923, rs28936670) are associated with cardiac septal defect in Egyptian children.
Title: Association of NKX2-5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children.

Submit: New GeneRIF Correction See all GeneRIFs (147)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Atrial septal defect 7 with or without atrioventricular conduction defects MedGen: C3276096 OMIM: 108900 GeneReviews: Not available	Compare labs
Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis. GeneReviews: Not available
Conotruncal heart malformations MedGen: C1857586 OMIM: 217095 GeneReviews: Not available	Compare labs
Genome-wide association study of PR interval. GeneReviews: Not available
Hypoplastic left heart syndrome 2 MedGen: C3280795 OMIM: 614435 GeneReviews: Not available	Compare labs
Hypothyroidism, congenital, nongoitrous, 5 MedGen: C2673630 OMIM: 225250 GeneReviews: Not available	Compare labs
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. GeneReviews: Not available
Tetralogy of Fallot MedGen: C0039685 OMIM: 187500 GeneReviews: Not available	Compare labs
Ventricular septal defect 3 MedGen: C3280785 OMIM: 614432 GeneReviews: Not available	Compare labs

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated (2020-07-22) ClinGen Genome Curation Page Haploinsufficency Sufficient evidence for dosage pathogenicity (Last evaluated (2020-07-22) ClinGen Genome Curation PagePubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Homology

Homologs of the NKX2-5 gene: The NKX2-5 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 306 organisms have orthologs with human gene NKX2-5
Orthologs

Clone Names

FLJ52202, FLJ97166, FLJ97195, FLJ97197, FLJ99536

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
DNA binding	IDA Inferred from Direct Assay more info	PubMed
DNA-binding transcription activator activity, RNA polymerase II-specific	IDA Inferred from Direct Assay more info	PubMed
DNA-binding transcription activator activity, RNA polymerase II-specific	IMP Inferred from Mutant Phenotype more info	PubMed
DNA-binding transcription factor activity	IDA Inferred from Direct Assay more info	PubMed
contributes_to DNA-binding transcription factor activity	IDA Inferred from Direct Assay more info	PubMed
DNA-binding transcription factor activity	IMP Inferred from Mutant Phenotype more info	PubMed
DNA-binding transcription factor activity, RNA polymerase II-specific	IBA Inferred from Biological aspect of Ancestor more info	PubMed
DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment more info
DNA-binding transcription factor activity, RNA polymerase II-specific	ISM Inferred from Sequence Model more info	PubMed
RNA polymerase II proximal promoter sequence-specific DNA binding	IBA Inferred from Biological aspect of Ancestor more info	PubMed
RNA polymerase II proximal promoter sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
RNA polymerase II proximal promoter sequence-specific DNA binding	IMP Inferred from Mutant Phenotype more info	PubMed
RNA polymerase II proximal promoter sequence-specific DNA binding	ISS Inferred from Sequence or Structural Similarity more info	PubMed
chromatin binding	IDA Inferred from Direct Assay more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein homodimerization activity	IEA Inferred from Electronic Annotation more info
sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed
sequence-specific double-stranded DNA binding	IDA Inferred from Direct Assay more info	PubMed
transcription factor binding	IPI Inferred from Physical Interaction more info	PubMed
transcription regulatory region sequence-specific DNA binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
Purkinje myocyte differentiation	IEA Inferred from Electronic Annotation more info
adult heart development	IMP Inferred from Mutant Phenotype more info	PubMed
apoptotic process involved in heart morphogenesis	IEA Inferred from Electronic Annotation more info
atrial cardiac muscle cell development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
atrial septum morphogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
atrioventricular node cell development	IEA Inferred from Electronic Annotation more info
atrioventricular node cell fate commitment	IEA Inferred from Electronic Annotation more info
bundle of His development	IEA Inferred from Electronic Annotation more info
cardiac conduction system development	IMP Inferred from Mutant Phenotype more info	PubMed
cardiac muscle cell differentiation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
cardiac muscle cell proliferation	IEA Inferred from Electronic Annotation more info
cardiac muscle contraction	IEA Inferred from Electronic Annotation more info
cardiac muscle tissue morphogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
cardiac ventricle formation	IEA Inferred from Electronic Annotation more info
cell differentiation	IBA Inferred from Biological aspect of Ancestor more info	PubMed
cell differentiation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
embryonic heart tube development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
embryonic heart tube left/right pattern formation	IEA Inferred from Electronic Annotation more info
heart looping	ISS Inferred from Sequence or Structural Similarity more info	PubMed
heart morphogenesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
heart trabecula formation	IEA Inferred from Electronic Annotation more info
hemopoiesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
negative regulation of apoptotic process	ISS Inferred from Sequence or Structural Similarity more info	PubMed
negative regulation of canonical Wnt signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of cardiac muscle cell apoptotic process	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of myotube differentiation	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of transcription by RNA polymerase II	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info	PubMed
negative regulation of transcription, DNA-templated	ISS Inferred from Sequence or Structural Similarity more info	PubMed
outflow tract septum morphogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
pharyngeal system development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of cardioblast differentiation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of cell proliferation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of heart contraction	ISS Inferred from Sequence or Structural Similarity more info
positive regulation of neuron differentiation	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of sodium ion transport	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of transcription by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
positive regulation of transcription by RNA polymerase II	IGI Inferred from Genetic Interaction more info	PubMed
positive regulation of transcription by RNA polymerase II	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of transcription by RNA polymerase II	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of transcription initiation from RNA polymerase II promoter	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of transcription via serum response element binding	ISS Inferred from Sequence or Structural Similarity more info	PubMed
positive regulation of transcription, DNA-templated	IDA Inferred from Direct Assay more info	PubMed
positive regulation of transcription, DNA-templated	ISS Inferred from Sequence or Structural Similarity more info	PubMed
proepicardium development	IEA Inferred from Electronic Annotation more info
pulmonary myocardium development	IEA Inferred from Electronic Annotation more info
regulation of cardiac conduction	ISS Inferred from Sequence or Structural Similarity more info	PubMed
regulation of cardiac muscle cell proliferation	IEA Inferred from Electronic Annotation more info
regulation of cardiac muscle contraction	ISS Inferred from Sequence or Structural Similarity more info	PubMed
regulation of transcription by RNA polymerase II	IBA Inferred from Biological aspect of Ancestor more info	PubMed
right ventricular cardiac muscle tissue morphogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
sarcomere organization	IEA Inferred from Electronic Annotation more info
septum secundum development	IMP Inferred from Mutant Phenotype more info	PubMed
spleen development	IMP Inferred from Mutant Phenotype more info	PubMed
spleen development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
thyroid gland development	IMP Inferred from Mutant Phenotype more info	PubMed
vasculogenesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
ventricular cardiac muscle cell development	ISS Inferred from Sequence or Structural Similarity more info	PubMed
ventricular cardiac myofibril assembly	IEA Inferred from Electronic Annotation more info
ventricular septum morphogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
ventricular trabecula myocardium morphogenesis	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
RNA polymerase II transcription factor complex	IDA Inferred from Direct Assay more info	PubMed
cytoplasm	IEA Inferred from Electronic Annotation more info
nuclear chromatin	ISA Inferred from Sequence Alignment more info
nucleus	IBA Inferred from Biological aspect of Ancestor more info	PubMed
nucleus	IDA Inferred from Direct Assay more info	PubMed
protein-DNA complex	IDA Inferred from Direct Assay more info	PubMed
protein-containing complex	IDA Inferred from Direct Assay more info	PubMed
transcription factor complex	IC Inferred by Curator more info	PubMed

General protein information

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Preferred Names: homeobox protein Nkx-2.5

Names: NK2 transcription factor related, locus 5; NKX 2-5; cardiac-specific homeobox 1; homeobox protein CSX; homeobox protein NK-2 homolog E; homeobox protein NKX 2-5; tinman homolog; tinman paralog

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_013340.1 RefSeqGene

Range

5107..8204

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001166175.2 → NP_001159647.1 homeobox protein Nkx-2.5 isoform 2

See identical proteins and their annotated locations for NP_001159647.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) differs in the 3' coding region and 3' UTR, compared to variant 1. The encoded isoform (2) has a distinct C-terminus and is shorter than isoform 1.

Source sequence(s)

AI609745, AK290615, AK307247

Consensus CDS

CCDS54950.1

UniProtKB/Swiss-Prot

P52952

UniProtKB/TrEMBL

A0A0S2Z3K2

Related

ENSP00000395378.2, ENST00000424406.2
NM_001166176.2 → NP_001159648.1 homeobox protein Nkx-2.5 isoform 3

See identical proteins and their annotated locations for NP_001159648.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) differs in the 3' coding region and 3' UTR, compared to variant 1. The encoded isoform (3) has a distinct C-terminus and is shorter than isoform 1.

Source sequence(s)

AI609745, AK290615, AK297844

Consensus CDS

CCDS54949.1

UniProtKB/Swiss-Prot

P52952

Related

ENSP00000427906.1, ENST00000521848.1
NM_004387.4 → NP_004378.1 homeobox protein Nkx-2.5 isoform 1

See identical proteins and their annotated locations for NP_004378.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the shortest transcript but encodes the longest isoform (1).

Source sequence(s)

BC025711, DA559427

Consensus CDS

CCDS4387.1

UniProtKB/Swiss-Prot

P52952

UniProtKB/TrEMBL

A0A0S2Z383

Related

ENSP00000327758.4, ENST00000329198.5

Conserved Domains (1) summary

pfam00046
Location:145 → 194

Homeobox; Homeobox domain