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Symbol NKX2-5 contributors: mct/npt/pgu - updated : 01-06-2017
HGNC name NK2 transcription factor related, locus 5 (Drosophila)
HGNC id 2488
Corresponding disease
ASD7 atrial septal defect 7
CHNG5 hypothyroidism, congenital nongoitrous, 5
CSX non syndromic congenital heart disease
DUP5QD chromosome 5q distal duplication
Location 5q35.1      Physical location : 172.659.106 - 172.662.315
Synonym name
  • tinman
  • cardiac specific homeobox
  • tinman paralog (Drosophila)
  • homeobox protein CSX
    • Synonym symbol(s) CSX1, CSX, NKX2E, NKX2.5, CHNG5, NKX4-1, FLJ97195, FLJ97197, FLJ52202, FLJ97166, FLJ99536
    DNA
    TYPE functioning gene
    STRUCTURE 3.13 kb     2 Exon(s)
    MAPPING cloned Y linked N status confirmed
    Map see D5S2360
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 1669 35 324 - 2002 11889119
    also called CSX1a
    - initiation site 1961 12 112 - 2002 11889119
  • also called CSX1b
  • truncated form lacking the homeo domain
    • - initiation site 1924 - 151 - 2002 11889119
  • also called CSX1c
  • truncated form lacking the homeo domain
    		•
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestiveintestinesmall intestine   
    Lymphoid/Immunespleen    
    Reproductivefemale systemovary   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal, pregnancy
    Text heart
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a TN domain
  • a C terminal helix-turn-helix
  • DNA binding domain (isoform CSX1a)
    • conjugated ubiquitinated
    mono polymer homomer , heteromer , dimer
    HOMOLOGY
    interspecies homolog to murine Csk/Nkx2.5 homeobox gene
    homolog to Drosophila tinman gene
    Homologene
    FAMILY
  • NK-2 homeobox proteins family (meta HOX)
    • CATEGORY DNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus
    basic FUNCTION
  • promoting cardiomyocyte differentiation in synergy with TBX5
  • required for atrioventricular node function throughout life, and for regulation of septation during cardiac morphogenesis
  • key factor in the regulation of connexin expression and in the maintenance of normal cardiac conduction
  • involved in the regulation of the left/right axis
  • acts as a modifier of RNA toxicity in the heart
  • plays a role in thyroid organogenesis
  • essential role of NKX2
    • 5 and downstream target gene in the specification of endocardial/endothelial fate during development
  • SUMOylation strongly enhances NKX2-5 transcriptional activity and that AA K51 of NKX2-5 is a SUMOylation target
  • essential for heart specification and morphogenesis
  • transcription factors NKX2-5 and GATA4 cooperatively regulate cardiac-specific expression of LRRC10
  • NKX2.5 is necessary to sustain ventricular chamber attributes through repression of atrial chamber identity
    • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS cardiovascular , development
    PATHWAY
    metabolism
    signaling
    a component
  • heterodimer with NKX2C
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • associating with TBX5
  • with PHC1 (role essential for cardiac morphogenesis)
  • interacting with NKX2-6 (target promoter for its activity)
  • interacting with other transcription factors such as GATA4 and SRF19
  • interacting with DMPK
  • synergistic interactions between TBX20 and other cardiac transcription factors, including tinman/Nkx2
    • 5, in regulating cardiac performance, rhythmicity, and cardiomyocyte structure
  • FBXO25 acts as an ubiquitin E3 ligase to target cardiac transcription factors including NKX2-5, ISL1, and HAND1, indicating that cardiac protein homeostasis through FBXO25 has a pivotal impact on cardiac development
  • interacting with NPPA (NKX2-5 and its responsive cis-regulatory DNA elements are essential for NPPA expression selectively in the developing heart)
  • critical role of CITED2 in cardiomyocyte differentiation by affecting the expression of NFATC4 leading to down-regulation of NKX2.5 and beta-MHC cardiomyocyte genes
  • interaction between NKX2-5 and PPP1R12A (promoting this interaction represents a novel mechanism whereby WNT3A regulates NKX2-5 and inhibits cardiomyogenesis)
  • NKX2-5 mediates differential cardiac differentiation through interaction with HOXA10
  • LRRC10 is a transcriptional target of NKX2-5 and GATA4
  • FBXO25 directly interacts with TBX5 and NKX2-5, and controls TBX5 and NKX2-5 transcriptional activity to regulate cardiomyocyte development
  • plays likely an essential role in cardiomyocyte differentiation by controlling not only transcription but also the nuclear localization of NKX2-5
    • cell & other
    REGULATION
    activated by CALR during cardiac developement
    inhibited by NR2F1 in activation of CALR during cardiac development
    Other SUMOylation of lysine 51 (K51)is essential for its DNA binding and transcriptional activation
    ASSOCIATED DISORDERS
    corresponding disease(s) CSX , DUP5QD , ASD7 , CHNG5
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation deletion    
    novel mechanism of disease in complex congenital heart defect(ventricular or atrioventricular septal defect))
    constitutional     --over  
    overexpression and its consequent effects on CX40 and CX43 provide a plausible molecular mechanism for cardiac conduction defects in DM1 (myotonic dystrophy 1)
    constitutional germinal mutation      
    interacting with GATA4 in causing heart septation defects (ASD)
    Susceptibility
  • to thyroid dysgenensis (TD)
  • to systemic lupus erythematosus (SLE)
  • to accessory atrioventricular connections
    • Variant & Polymorphism
  • three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD
  • SNPs related to an increased risk for SLE
    • Candidate gene for congenital heart defects in deletion and partial trisomy of distal 5q
    Marker
    Therapy target
    ANIMAL & CELL MODELS