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FLASH GENE
Symbol GJA1 contributors: shn - updated : 23-09-2016
HGNC name gap junction protein, alpha 1, 43kDa
HGNC id 4274
Corresponding disease
AVSD3 atrioventricular septal defect 3
CMDR craniometaphyseal dysplasia, rare autosomal recessive type
DFNB34 neurosensory deafness 34
EKVP3 erythrokeratodermia variabilis et progressiva 3
HLHS1 hypoplastic left heart syndrome 1
ODDD oculodentodigital syndrome
SDTY3 syndactyly type 3
Location 6q22.31      Physical location : 121.756.744 - 121.770.872
Synonym name
  • connexin 43
  • gap junction protein, alpha-like
  • gap junction 43 kDa heart protein
  • oculodentodigital dysplasia (syndactyly type III)
  • connexin 43
  • Synonym symbol(s) CX43, CXA1, GJAL, DFNB38, ODD, ODOD
    DNA
    TYPE functioning gene
    STRUCTURE 14.13 kb     2 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • two activator protein-1 (AP-1) binding elements in the promoter region were identified as being responsible for the MAP2K4-regulated GJA1 expression
  • promoter contains an evolutionarily conserved element harboring a putative IRX3 binding site (37–39), which overlaps with an NKX2-5 binding motif (Irx/NKE) immediately upstream of conserved T-box binding elements
  • MAPPING cloned Y linked N status confirmed
    Map cen - D6S1657 - D6S1608 - GJA1 - D6S1712 - D6S1639 - qter
    Physical map
    VGLL2 6q22.31 vestigial like 2 (Drosophila) ROS1 6q21-q22 v-ros UR2 sarcoma virus oncogene homolog 1 (avian) DCBLD1 6q22.31 discoidin, CUB and LCCL domain containing 1 GOPC 6q21 golgi associated PDZ and coiled-coil motif containing LOC221308 6q22.31 similar to RIKEN cDNA 5730521E12 C6orf68 6q22.31 chromosome 6 open reading frame 68 SLC35F1 6q22.31 solute carrier family 35, member F1 LOC391965 6 hypothetical gene supported by BX647084 BP75 6q22.1-q22.33 hypothetical gene supported by BX647084 PLN 6q22.1 phospholamban psiSSX10 6q22 SSX10 pseudogene C6orf61 6q22.31 chromosome 6 open reading frame 61 ASF1A 6q22.32 ASF1 anti-silencing function 1 homolog A (S. cerevisiae) MCMDC1 6q22.31 minichromosome maintenance deficient domain containing 1 C6orf60 6q22.31 chromosome 6 open reading frame 60 MAN1A1 6q22 mannosidase, alpha, class 1A, member 1 C6orf170 6q22.32 chromosome 6 open reading frame 170 GJA1 6q22.3 gap junction protein, alpha 1, 43kDa (connexin 43) LOC260339 6q22.32 processed pseudogene mtTFA 3 LOC391966 6 similar to ADP,ATP carrier protein, fibroblast isoform (ADP/ATP translocase 2) (Adenine nucleotide translocator 2) (ANT 2) LOC391967 6 similar to 60S ribosomal protein L23a HSF2 6q22.33 heat shock transcription factor 2 TDE2 6q22.32 tumor differentially expressed 2 PKIB 6q22.32 protein kinase (cAMP-dependent, catalytic) inhibitor beta FABP7 6q22-q23 fatty acid binding protein 7, brain SMPDL3A 6q22.32 sphingomyelin phosphodiesterase, acid-like 3A C6orf213 6q22.32 chromosome 6 open reading frame 213 TRDN 6q22-q23 triadin TCBA1 6q21-q22 T-cell lymphoma breakpoint associated target 1 IBRDC1 6q22.33 IBR domain containing 1 TPD52L1 6q22-q23 tumor protein D52-like 1 C6orf74 6q13-q24.3 chromosome 6 open reading frame 74 LOC256096 6q22.33 hypothetical LOC256096 HEY2 6q22.2-q22.33 hairy/enhancer-of-split related with YRPW motif 2 NCOA7 6q22.33 nuclear receptor coactivator 7
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 3130 45 382 . in human gap-junction mammary epithelial cells (76N) . in cell membranes of arachnoid villi and meningiomas . in T and B lymphocytes 2004 15328338
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheartatrium  highly Homo sapiens
     vessel     Homo sapiens
    Reproductivemale systemtestis  predominantly Homo sapiens
     male systemmale genital tractepididymis   Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularsmoothvessel  
    Muscularstriatumcardiacmyocardiumpredominantly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/ImmuneB cell
    Lymphoid/ImmuneT cell
    Nervousastrocyte
    Nervousglia
    Skin/Tegumentkeratinocyte
    cell lineage
    cell lines 76N and 81N cells
    fluid/secretion
    at STAGE
    physiological period fetal
    cell cycle     cell cycle
    Text cochlea, heart
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four membrane spanning alpha helices, separating the N terminal intracellular domain
  • two extracellular loops
  • the 241-382 AAs region required for interaction with BAX
  • a C terminal intracellular domain, interacting with C-terminus of GJA5 (interaction important for the regulation of heteromeric channels)
  • mono polymer heteromer
    HOMOLOGY
    interspecies ortholog to Gja1, Mus musculus
    ortholog to Gja1, Rattus norvegicus
    ortholog to gja1, Xenopus (Silurana) tropicalis
    ortholog to GJA1, Pan troglodytes
    Homologene
    FAMILY
  • connexin family
  • alpha-type (group II) subfamily
  • CATEGORY adhesion , structural protein , transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane,junction,gap
        intracellular
    intracellular,cytoplasm,organelle,mitochondria,outer
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text localized in cardiomyocyte mitochondria, at least in part in the inner mitochondrial membrane, where it is imported by the general mitochondrial membrane translocase system
    basic FUNCTION
  • cytoplasmic tail domain of connexin 43 is an important determinant of the unitary conductance event of gap junction channels
  • Cx43 plays an essential role in heart development
  • member of the connexin of intercellular channels, providing a route for the diffusion of materials of low molecular weight from cell to cell
  • contributes to retinal pigment epithelial cells differentiation via cAMP signaling
  • promotes the formation and growth of gap junctional plaques
  • CX43-mediated gap junctions may serve as conduits for the spread of proinflammatory signals in the lung capillary bed
  • CX43 is necessary for glial-guided neuronal migration
  • mediates the expression of an array of genes involved in cardiogenesis, in addition to intercellular communication
  • GJA1 plays a key role in eye development and in the development of glaucoma
  • plays a role in protection during myocardial ischaemic and pharmacological preconditioning and this role is independent from gap junction-mediated communication
  • can mediate cell–cell communication
  • involved in conferring cell adhesion in the seminiferous epithelium
  • crucial for ight junctions reassembly at the BTB (blood–testis barrier) during its cyclic restructuring throughout the seminiferous epithelial cycle of spermatogenesis
  • crucial for the reassembly of the disrupted Sertoli cell TJ-permeability barrier
  • may be responsible for the necessary crosstalk between different junction complexes to maintain their adhesive function and to coordinate different junctions to maintain the immunological barrier integrity during the transit of preleptotene spermatocytes
  • local regulation of monocyte GJA1 activity within the vasculature can dynamically modulate the monocyte–endothelial adhesion that is an initiating event in vascular inflammatory pathologies
  • GJA1 function in monocytes rapidly decreases adhesion via ATP release
  • seems to be a pivotal player in defining how well and where monocytes will adhere to endothelial cells and thereby promote atherosclerotic development and progression of other vascular pathologies
  • regulates the passage of migrating neurons through their multipolar stage via CDKN1B signaling and interference with this process, by either genetic and/or environmental factors, may cause cortical malformations
  • exerts a protective role and regulates the Hematopoietic stem cell (HSC)/progenitors ROS content through ROS transfer to the hematopoietic microenvironment (HM), resulting in HSC protection during stress hematopoietic regeneration
  • is more than a passive channel; rather, it actively participates in the generation and modulation of cellular signals that drive skeletal development and homeostasis
  • involvement in mechanotransduction of fluid shear stress and in the modulation of mechanical loading-related apoptosis, osteogenesis, and osteoclastogenesis of osteocytes
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS endocytosis transport
    PATHWAY
    metabolism
    signaling sensory transduction/hearing , sensory transduction/vision
    may be participating in the recycling of potassium to the cochlear endolymph
    a component
  • monomer constituent of the connexon (six subunits), docking with its counterpart in the neighboring cell to form the gap junction channel
  • protein complex consisting of GJA1 and plakophilin-2 (PKP2) at the desmosome-like junction
  • is a SUMOylation target protein and represent the first evidence that gap junctions are regulated by the SUMO system
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • tight junction protein 1, TJP1 (Giepmans et al, 1998)
  • TJP1 and gap junction protein, gamma 1, 45kDa (GJC1) in osteoblastic cells
  • gap junction protein alpha 3 46kDa, GJA3
  • gap junction protein alpha 5 40kDa, GJA5
  • caveolin 1 caveolae protein 22kDa, CAV1
  • casein kinase 1, CK1
  • mitogen-activated protein kinase 7, MAPK7
  • nephroblastoma overexpressed gene, NOV
  • connexin 43-interacting protein, 150kD (CIP150)
  • Cx43-interacting protein of 85-kDa, CIP85
  • desmosomal protein PKP2 (form a protein complex within the desmosome-like junction to regulate cell adhesion at the blood–testis barrier, partly through its effects on the occludin/ZO-1 complex, so as to facilitate the transit of primary preleptotene spermatocytes)
  • interacting with ERP29 (new role for ERP29 as a chaperone that helps stabilize monomeric GJA1 to enable oligomerization to occur in the Golgi apparatus)
  • binding of the growth regulator CCN3 (NOV) at the C-terminus of GJA1
  • TBX18 directly represses the GJA1 promoter
  • is a downstream target molecule of NONO
  • can regulate GJA1 expression at the transcription level and decreases in POR reduce gap junctional intercellular communication, as well as hemichannel activity
  • TCF12 functions as a regulator of EMT by affecting the expression of CDH1 as well as that of GJA1 and GJB2
  • CASK directly interacts with GJA1
  • integrin alpha5beta1 interacts directly with GJA1 and this interaction is required for mechanical stimulation-induced opening of the GJA1 hemichannel
  • both SENP1 and -2 induce deSUMOylation of GJA1
  • regulates the passage of migrating neurons through their multipolar stage via CDKN1B signaling
  • MAPK-phosphorylated GJA1 is a novel interacting partner of cyclin E in VSMC (vascular smooth muscle cells) and this interaction is critical for VSMC proliferation
  • in the context of apoptosis, translocated to the mitochondria, where it interacted with BAX to initiate the mitochondrial apoptotic pathway
  • associates with SCN5A in the cardiomyocyte perinexus
  • NR1D1 activates GJA1 transcription by forming a complex with SP1
  • CTTNBP2NL dephosphorylated GJA1
  • PPP2R2A is required for GJA1 dephosphorlyation during epidermal barrier acquisition
  • interaction between the T-cell protein tyrosine phosphatase (PTPN2) and the C-terminus of connexin43 (GJA1)
  • PRKAA1 stimulates ubiquitination of the gap junction protein GJA1, thereby contributing to gap junction remodeling following pressure overload
  • intermittent hypoxia causes reductions and remodeling of atrial GJA5, GJA1, generated in response to reactive oxygen species
  • by CYBB, and likely contributing to the substrate for atrial fibrillation that develops in response to obstructive sleep apnea
  • EXOSC10 was likely required for CELF1-mediated GJA1 mRNA degradation
  • cell & other
    REGULATION
    activated by phytohaemagglutinin(PHA) and lipopolysaccharide (LPS)
    repressed by TJP1 (plays a role in the down-regulation and decreased size of GJA1 gap junctions in congestive heart failure)
    TBX18 overexpression that specifically and significantly down-regulates GJA1, and suppression of GJA1 by TBX18 occurs in adult ventricular myocardium as well as in neonatal cardiomyocytes, and the down-regulation persists even after TBX18 expression fades
    IRX3, that directly represses GJA1 transcription
    Phosphorylated by TYK2 that can also inhibit gap junction communication by phosphorylating GJA1 (
    Other
  • phosphorylated by v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (v-src)
  • phosphorylated byprotein kinase C, PKC
  • posttranslationally modified by SUMOylation
    ASSOCIATED DISORDERS
    corresponding disease(s) DFNB34 , ODDD , HLHS1 , SDTY3 , CMDR , AVSD3 , EKVP3
    related resource Hereditary Hearing Loss Homepage
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in breast cancer cell (marker for detecting early oncogenesis in the breast)
    constitutional     --low  
    in congestive heart failure (contributing to contractile dysfunction)
    constitutional        
    in the heart results in sudden arrhythmic death due to increased gap junctional resistance and slowed conduction velocity, which form a substrate for re-entrant arrhythmias
    constitutional     --low  
    in azoospermic men decreased expression of EGFR may be responsible for decreasing GJA1 levels and increasing its cytosolic localization via the PI3K/AKT signaling pathway
    Susceptibility to Atrial Fibrillation (AF)
    Variant & Polymorphism SNP GJA1 variant rs13216675 associated with AF
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurosensorial  
    target for research into the treatment of various eye diseases due to RPE dysfunction
    ANIMAL & CELL MODELS
  • CX43 mutant embryos died at birth as a result of a failure in pulmonary gas exchange caused by a swelling and blockage of the right ventricular outflow tract from the hear
  • mice homozygous for CX43 exhibit an abnormal cardiac morphogenetic process
  • lack of expression of CX43 during embryogenesis compromising terminal stages of primary T and B cells differentiation
  • Blood pressure and heart rate measurements were significantly lower in the Cx43 knockout mice
  • mice lacking the C-terminal region of connexin-43 died shortly after birth. Female mice lacking the C-terminal region of connexin-43 are infertile due to impaired folliculogenesis
  • mouse model of ODDD (heterozygous for the human I130T mutation) showed a reduced Cx43 expression in hearts with preferential loss of phosphorylated forms, resulting in interference with trafficking and with assembly of gap junctions in the junctional membrane
  • adult Sertoli cell-specific Cx43 knockout (SC-Cx43 KO) mice displayed spermatogenic arrest at the spermatogonial level