CXG2_HUMAN
ID CXG2_HUMAN Reviewed; 439 AA.
AC Q5T442; O43440; Q7Z7J2; Q8IWJ9;
DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Gap junction gamma-2 protein;
DE AltName: Full=Connexin-46.6;
DE Short=Cx46.6;
DE AltName: Full=Connexin-47;
DE Short=Cx47;
DE AltName: Full=Gap junction alpha-12 protein;
GN Name=GJC2; Synonyms=GJA12;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Bloemker B.K., Swaroop A., Kimberling W.J.;
RT "Cloning and molecular characterization of human connexin46.6, a new gap
RT junction gene.";
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Chondrosarcoma;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-439.
RC TISSUE=Corpus callosum;
RA Enriquez A.D., Scherer S.S.;
RT "Human connexin47, updated ORF.";
RL Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION, DISEASE, VARIANTS HLD2 SER-90; ASP-272 AND THR-286, AND TISSUE
RP SPECIFICITY.
RX PubMed=15192806; DOI=10.1086/422763;
RA Uhlenberg B., Schuelke M., Rueschendorf F., Ruf N., Kaindl A.M.,
RA Henneke M., Thiele H., Stoltenburg-Didinger G., Aksu F., Topaloglu H.,
RA Nuernberg P., Huebner C., Weschke B., Gaertner J.;
RT "Mutations in the gene encoding gap junction protein alpha 12 (connexin
RT 46.6) cause Pelizaeus-Merzbacher-like disease.";
RL Am. J. Hum. Genet. 75:251-260(2004).
RN [6]
RP ERRATUM OF PUBMED:15192806.
RA Uhlenberg B., Schuelke M., Rueschendorf F., Ruf N., Kaindl A.M.,
RA Henneke M., Thiele H., Stoltenburg-Didinger G., Aksu F., Topaloglu H.,
RA Nuernberg P., Huebner C., Weschke B., Gaertner J.;
RL Am. J. Hum. Genet. 75:737-737(2004).
RN [7]
RP VARIANT SPG44 MET-36, AND CHARACTERIZATION OF VARIANT SPG44 MET-36.
RX PubMed=19056803; DOI=10.1093/brain/awn328;
RA Orthmann-Murphy J.L., Salsano E., Abrams C.K., Bizzi A., Uziel G.,
RA Freidin M.M., Lamantea E., Zeviani M., Scherer S.S., Pareyson D.;
RT "Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2
RT mutations.";
RL Brain 132:426-438(2009).
RN [8]
RP VARIANTS LMPHM3 LEU-48 AND CYS-260, AND VARIANTS PRO-19; GLN-125; SER-149
RP AND LEU-316.
RX PubMed=20537300; DOI=10.1016/j.ajhg.2010.04.010;
RA Ferrell R.E., Baty C.J., Kimak M.A., Karlsson J.M., Lawrence E.C.,
RA Franke-Snyder M., Meriney S.D., Feingold E., Finegold D.N.;
RT "GJC2 missense mutations cause human lymphedema.";
RL Am. J. Hum. Genet. 86:943-948(2010).
CC -!- FUNCTION: One gap junction consists of a cluster of closely packed
CC pairs of transmembrane channels, the connexons, through which materials
CC of low MW diffuse from one cell to a neighboring cell. May play a role
CC in myelination in central and peripheral nervous systems.
CC {ECO:0000269|PubMed:15192806}.
CC -!- SUBUNIT: A connexon is composed of a hexamer of connexins. Interacts
CC with TJP1 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. Cell
CC junction, gap junction.
CC -!- TISSUE SPECIFICITY: Expressed in central nervous system, in sciatic
CC nerve and sural nerve. Also detected in skeletal muscles.
CC {ECO:0000269|PubMed:15192806}.
CC -!- DISEASE: Leukodystrophy, hypomyelinating, 2 (HLD2) [MIM:608804]: An
CC autosomal recessive hypomyelinating leukodystrophy with symptoms of
CC Pelizaeus-Merzbacher disease. Clinically characterized by nystagmus,
CC impaired motor development, ataxia, choreoathetotic movements,
CC dysarthria, and progressive spasticity. {ECO:0000269|PubMed:15192806}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Spastic paraplegia 44, autosomal recessive (SPG44)
CC [MIM:613206]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. In some forms of the disorder, bladder
CC symptoms (such as incontinence) may appear, or the weakness and
CC stiffness may spread to other parts of the body.
CC {ECO:0000269|PubMed:19056803}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Lymphatic malformation 3 (LMPHM3) [MIM:613480]: A form of
CC primary lymphedema, a disease characterized by swelling of body parts
CC due to developmental anomalies and functional defects of the lymphatic
CC system. Patients with lymphedema may suffer from recurrent local
CC infections. LMPHM3 is an autosomal dominant form with variable severity
CC and reduced penetrance. Affected individuals manifest lymphedema of the
CC lower limbs and some patients have lymphedema of the hands.
CC {ECO:0000269|PubMed:20537300}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the connexin family. Gamma-type subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: It is uncertain whether Met-1 or Met-4 is the initiator.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB94511.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH35840.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF014643; AAB94511.1; ALT_INIT; Genomic_DNA.
DR EMBL; AL359510; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC035840; AAH35840.1; ALT_INIT; mRNA.
DR EMBL; BC089439; AAH89439.1; -; mRNA.
DR EMBL; AY285161; AAP37488.1; -; mRNA.
DR CCDS; CCDS1569.1; -.
DR RefSeq; NP_065168.2; NM_020435.3.
DR AlphaFoldDB; Q5T442; -.
DR SMR; Q5T442; -.
DR BioGRID; 121419; 8.
DR IntAct; Q5T442; 7.
DR MINT; Q5T442; -.
DR STRING; 9606.ENSP00000355675; -.
DR iPTMnet; Q5T442; -.
DR PhosphoSitePlus; Q5T442; -.
DR BioMuta; GJC2; -.
DR DMDM; 74744875; -.
DR MassIVE; Q5T442; -.
DR PaxDb; Q5T442; -.
DR PeptideAtlas; Q5T442; -.
DR PRIDE; Q5T442; -.
DR ProteomicsDB; 64429; -.
DR Antibodypedia; 34662; 194 antibodies from 28 providers.
DR DNASU; 57165; -.
DR Ensembl; ENST00000366714.3; ENSP00000355675.2; ENSG00000198835.4.
DR GeneID; 57165; -.
DR KEGG; hsa:57165; -.
DR MANE-Select; ENST00000366714.3; ENSP00000355675.2; NM_020435.4; NP_065168.2.
DR UCSC; uc001hsk.4; human.
DR CTD; 57165; -.
DR DisGeNET; 57165; -.
DR GeneCards; GJC2; -.
DR GeneReviews; GJC2; -.
DR HGNC; HGNC:17494; GJC2.
DR HPA; ENSG00000198835; Tissue enriched (brain).
DR MalaCards; GJC2; -.
DR MIM; 608803; gene.
DR MIM; 608804; phenotype.
DR MIM; 613206; phenotype.
DR MIM; 613480; phenotype.
DR neXtProt; NX_Q5T442; -.
DR OpenTargets; ENSG00000198835; -.
DR Orphanet; 320401; Autosomal recessive spastic paraplegia type 44.
DR Orphanet; 79452; Milroy disease.
DR Orphanet; 280282; Pelizaeus-Merzbacher-like disease due to GJC2 mutation.
DR PharmGKB; PA162389696; -.
DR VEuPathDB; HostDB:ENSG00000198835; -.
DR eggNOG; ENOG502QV2G; Eukaryota.
DR GeneTree; ENSGT01050000244833; -.
DR HOGENOM; CLU_037388_4_0_1; -.
DR InParanoid; Q5T442; -.
DR OMA; PPYNYAY; -.
DR OrthoDB; 959629at2759; -.
DR PhylomeDB; Q5T442; -.
DR TreeFam; TF329606; -.
DR PathwayCommons; Q5T442; -.
DR Reactome; R-HSA-190861; Gap junction assembly.
DR SignaLink; Q5T442; -.
DR BioGRID-ORCS; 57165; 7 hits in 1062 CRISPR screens.
DR GeneWiki; GJC2; -.
DR GenomeRNAi; 57165; -.
DR Pharos; Q5T442; Tbio.
DR PRO; PR:Q5T442; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q5T442; protein.
DR Bgee; ENSG00000198835; Expressed in C1 segment of cervical spinal cord and 142 other tissues.
DR ExpressionAtlas; Q5T442; baseline and differential.
DR Genevisible; Q5T442; HS.
DR GO; GO:0005922; C:connexin complex; IEA:InterPro.
DR GO; GO:0005921; C:gap junction; IMP:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043209; C:myelin sheath; IEA:Ensembl.
DR GO; GO:0033270; C:paranode region of axon; IEA:Ensembl.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:1990769; C:proximal neuron projection; IEA:Ensembl.
DR GO; GO:0005243; F:gap junction channel activity; IBA:GO_Central.
DR GO; GO:1903763; F:gap junction channel activity involved in cell communication by electrical coupling; IMP:UniProtKB.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0010644; P:cell communication by electrical coupling; IMP:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; IBA:GO_Central.
DR GO; GO:2000134; P:negative regulation of G1/S transition of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:1904427; P:positive regulation of calcium ion transmembrane transport; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0070447; P:positive regulation of oligodendrocyte progenitor proliferation; IEA:Ensembl.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR Gene3D; 1.20.1440.80; -; 1.
DR InterPro; IPR000500; Connexin.
DR InterPro; IPR019570; Connexin_CCC.
DR InterPro; IPR017990; Connexin_CS.
DR InterPro; IPR013092; Connexin_N.
DR InterPro; IPR038359; Connexin_N_sf.
DR PANTHER; PTHR11984; PTHR11984; 1.
DR Pfam; PF00029; Connexin; 1.
DR PRINTS; PR00206; CONNEXIN.
DR SMART; SM00037; CNX; 1.
DR SMART; SM01089; Connexin_CCC; 1.
DR PROSITE; PS00407; CONNEXINS_1; 1.
DR PROSITE; PS00408; CONNEXINS_2; 1.
PE 1: Evidence at protein level;
KW Cell junction; Cell membrane; Disease variant; Gap junction;
KW Hereditary spastic paraplegia; Leukodystrophy; Membrane; Neurodegeneration;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..439
FT /note="Gap junction gamma-2 protein"
FT /id="PRO_0000057842"
FT TOPO_DOM 1..25
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 26..46
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 47..78
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 79..99
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 100..216
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 217..237
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 238..265
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 266..286
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 287..439
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 108..178
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 364..439
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 146..172
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 371
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8BQU6"
FT VARIANT 19
FT /note="H -> P (associated with lymphedema in a small
FT family; dbSNP:rs149590094)"
FT /evidence="ECO:0000269|PubMed:20537300"
FT /id="VAR_063876"
FT VARIANT 36
FT /note="I -> M (in SPG44; does not form functional homotypic
FT channels; dbSNP:rs75469429)"
FT /evidence="ECO:0000269|PubMed:19056803"
FT /id="VAR_063172"
FT VARIANT 48
FT /note="S -> L (in LMPHM3; dbSNP:rs267606847)"
FT /evidence="ECO:0000269|PubMed:20537300"
FT /id="VAR_063877"
FT VARIANT 90
FT /note="P -> S (in HLD2; dbSNP:rs74315312)"
FT /evidence="ECO:0000269|PubMed:15192806"
FT /id="VAR_023754"
FT VARIANT 125
FT /note="R -> Q (associated with lymphedema in a small
FT family)"
FT /evidence="ECO:0000269|PubMed:20537300"
FT /id="VAR_063878"
FT VARIANT 149
FT /note="G -> S (associated with lymphedema in a small
FT family; dbSNP:rs577325764)"
FT /evidence="ECO:0000269|PubMed:20537300"
FT /id="VAR_063879"
FT VARIANT 260
FT /note="R -> C (in LMPHM3; dbSNP:rs267606846)"
FT /evidence="ECO:0000269|PubMed:20537300"
FT /id="VAR_063880"
FT VARIANT 272
FT /note="Y -> D (in HLD2; dbSNP:rs74315314)"
FT /evidence="ECO:0000269|PubMed:15192806"
FT /id="VAR_023755"
FT VARIANT 286
FT /note="M -> T (in HLD2; dbSNP:rs74315311)"
FT /evidence="ECO:0000269|PubMed:15192806"
FT /id="VAR_023756"
FT VARIANT 316
FT /note="P -> L (associated with lymphedema in a small
FT family; dbSNP:rs760502262)"
FT /evidence="ECO:0000269|PubMed:20537300"
FT /id="VAR_063881"
FT CONFLICT 83
FT /note="Q -> H (in Ref. 1; AAB94511)"
FT /evidence="ECO:0000305"
FT CONFLICT 252
FT /note="H -> Q (in Ref. 1; AAB94511)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 439 AA; 47002 MW; 09725B5DC476672A CRC64;
MTNMSWSFLT RLLEEIHNHS TFVGKVWLTV LVVFRIVLTA VGGEAIYSDE QAKFTCNTRQ
PGCDNVCYDA FAPLSHVRFW VFQIVVISTP SVMYLGYAVH RLARASEQER RRALRRRPGP
RRAPRAHLPP PHAGWPEPAD LGEEEPMLGL GEEEEEEETG AAEGAGEEAE EAGAEEACTK
AVGADGKAAG TPGPTGQHDG RRRIQREGLM RVYVAQLVAR AAFEVAFLVG QYLLYGFEVR
PFFPCSRQPC PHVVDCFVSR PTEKTVFLLV MYVVSCLCLL LNLCEMAHLG LGSAQDAVRG
RRGPPASAPA PAPRPPPCAF PAAAAGLACP PDYSLVVRAA ERARAHDQNL ANLALQALRD
GAAAGDRDRD SSPCVGLPAA SRGPPRAGAP ASRTGSATSA GTVGEQGRPG THERPGAKPR
AGSEKGSASS RDGKTTVWI
