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 24-JAN-2024, entry version 166. 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 GlyGen; Q5T442; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q5T442; -. DR PhosphoSitePlus; Q5T442; -. DR BioMuta; GJC2; -. DR DMDM; 74744875; -. DR MassIVE; Q5T442; -. DR PaxDb; 9606-ENSP00000355675; -. DR PeptideAtlas; Q5T442; -. DR ProteomicsDB; 64429; -. DR Antibodypedia; 34662; 228 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 AGR; HGNC:17494; -. 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; ENSGT01090000260005; -. DR HOGENOM; CLU_037388_4_0_1; -. DR InParanoid; Q5T442; -. DR OMA; ACTKGAG; -. DR OrthoDB; 4640981at2759; -. DR PhylomeDB; Q5T442; -. DR TreeFam; TF329606; -. DR PathwayCommons; Q5T442; -. DR Reactome; R-HSA-190861; Gap junction assembly. DR SignaLink; Q5T442; -. DR BioGRID-ORCS; 57165; 10 hits in 1140 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 143 other cell types or tissues. DR ExpressionAtlas; Q5T442; baseline and differential. DR GO; GO:0005922; C:connexin complex; IBA:GO_Central. DR GO; GO:0005921; C:gap junction; IMP:UniProtKB. 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: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; Gap junction channel protein cysteine-rich domain; 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; CONNEXIN; 1. DR PANTHER; PTHR11984:SF52; GAP JUNCTION GAMMA-2 PROTEIN; 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. DR Genevisible; Q5T442; HS. 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 //