CXB4_HUMAN
ID CXB4_HUMAN Reviewed; 266 AA.
AC Q9NTQ9; B3KQ82;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Gap junction beta-4 protein;
DE AltName: Full=Connexin-30.3;
DE Short=Cx30.3;
GN Name=GJB4;
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 [LARGE SCALE MRNA].
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
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 GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
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 [5]
RP INVOLVEMENT IN EKVP2, AND VARIANT EKVP2 LEU-137.
RX PubMed=11017804; DOI=10.1016/s0002-9297(07)62957-7;
RA Macari F., Landau M., Cousin P., Mevorah B., Brenner S., Panizzon R.,
RA Schorderet D.F., Hohl D., Huber M.;
RT "Mutation in the gene for connexin 30.3 in a family with
RT erythrokeratodermia variabilis.";
RL Am. J. Hum. Genet. 67:1296-1301(2000).
RN [6]
RP VARIANTS CYS-103; GLN-124; CYS-160; TRP-169 AND ALA-204.
RX PubMed=11933201; DOI=10.1002/humu.9023;
RA Lopez-Bigas N., Melchionda S., Gasparini P., Borragan A., Arbones M.L.,
RA Estivill X.;
RT "A common frameshift mutation and other variants in GJB4 (connexin 30.3):
RT analysis of hearing impairment families.";
RL Hum. Mutat. 19:458-458(2002).
RN [7]
RP VARIANTS EKVP2 ASP-12; HIS-22; PRO-85; LEU-137 AND TYR-189, AND VARIANTS
RP GLN-124; TRP-169 AND ALA-204.
RX PubMed=12648223; DOI=10.1046/j.1523-1747.2003.12080.x;
RA Richard G., Brown N., Rouan F., Van der Schroeff J.G., Bijlsma E.,
RA Eichenfield L.F., Sybert V.P., Greer K.E., Hogan P., Campanelli C.,
RA Compton J.G., Bale S.J., DiGiovanna J.J., Uitto J.;
RT "Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations
RT in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.";
RL J. Invest. Dermatol. 120:601-609(2003).
RN [8]
RP VARIANT EKVP2 ASP-12.
RX PubMed=19291775; DOI=10.1002/ajmg.a.32744;
RA van Steensel M.A., Oranje A.P., van der Schroeff J.G., Wagner A.,
RA van Geel M.;
RT "The missense mutation G12D in connexin30.3 can cause both
RT erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric
RT erythrokeratodermia of Gottron.";
RL Am. J. Med. Genet. A 149A:657-661(2009).
CC -!- FUNCTION: Structural component of gap junctions (By similarity). Gap
CC junctions are dodecameric channels that connect the cytoplasm of
CC adjoining cells. They are formed by the docking of two hexameric
CC hemichannels, one from each cell membrane (By similarity). Small
CC molecules and ions diffuse from one cell to a neighboring cell via the
CC central pore (By similarity). {ECO:0000250|UniProtKB:P29033,
CC ECO:0000250|UniProtKB:Q02738}.
CC -!- SUBUNIT: A hemichannel or connexon is composed of a hexamer of
CC connexins. A functional gap junction is formed by the apposition of two
CC hemichannels (By similarity). Forms heteromeric channels with GJB2 (By
CC similarity). {ECO:0000250|UniProtKB:P29033,
CC ECO:0000250|UniProtKB:Q02738}.
CC -!- INTERACTION:
CC Q9NTQ9; Q8WVX3-2: C4orf3; NbExp=3; IntAct=EBI-12831526, EBI-12003442;
CC Q9NTQ9; P21964: COMT; NbExp=3; IntAct=EBI-12831526, EBI-372265;
CC Q9NTQ9; P26715: KLRC1; NbExp=3; IntAct=EBI-12831526, EBI-9018187;
CC Q9NTQ9; Q8TAF8: LHFPL5; NbExp=3; IntAct=EBI-12831526, EBI-2820517;
CC Q9NTQ9; P48230: TM4SF4; NbExp=3; IntAct=EBI-12831526, EBI-8650934;
CC Q9NTQ9; P55061: TMBIM6; NbExp=3; IntAct=EBI-12831526, EBI-1045825;
CC Q9NTQ9; P17152: TMEM11; NbExp=3; IntAct=EBI-12831526, EBI-723946;
CC Q9NTQ9; A2RU14: TMEM218; NbExp=3; IntAct=EBI-12831526, EBI-10173151;
CC Q9NTQ9; Q8N2M4: TMEM86A; NbExp=3; IntAct=EBI-12831526, EBI-12015604;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q02738};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q02738}. Cell
CC junction, gap junction {ECO:0000250|UniProtKB:Q02738}. Note=Colocalizes
CC with GJB2 at gap junction plaques in the cochlea.
CC {ECO:0000250|UniProtKB:Q02738}.
CC -!- DISEASE: Erythrokeratodermia variabilis et progressiva 2 (EKVP2)
CC [MIM:617524]: A form of erythrokeratodermia variabilis et progressiva,
CC a genodermatosis characterized by the coexistence of two independent
CC skin lesions: transient erythema and hyperkeratosis that is usually
CC localized but occasionally occurs in its generalized form. Clinical
CC presentation varies significantly within a family and from one family
CC to another. Palmoplantar keratoderma is present in around 50% of cases.
CC {ECO:0000269|PubMed:11017804, ECO:0000269|PubMed:12648223,
CC ECO:0000269|PubMed:19291775}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the connexin family. Beta-type (group I)
CC subfamily. {ECO:0000305}.
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DR EMBL; AK057628; BAG51944.1; -; mRNA.
DR EMBL; AL121988; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471059; EAX07443.1; -; Genomic_DNA.
DR EMBL; BC034709; AAH34709.1; -; mRNA.
DR CCDS; CCDS383.1; -.
DR RefSeq; NP_694944.1; NM_153212.2.
DR RefSeq; XP_011538981.1; XM_011540679.2.
DR AlphaFoldDB; Q9NTQ9; -.
DR SMR; Q9NTQ9; -.
DR BioGRID; 126063; 10.
DR IntAct; Q9NTQ9; 10.
DR STRING; 9606.ENSP00000345868; -.
DR TCDB; 1.A.24.1.14; the gap junction-forming connexin (connexin) family.
DR iPTMnet; Q9NTQ9; -.
DR PhosphoSitePlus; Q9NTQ9; -.
DR BioMuta; GJB4; -.
DR DMDM; 12229761; -.
DR jPOST; Q9NTQ9; -.
DR MassIVE; Q9NTQ9; -.
DR PaxDb; Q9NTQ9; -.
DR PeptideAtlas; Q9NTQ9; -.
DR PRIDE; Q9NTQ9; -.
DR Antibodypedia; 17219; 177 antibodies from 25 providers.
DR DNASU; 127534; -.
DR Ensembl; ENST00000339480.3; ENSP00000345868.1; ENSG00000189433.7.
DR GeneID; 127534; -.
DR KEGG; hsa:127534; -.
DR MANE-Select; ENST00000339480.3; ENSP00000345868.1; NM_153212.3; NP_694944.1.
DR UCSC; uc001bxv.1; human.
DR CTD; 127534; -.
DR DisGeNET; 127534; -.
DR GeneCards; GJB4; -.
DR HGNC; HGNC:4286; GJB4.
DR HPA; ENSG00000189433; Tissue enriched (skin).
DR MalaCards; GJB4; -.
DR MIM; 605425; gene.
DR MIM; 617524; phenotype.
DR neXtProt; NX_Q9NTQ9; -.
DR OpenTargets; ENSG00000189433; -.
DR Orphanet; 317; Erythrokeratodermia variabilis.
DR PharmGKB; PA28697; -.
DR VEuPathDB; HostDB:ENSG00000189433; -.
DR eggNOG; ENOG502R3YE; Eukaryota.
DR GeneTree; ENSGT01030000234513; -.
DR HOGENOM; CLU_037388_4_1_1; -.
DR InParanoid; Q9NTQ9; -.
DR OMA; QDYDMPR; -.
DR OrthoDB; 955506at2759; -.
DR PhylomeDB; Q9NTQ9; -.
DR TreeFam; TF329606; -.
DR PathwayCommons; Q9NTQ9; -.
DR Reactome; R-HSA-190861; Gap junction assembly.
DR SignaLink; Q9NTQ9; -.
DR BioGRID-ORCS; 127534; 5 hits in 1059 CRISPR screens.
DR GeneWiki; GJB4; -.
DR GenomeRNAi; 127534; -.
DR Pharos; Q9NTQ9; Tbio.
DR PRO; PR:Q9NTQ9; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9NTQ9; protein.
DR Bgee; ENSG00000189433; Expressed in skin of abdomen and 48 other tissues.
DR ExpressionAtlas; Q9NTQ9; baseline and differential.
DR Genevisible; Q9NTQ9; HS.
DR GO; GO:0030054; C:cell junction; IDA:HPA.
DR GO; GO:0005922; C:connexin complex; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005243; F:gap junction channel activity; ISS:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; ISS:UniProtKB.
DR GO; GO:1990349; P:gap junction-mediated intercellular transport; ISS:UniProtKB.
DR GO; GO:0042048; P:olfactory behavior; IEA:Ensembl.
DR GO; GO:0007608; P:sensory perception of smell; IEA:Ensembl.
DR Gene3D; 1.20.1440.80; -; 1.
DR InterPro; IPR000500; Connexin.
DR InterPro; IPR002270; Connexin-30.3.
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 PANTHER; PTHR11984:SF30; PTHR11984:SF30; 1.
DR Pfam; PF00029; Connexin; 1.
DR PRINTS; PR00206; CONNEXIN.
DR PRINTS; PR01142; CONNEXINB5.
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; Disulfide bond;
KW Gap junction; Membrane; Palmoplantar keratoderma; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..266
FT /note="Gap junction beta-4 protein"
FT /id="PRO_0000057865"
FT INTRAMEM 2..13
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT TOPO_DOM 14..20
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 21..40
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT TOPO_DOM 41..73
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 74..94
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT TOPO_DOM 95..130
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 131..151
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT TOPO_DOM 152..184
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 185..205
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT TOPO_DOM 206..266
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DISULFID 53..175
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT DISULFID 60..169
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT DISULFID 64..164
FT /evidence="ECO:0000250|UniProtKB:P29033"
FT VARIANT 12
FT /note="G -> D (in EKVP2; dbSNP:rs80358211)"
FT /evidence="ECO:0000269|PubMed:12648223,
FT ECO:0000269|PubMed:19291775"
FT /id="VAR_079194"
FT VARIANT 22
FT /note="R -> H (in EKVP2; dbSNP:rs80358212)"
FT /evidence="ECO:0000269|PubMed:12648223"
FT /id="VAR_079195"
FT VARIANT 85
FT /note="T -> P (in EKVP2; dbSNP:rs80358210)"
FT /evidence="ECO:0000269|PubMed:12648223"
FT /id="VAR_079196"
FT VARIANT 103
FT /note="R -> C (in dbSNP:rs9426009)"
FT /evidence="ECO:0000269|PubMed:11933201"
FT /id="VAR_015088"
FT VARIANT 124
FT /note="R -> Q (in dbSNP:rs140996335)"
FT /evidence="ECO:0000269|PubMed:11933201,
FT ECO:0000269|PubMed:12648223"
FT /id="VAR_015089"
FT VARIANT 137
FT /note="F -> L (in EKVP2; dbSNP:rs80358206)"
FT /evidence="ECO:0000269|PubMed:11017804,
FT ECO:0000269|PubMed:12648223"
FT /id="VAR_010206"
FT VARIANT 160
FT /note="R -> C (in dbSNP:rs148710003)"
FT /evidence="ECO:0000269|PubMed:11933201"
FT /id="VAR_015090"
FT VARIANT 169
FT /note="C -> W (in dbSNP:rs79193415)"
FT /evidence="ECO:0000269|PubMed:11933201,
FT ECO:0000269|PubMed:12648223"
FT /id="VAR_015091"
FT VARIANT 189
FT /note="F -> Y (in EKVP2; dbSNP:rs80358213)"
FT /evidence="ECO:0000269|PubMed:12648223"
FT /id="VAR_079197"
FT VARIANT 204
FT /note="E -> A (in dbSNP:rs3738346)"
FT /evidence="ECO:0000269|PubMed:11933201,
FT ECO:0000269|PubMed:12648223"
FT /id="VAR_015092"
SQ SEQUENCE 266 AA; 30419 MW; F136B3706AA14648 CRC64;
MNWAFLQGLL SGVNKYSTVL SRIWLSVVFI FRVLVYVVAA EEVWDDEQKD FVCNTKQPGC
PNVCYDEFFP VSHVRLWALQ LILVTCPSLL VVMHVAYREE RERKHHLKHG PNAPSLYDNL
SKKRGGLWWT YLLSLIFKAA VDAGFLYIFH RLYKDYDMPR VVACSVEPCP HTVDCYISRP
TEKKVFTYFM VTTAAICILL NLSEVFYLVG KRCMEIFGPR HRRPRCRECL PDTCPPYVLS
QGGHPEDGNS VLMKAGSAPV DAGGYP
