ID PHX2B_HUMAN Reviewed; 314 AA. AC Q99453; Q6PJD9; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 27-MAR-2024, entry version 200. DE RecName: Full=Paired mesoderm homeobox protein 2B; DE AltName: Full=Neuroblastoma Phox; DE Short=NBPhox; DE AltName: Full=PHOX2B homeodomain protein; DE AltName: Full=Paired-like homeobox 2B; GN Name=PHOX2B; Synonyms=PMX2B; 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 [MRNA]. RC TISSUE=Neuroblastoma; RX PubMed=9039501; DOI=10.1093/dnares/3.5.311; RA Yokoyama M., Nishi Y., Yoshii J., Okubo K., Matsubara K.; RT "Identification and cloning of neuroblastoma-specific and nerve tissue- RT specific genes through compiled expression profiles."; RL DNA Res. 3:311-320(1996). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11034547; DOI=10.1089/104454900439773; RA Adachi M., Browne D., Lewis E.J.; RT "Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have RT similar genetic organization and independently regulate dopamine beta- RT hydroxylase gene transcription."; RL DNA Cell Biol. 19:539-554(2000). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10395798; DOI=10.1006/geno.1999.5845; RA Yokoyama M., Watanabe H., Nakamura M.; RT "Genomic structure and functional characterization of NBPhox (PMX2B), a RT homeodomain protein specific to catecholaminergic cells that is involved in RT second messenger-mediated transcriptional activation."; RL Genomics 59:40-50(1999). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; 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 VARIANT CCHS1 ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-241 INS, AND VARIANTS RP 254-ALA--ALA-258 DEL AND 255-ALA--ALA-259 DEL. RX PubMed=14566559; DOI=10.1007/s00439-003-1036-z; RA Sasaki A., Kanai M., Kijima K., Akaba K., Hashimoto M., Hasegawa H., RA Otaki S., Koizumi T., Kusuda S., Ogawa Y., Tuchiya K., Yamamoto W., RA Nakamura T., Hayasaka K.; RT "Molecular analysis of congenital central hypoventilation syndrome."; RL Hum. Genet. 114:22-26(2003). RN [6] RP INVOLVEMENT IN CCHS1, AND TRIPLET REPEAT EXPANSION. RX PubMed=12640453; DOI=10.1038/ng1130; RA Amiel J., Laudier B., Attie-Bitach T., Trang H., de Pontual L., Gener B., RA Trochet D., Etchevers H., Ray P., Simonneau M., Vekemans M., Munnich A., RA Gaultier C., Lyonnet S.; RT "Polyalanine expansion and frameshift mutations of the paired-like homeobox RT gene PHOX2B in congenital central hypoventilation syndrome."; RL Nat. Genet. 33:459-461(2003). RN [7] RP VARIANTS LEU-100 AND GLY-141, AND POSSIBLE INVOLVEMENT IN NBLST2. RX PubMed=15024693; DOI=10.1086/383253; RA Trochet D., Bourdeaut F., Janoueix-Lerosey I., Deville A., de Pontual L., RA Schleiermacher G., Coze C., Philip N., Frebourg T., Munnich A., Lyonnet S., RA Delattre O., Amiel J.; RT "Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in RT neuroblastoma."; RL Am. J. Hum. Genet. 74:761-764(2004). RN [8] RP VARIANTS CCHS1 GLN-141 AND ARG-143, AND TRIPLET REPEAT EXPANSION. RX PubMed=15657873; DOI=10.1086/428366; RA Trochet D., O'Brien L.M., Gozal D., Trang H., Nordenskjoeld A., Laudier B., RA Svensson P.-J., Uhrig S., Cole T., Niemann S., Munnich A., Gaultier C., RA Lyonnet S., Amiel J.; RT "PHOX2B genotype allows for prediction of tumor risk in congenital central RT hypoventilation syndrome."; RL Am. J. Hum. Genet. 76:421-426(2005). RN [9] RP ERRATUM OF PUBMED:15657873. RA Trochet D., O'Brien L.M., Gozal D., Trang H., Nordenskjoeld A., Laudier B., RA Svensson P.-J., Uhrig S., Cole T., Niemann S., Munnich A., Gaultier C., RA Lyonnet S., Amiel J.; RL Am. J. Hum. Genet. 76:715-715(2002). RN [10] RP VARIANT ASP-197, AND NEUROBLASTOMA SUSCEPTIBILITY. RX PubMed=16691592; DOI=10.1002/ajmg.a.31278; RA McConville C., Reid S., Baskcomb L., Douglas J., Rahman N.; RT "PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations RT and genotype-phenotype associations."; RL Am. J. Med. Genet. A 140:1297-1301(2006). CC -!- FUNCTION: Involved in the development of several major noradrenergic CC neuron populations, including the locus coeruleus. Transcription factor CC which could determine a neurotransmitter phenotype in vertebrates. CC Enhances second-messenger-mediated activation of the dopamine beta- CC hydrolase and c-fos promoters, and of several enhancers including cAMP- CC response element and serum-response element. CC -!- SUBUNIT: Interacts with TRIM11. {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00108}. CC -!- TISSUE SPECIFICITY: Expressed in neuroblastoma, brain and adrenal CC gland. CC -!- DISEASE: Central hypoventilation syndrome, congenital, 1 (CCHS1) CC [MIM:209880]: An autosomal dominant form of congenital central CC hypoventilation syndrome, a rare disorder characterized by abnormal CC control of respiration in the absence of neuromuscular or lung disease, CC or an identifiable brain stem lesion. A deficiency in autonomic control CC of respiration results in inadequate or negligible ventilatory and CC arousal responses to hypercapnia and hypoxemia. CC {ECO:0000269|PubMed:12640453, ECO:0000269|PubMed:14566559, CC ECO:0000269|PubMed:15657873}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Neuroblastoma 2 (NBLST2) [MIM:613013]: A common neoplasm of CC early childhood arising from embryonic cells that form the primitive CC neural crest and give rise to the adrenal medulla and the sympathetic CC nervous system. {ECO:0000305|PubMed:15024693}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the paired homeobox family. {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; D82344; BAA11555.1; -; mRNA. DR EMBL; AF117979; AAD26698.1; -; Genomic_DNA. DR EMBL; AB015671; BAA82670.1; -; Genomic_DNA. DR EMBL; BC017199; AAH17199.1; -; mRNA. DR CCDS; CCDS3463.1; -. DR PIR; JC5273; JC5273. DR RefSeq; NP_003915.2; NM_003924.3. DR PDB; 7MJA; X-ray; 1.69 A; C=43-51. DR PDB; 8EK5; X-ray; 2.11 A; C=43-51. DR PDBsum; 7MJA; -. DR PDBsum; 8EK5; -. DR AlphaFoldDB; Q99453; -. DR SMR; Q99453; -. DR BioGRID; 114443; 2. DR STRING; 9606.ENSP00000226382; -. DR iPTMnet; Q99453; -. DR PhosphoSitePlus; Q99453; -. DR BioMuta; PHOX2B; -. DR DMDM; 116242712; -. DR EPD; Q99453; -. DR jPOST; Q99453; -. DR MassIVE; Q99453; -. DR MaxQB; Q99453; -. DR PaxDb; 9606-ENSP00000226382; -. DR PeptideAtlas; Q99453; -. DR ProteomicsDB; 78274; -. DR Antibodypedia; 11895; 226 antibodies from 33 providers. DR DNASU; 8929; -. DR Ensembl; ENST00000226382.4; ENSP00000226382.2; ENSG00000109132.7. DR GeneID; 8929; -. DR KEGG; hsa:8929; -. DR MANE-Select; ENST00000226382.4; ENSP00000226382.2; NM_003924.4; NP_003915.2. DR UCSC; uc003gwf.4; human. DR AGR; HGNC:9143; -. DR CTD; 8929; -. DR DisGeNET; 8929; -. DR GeneCards; PHOX2B; -. DR GeneReviews; PHOX2B; -. DR HGNC; HGNC:9143; PHOX2B. DR HPA; ENSG00000109132; Group enriched (adrenal gland, intestine). DR MalaCards; PHOX2B; -. DR MIM; 209880; phenotype. DR MIM; 603851; gene. DR MIM; 613013; phenotype. DR neXtProt; NX_Q99453; -. DR OpenTargets; ENSG00000109132; -. DR Orphanet; 661; Congenital central hypoventilation syndrome. DR Orphanet; 99803; Haddad syndrome. DR Orphanet; 2151; Hirschsprung disease-ganglioneuroblastoma syndrome. DR Orphanet; 635; Neuroblastoma. DR PharmGKB; PA33467; -. DR VEuPathDB; HostDB:ENSG00000109132; -. DR eggNOG; KOG0484; Eukaryota. DR GeneTree; ENSGT00940000159958; -. DR HOGENOM; CLU_081152_0_0_1; -. DR InParanoid; Q99453; -. DR OMA; QSQGWAT; -. DR OrthoDB; 2901226at2759; -. DR PhylomeDB; Q99453; -. DR TreeFam; TF351612; -. DR PathwayCommons; Q99453; -. DR SignaLink; Q99453; -. DR SIGNOR; Q99453; -. DR BioGRID-ORCS; 8929; 14 hits in 1167 CRISPR screens. DR ChiTaRS; PHOX2B; human. DR GeneWiki; PHOX2B; -. DR GenomeRNAi; 8929; -. DR Pharos; Q99453; Tbio. DR PRO; PR:Q99453; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q99453; Protein. DR Bgee; ENSG00000109132; Expressed in muscle layer of sigmoid colon and 40 other cell types or tissues. DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:BHF-UCL. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0048483; P:autonomic nervous system development; IMP:BHF-UCL. DR GO; GO:0003360; P:brainstem development; IEP:BHF-UCL. DR GO; GO:0021533; P:cell differentiation in hindbrain; ISS:BHF-UCL. DR GO; GO:0071773; P:cellular response to BMP stimulus; ISS:BHF-UCL. DR GO; GO:0071244; P:cellular response to carbon dioxide; IEA:Ensembl. DR GO; GO:0071542; P:dopaminergic neuron differentiation; ISS:BHF-UCL. DR GO; GO:0048894; P:efferent axon development in a lateral line nerve; ISS:BHF-UCL. DR GO; GO:0048484; P:enteric nervous system development; IEP:BHF-UCL. DR GO; GO:0010001; P:glial cell differentiation; ISS:BHF-UCL. DR GO; GO:0021934; P:hindbrain tangential cell migration; ISS:BHF-UCL. DR GO; GO:0048839; P:inner ear development; ISS:BHF-UCL. DR GO; GO:0021723; P:medullary reticular formation development; ISS:BHF-UCL. DR GO; GO:0051899; P:membrane depolarization; IEA:Ensembl. DR GO; GO:0097475; P:motor neuron migration; IEA:Ensembl. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl. DR GO; GO:1904691; P:negative regulation of type B pancreatic cell proliferation; IEA:Ensembl. DR GO; GO:1901166; P:neural crest cell migration involved in autonomic nervous system development; ISS:BHF-UCL. DR GO; GO:0001764; P:neuron migration; ISS:BHF-UCL. DR GO; GO:0003358; P:noradrenergic neuron development; ISS:UniProtKB. DR GO; GO:0003357; P:noradrenergic neuron differentiation; ISS:BHF-UCL. DR GO; GO:0048486; P:parasympathetic nervous system development; ISS:BHF-UCL. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; ISS:UniProtKB. DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0010468; P:regulation of gene expression; ISS:UniProtKB. DR GO; GO:0002087; P:regulation of respiratory gaseous exchange by nervous system process; ISS:BHF-UCL. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:MGI. DR GO; GO:0060541; P:respiratory system development; ISS:BHF-UCL. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0061452; P:retrotrapezoid nucleus neuron differentiation; ISS:BHF-UCL. DR GO; GO:0035914; P:skeletal muscle cell differentiation; IEA:Ensembl. DR GO; GO:0061549; P:sympathetic ganglion development; ISS:UniProtKB. DR GO; GO:0048485; P:sympathetic nervous system development; ISS:BHF-UCL. DR GO; GO:0044342; P:type B pancreatic cell proliferation; IEA:Ensembl. DR CDD; cd00086; homeodomain; 1. DR Gene3D; 1.10.10.60; Homeodomain-like; 1. DR InterPro; IPR009057; Homeobox-like_sf. DR InterPro; IPR017970; Homeobox_CS. DR InterPro; IPR001356; Homeobox_dom. DR PANTHER; PTHR24329; HOMEOBOX PROTEIN ARISTALESS; 1. DR PANTHER; PTHR24329:SF301; PAIRED MESODERM HOMEOBOX PROTEIN 2B; 1. DR Pfam; PF00046; Homeodomain; 1. DR SMART; SM00389; HOX; 1. DR SUPFAM; SSF46689; Homeodomain-like; 1. DR PROSITE; PS00027; HOMEOBOX_1; 1. DR PROSITE; PS50071; HOMEOBOX_2; 1. DR Genevisible; Q99453; HS. PE 1: Evidence at protein level; KW 3D-structure; Activator; Developmental protein; Disease variant; KW DNA-binding; Homeobox; Nucleus; Reference proteome; Transcription; KW Transcription regulation; Triplet repeat expansion. FT CHAIN 1..314 FT /note="Paired mesoderm homeobox protein 2B" FT /id="PRO_0000049262" FT DNA_BIND 98..157 FT /note="Homeobox" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108" FT REGION 162..246 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 259..289 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 174..190 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 100 FT /note="R -> L (confers susceptibility to neuroblastoma; FT found as germline mutation in a neuroblastoma family; FT dbSNP:rs104893855)" FT /evidence="ECO:0000269|PubMed:15024693" FT /id="VAR_026969" FT VARIANT 141 FT /note="R -> G (in dbSNP:rs28939716)" FT /evidence="ECO:0000269|PubMed:15024693" FT /id="VAR_026970" FT VARIANT 141 FT /note="R -> Q (in CCHS1; dbSNP:rs1733941453)" FT /evidence="ECO:0000269|PubMed:15657873" FT /id="VAR_046900" FT VARIANT 143 FT /note="Q -> R (in CCHS1)" FT /evidence="ECO:0000269|PubMed:15657873" FT /id="VAR_046901" FT VARIANT 197 FT /note="G -> D (confers susceptibility to neuroblastoma; FT dbSNP:rs104893856)" FT /evidence="ECO:0000269|PubMed:16691592" FT /id="VAR_046902" FT VARIANT 241 FT /note="A -> AAAAAAAAAAA (in CCHS1)" FT /evidence="ECO:0000269|PubMed:14566559" FT /id="VAR_018257" FT VARIANT 254..258 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:14566559" FT /id="VAR_018258" FT VARIANT 255..259 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:14566559" FT /id="VAR_018259" FT CONFLICT 292 FT /note="A -> G (in Ref. 1; BAA11555, 2; AAD26698 and 3; FT BAA82670)" FT /evidence="ECO:0000305" SQ SEQUENCE 314 AA; 31621 MW; 40737F71948B595A CRC64; MYKMEYSYLN SSAYESCMAG MDTSSLASAY ADFSSCSQAS GFQYNPIRTT FGATSGCPSL TPGSCSLGTL RDHQSSPYAA VPYKLFTDHG GLNEKRKQRR IRTTFTSAQL KELERVFAET HYPDIYTREE LALKIDLTEA RVQVWFQNRR AKFRKQERAA AAAAAAAKNG SSGKKSDSSR DDESKEAKST DPDSTGGPGP NPNPTPSCGA NGGGGGGPSP AGAPGAAGPG GPGGEPGKGG AAAAAAAAAA AAAAAAAAAA GGLAAAGGPG QGWAPGPGPI TSIPDSLGGP FASVLSSLQR PNGAKAALVK SSMF //