PHX2B_HUMAN
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 03-AUG-2022, entry version 192.
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}.
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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 PDBsum; 7MJA; -.
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; Q99453; -.
DR PeptideAtlas; Q99453; -.
DR PRIDE; Q99453; -.
DR ProteomicsDB; 78274; -.
DR Antibodypedia; 11895; 192 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 CTD; 8929; -.
DR DisGeNET; 8929; -.
DR GeneCards; PHOX2B; -.
DR GeneReviews; PHOX2B; -.
DR HGNC; HGNC:9143; PHOX2B.
DR HPA; ENSG00000109132; Group enriched (adrenal gland, brain).
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; 1505098at2759; -.
DR PhylomeDB; Q99453; -.
DR TreeFam; TF351612; -.
DR PathwayCommons; Q99453; -.
DR SignaLink; Q99453; -.
DR SIGNOR; Q99453; -.
DR BioGRID-ORCS; 8929; 13 hits in 1084 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 tissues.
DR Genevisible; Q99453; HS.
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: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: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: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 InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR017970; Homeobox_CS.
DR InterPro; IPR001356; Homeobox_dom.
DR Pfam; PF00046; Homeodomain; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF46689; SSF46689; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
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)"
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
