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Reviewed, UniProtKB/Swiss-Prot Q99453 (PHX2B_HUMAN)

Last modified June 16, 2009. Version 90. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Paired mesoderm homeobox protein 2B
Alternative name(s):
    Paired-like homeobox 2B
    PHOX2B homeodomain protein
    Neuroblastoma Phox
      Short name=NBPhox
Gene names
Name: PHOX2B
Synonyms: PMX2B
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length314 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. Transcription factor which could determine a neurotransmitter phenotype in vertebrates. Enhances second-messenger-mediated activation of the dopamine beta-hydrolase and c-fos promoters, and of several enhancers including cAMP-response element and serum-response element.

Subcellular location

Nucleus By similarity.

Tissue specificity

Expressed in neuroblastoma, brain and adrenal gland.

Involvement in disease

Defects in PHOX2B are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:209880]; also known as congenital failure of autonomic control or Ondine curse. Most mutations consist of 5-10 alanine expansions in the poly-Ala region from amino acids 241-260. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. CCHS is frequently complicated with neurocristopathies such as Hirschsprung disease that occurs in about 16% of CCHS cases. Ref.5 Ref.6 Ref.8

Defects in PHOX2B predispose to hereditary neuroblastoma (NB) [MIM:256700]. NB is a tumor of the sympathetic nervous system that account for about 10% of all cancers in childhood. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells-namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS).

Sequence similarities

Belongs to the paired homeobox family.

Contains 1 homeobox DNA-binding domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityTriplet repeat expansion
   DiseaseDisease mutation
   DomainHomeobox
   LigandDNA-binding
   Molecular functionActivator
Developmental protein
Gene Ontology (GO)
   Biological processregulation of transcription, DNA-dependent

Inferred from electronic annotation. Source: UniProtKB-KW

transcription

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular componentnucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular functionsequence-specific DNA binding

Inferred from electronic annotation. Source: InterPro

transcription cofactor activity Ref.3

Traceable author statement. Source: ProtInc

transcription factor activity Ref.3

Traceable author statement. Source: ProtInc

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 314314Paired mesoderm homeobox protein 2B
PRO_0000049262

Regions

DNA binding98 – 15760Homeobox
Compositional bias159 – 1679Poly-Ala
Compositional bias212 – 2176Poly-Gly
Compositional bias241 – 26020Poly-Ala

Natural variations

Natural variant1001R → L Germline mutation which predisposes to NB; familial case of NB. Ref.7
VAR_026969
Natural variant1411R → G Germline mutation which predisposes to NB; isolated case of NB associated with HSCR. Ref.8 Ref.7
VAR_026970
Natural variant1411R → Q in CCHS. Ref.8
VAR_046900
Natural variant1431Q → R in CCHS. Ref.8
VAR_046901
Natural variant1971G → D Mutation which predisposes to NB. Ref.10
VAR_046902
Natural variant2411A → AAAAAAAAAAA in CCHS.
VAR_018257
Natural variant254 – 2585Missing Ref.5
VAR_018258
Natural variant255 – 2595Missing Ref.5
VAR_018259

Experimental info

Sequence conflict2921A → G in BAA11555. Ref.1
Sequence conflict2921A → G in AAD26698. Ref.2
Sequence conflict2921A → G in BAA82670. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Q99453-1 [UniParc].

Last modified October 17, 2006. Version 2.
Checksum: 40737F71948B595A

FASTA31431,621
        10         20         30         40         50         60 
MYKMEYSYLN SSAYESCMAG MDTSSLASAY ADFSSCSQAS GFQYNPIRTT FGATSGCPSL 

        70         80         90        100        110        120 
TPGSCSLGTL RDHQSSPYAA VPYKLFTDHG GLNEKRKQRR IRTTFTSAQL KELERVFAET 

       130        140        150        160        170        180 
HYPDIYTREE LALKIDLTEA RVQVWFQNRR AKFRKQERAA AAAAAAAKNG SSGKKSDSSR 

       190        200        210        220        230        240 
DDESKEAKST DPDSTGGPGP NPNPTPSCGA NGGGGGGPSP AGAPGAAGPG GPGGEPGKGG 

       250        260        270        280        290        300 
AAAAAAAAAA AAAAAAAAAA GGLAAAGGPG QGWAPGPGPI TSIPDSLGGP FASVLSSLQR 

       310 
PNGAKAALVK SSMF 

« Hide

References

« Hide 'large scale' references
[1]"Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles."
Yokoyama M., Nishi Y., Yoshii J., Okubo K., Matsubara K.
DNA Res. 3:311-320(1996) [PubMed: 9039501] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Neuroblastoma.
[2]"Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription."
Adachi M., Browne D., Lewis E.J.
DNA Cell Biol. 19:539-554(2000) [PubMed: 11034547] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Genomic structure and functional characterization of NBPhox (PMX2B), a homeodomain protein specific to catecholaminergic cells that is involved in second messenger-mediated transcriptional activation."
Yokoyama M., Watanabe H., Nakamura M.
Genomics 59:40-50(1999) [PubMed: 10395798] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[5]"Molecular analysis of congenital central hypoventilation syndrome."
Sasaki A., Kanai M., Kijima K., Akaba K., Hashimoto M., Hasegawa H., Otaki S., Koizumi T., Kusuda S., Ogawa Y., Tuchiya K., Yamamoto W., Nakamura T., Hayasaka K.
Hum. Genet. 114:22-26(2003) [PubMed: 14566559] [Abstract]
Cited for: VARIANT CCHS ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-ALA-241 INS, VARIANTS 254-ALA--ALA-258 DEL AND 255-ALA--ALA-259 DEL.
[6]"Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome."
Amiel J., Laudier B., Attie-Bitach T., Trang H., de Pontual L., Gener B., Trochet D., Etchevers H., Ray P., Simonneau M., Vekemans M., Munnich A., Gaultier C., Lyonnet S.
Nat. Genet. 33:459-461(2003) [PubMed: 12640453] [Abstract]
Cited for: INVOLVEMENT IN CCHS, TRIPLET REPEAT EXPANSION.
[7]"Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma."
Trochet D., Bourdeaut F., Janoueix-Lerosey I., Deville A., de Pontual L., Schleiermacher G., Coze C., Philip N., Frebourg T., Munnich A., Lyonnet S., Delattre O., Amiel J.
Am. J. Hum. Genet. 74:761-764(2004) [PubMed: 15024693] [Abstract]
Cited for: VARIANTS LEU-100 AND GLY-141.
[8]"PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome."
Trochet D., O'Brien L.M., Gozal D., Trang H., Nordenskjoeld A., Laudier B., Svensson P.-J., Uhrig S., Cole T., Niemann S., Munnich A., Gaultier C., Lyonnet S., Amiel J.
Am. J. Hum. Genet. 76:421-426(2005) [PubMed: 15657873] [Abstract]
Cited for: VARIANTS CCHS GLN-141 AND ARG-143, TRIPLET REPEAT EXPANSION.
[9]Erratum
Trochet D., O'Brien L.M., Gozal D., Trang H., Nordenskjoeld A., Laudier B., Svensson P.-J., Uhrig S., Cole T., Niemann S., Munnich A., Gaultier C., Lyonnet S., Amiel J.
Am. J. Hum. Genet. 76:715-715(2002)
[10]"PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations."
McConville C., Reid S., Baskcomb L., Douglas J., Rahman N.
Am. J. Med. Genet. A 140:1297-1301(2006) [PubMed: 16691592] [Abstract]
Cited for: VARIANT ASP-197, NEUROBLASTOMA SUCEPTIBILITY.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

D82344 mRNA. Translation: BAA11555.1.
AF117979 Genomic DNA. Translation: AAD26698.1.
AB015671 Genomic DNA. Translation: BAA82670.1.
BC017199 mRNA. Translation: AAH17199.1.
IPIIPI00293143.
PIRJC5273.
RefSeqNP_003915.2.
UniGeneHs.87202

3D structure databases

HSSPHSSP built from PDB template 1FJL based on UniProtKB P06601.
ModBaseSearch...

Genome annotation databases

EnsemblENSG00000109132. Homo sapiens. [Contig view]
GeneID8929.
KEGGhsa:8929.

Organism-specific databases

GeneCardsGC04M041440.
H-InvDBHIX0004178.
HGNCHGNC:9143. PHOX2B.
MIM209880. phenotype.
256700. phenotype.
603851. gene.
Orphanet635. Neuroblastoma.
661. Ondine syndrome.
PharmGKBPA33467.
GenAtlasSearch...

Phylogenomic databases

HOGENOMQ99453.
HOVERGENQ99453.
OMAQ99453. LVKTSMF.

Gene expression databases

ArrayExpressQ99453.
BgeeQ99453.
CleanExHS_PHOX2B.
GermOnlineENSG00000109132. Homo sapiens.

Family and domain databases

InterProIPR001356. Homeobox.
IPR017970. Homeobox_CS.
IPR012287. Homeodomain-rel.
[Graphical view]
Gene3DG3DSA:1.10.10.60. Homeodomain-rel. 1 hit.
PfamPF00046. Homeobox. 1 hit.
[Graphical view]
ProDomPD000010. Homeobox. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTSM00389. HOX. 1 hit.
[Graphical view]
PROSITEPS00027. HOMEOBOX_1. 1 hit.
PS50071. HOMEOBOX_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio33574.
SOURCESearch...

Entry information

Entry namePHX2B_HUMAN
AccessionPrimary (citable) accession number: Q99453
Secondary accession number(s): Q6PJD9
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: October 17, 2006
Last modified: June 16, 2009
This is version 90 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Human chromosome 4

Human chromosome 4: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents