Reviewed, UniProtKB/Swiss-Prot Q99453 (PHX2B_HUMAN)

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	314 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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 process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Triplet repeat expansion
Disease	Disease mutation
Domain	Homeobox
Ligand	DNA-binding
Molecular function	Activator Developmental protein
Gene Ontology (GO)
Biological process	regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	sequence-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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 314	314	Paired mesoderm homeobox protein 2B		PRO_0000049262
Regions
	DNA binding	98 – 157	60	Homeobox
	Compositional bias	159 – 167	9	Poly-Ala
	Compositional bias	212 – 217	6	Poly-Gly
	Compositional bias	241 – 260	20	Poly-Ala
Natural variations
	Natural variant	100	1	R → L Germline mutation which predisposes to NB; familial case of NB. Ref.7		VAR_026969
	Natural variant	141	1	R → G Germline mutation which predisposes to NB; isolated case of NB associated with HSCR. Ref.8 Ref.7		VAR_026970
	Natural variant	141	1	R → Q in CCHS. Ref.8		VAR_046900
	Natural variant	143	1	Q → R in CCHS. Ref.8		VAR_046901
	Natural variant	197	1	G → D Mutation which predisposes to NB. Ref.10		VAR_046902
	Natural variant	241	1	A → AAAAAAAAAAA in CCHS.		VAR_018257
	Natural variant	254 – 258	5	Missing Ref.5		VAR_018258
	Natural variant	255 – 259	5	Missing Ref.5		VAR_018259
Experimental info
	Sequence conflict	292	1	A → G in BAA11555. Ref.1
	Sequence conflict	292	1	A → G in AAD26698. Ref.2
	Sequence conflict	292	1	A → G in BAA82670. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q99453-1 [UniParc]. Last modified October 17, 2006. Version 2. Checksum: 40737F71948B595A	FASTA	314	31,621
	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

References

	« Hide 'large scale' referencesShow '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

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	D82344 mRNA. Translation: BAA11555.1. AF117979 Genomic DNA. Translation: AAD26698.1. AB015671 Genomic DNA. Translation: BAA82670.1. BC017199 mRNA. Translation: AAH17199.1.
IPI	IPI00293143.
PIR	JC5273.
RefSeq	NP_003915.2.
UniGene	Hs.87202
3D structure databases
HSSP	HSSP built from PDB template 1FJL based on UniProtKB P06601.
ModBase	Search...
Genome annotation databases
Ensembl	ENSG00000109132. Homo sapiens. [Contig view]
GeneID	8929.
KEGG	hsa:8929.
Organism-specific databases
GeneCards	GC04M041440.
H-InvDB	HIX0004178.
HGNC	HGNC:9143. PHOX2B.
MIM	209880. phenotype. 256700. phenotype. 603851. gene.
Orphanet	635. Neuroblastoma. 661. Ondine syndrome.
PharmGKB	PA33467.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q99453.
HOVERGEN	Q99453.
OMA	Q99453. LVKTSMF.
Gene expression databases
ArrayExpress	Q99453.
Bgee	Q99453.
CleanEx	HS_PHOX2B.
GermOnline	ENSG00000109132. Homo sapiens.
Family and domain databases
InterPro	IPR001356. Homeobox. IPR017970. Homeobox_CS. IPR012287. Homeodomain-rel. [Graphical view]
Gene3D	G3DSA:1.10.10.60. Homeodomain-rel. 1 hit.
Pfam	PF00046. Homeobox. 1 hit. [Graphical view]
ProDom	PD000010. Homeobox. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00389. HOX. 1 hit. [Graphical view]
PROSITE	PS00027. HOMEOBOX_1. 1 hit. PS50071. HOMEOBOX_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	33574.
SOURCE	Search...

Entry information

Entry name

PHX2B_HUMAN

Accession

Primary (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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)