Download Gene Section PHOX2B (paired-like homeobox 2b) Atlas of Genetics and Cytogenetics

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in Oncology and Haematology
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Gene Section
Review
PHOX2B (paired-like homeobox 2b)
Tiziana Bachetti, Isabella Ceccherini
UOC Medical Genetics, G Gaslini Institute, 16147 Genova, Italy (TB, IC)
Published in Atlas Database: April 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/PHOX2BID126ch4p13.html
DOI: 10.4267/2042/51812
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: NBLST2, NBPhox, PMX2B
HGNC (Hugo): PHOX2B
Location: 4p13
Local order: APBB2 - UCHL1 - LIMCH1 - PHOX2B
- TMEM33 - DCAF4L1 - ATP1B1P1 - SLC30A9.
Note
NCBI Reference Sequence: NP_003915.2.
Description
Note
Genomic: NCBI Reference Sequence: NG_008243.1.
PHOX2B protein is 314 aminoacids long. A
homeodomain region spanning exons 1 and 2 (from
residue 99 to residue 148) is responsible for the binding
of this transcription factor to target DNA elements.
In exon 3 there are two sequences characterized by
stretches of 9 and 20 alanine residues, encoded by
GC(N) triplets. Their functional role is still unknown.
Description
Expression
The PHOX2B gene is 4888bp long; the coding region
(CDS) is 945bp and is composed of 3 exons: exon 1
(241bp), exon 2 (188bp), exon 3 (516bp).
Other features: 5'UTR: 361bp; 3'UTR: 1725bp.
PHOX2B is expressed during neural development in
central autonomic circuits and peripheral neural crest
derivatives, and particularly in the retrotrapezoid
nucleus, noradrenergic centres and hindbrain (Pattyn et
al., 1997; Dubreuil et al., 2002; Stornetta et al., 2006;
Kang et al., 2007).
PHOX2B expression is transcriptionally regulated by
the PHOX2B protein itself, through its direct binding to
four promoter elements which give rise to a positive
autoregulatory loop (Cargnin et al., 2005).
DNA/RNA
Transcription
mRNA: NCBI Reference Sequence NM_003924.3. The
PHOX2B mRNA is 3218bp long; no alternative splice
site is known.
Pseudogene
No pseudogene is reported.
Cytogenetic location of PHOX2B on chromosome 4.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
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PHOX2B (paired-like homeobox 2b)
Bachetti T, Ceccherini I
PHOX2B gene structure. Untranslated regions (orange boxes), introns (black lines) and coding regions (blue boxes) are shown.
Representation of the PHOX2B protein. The three exons (blue) are shown, with the number of aminoacids (aa) they code for, in
addition to the homeodomain (red) and the polyalanine stretches (yellow). In the upper part of the figure, the first and last aminoacid
positions for each of these crucial regions is indicated.
100% identical to those of the chimpanzee, rat and
mouse, suggesting that the function of PHOX2B is
highly conserved in Mammals.
In addition, PHOX2B expression is known to be
regulated at specific sympathetic and enteric nervous
system developmental stages by E2a and Hand2
(Hashimoto et al., 2011).
Finally, SOX10 (Nagashimada et al., 2012), as well as
PHOX2A and HASH1 (reviewed by Brunet and Pattyn,
2002) have shown a degree of cross-regulation with
respect to PHOX2B. Hoxb1 and Hoxb2 have also
shown to form a trimer with Pbx1 and Meis 1 to
regulate PHOX2B transcription (Samad et al., 2004).
Mutations
Germinal
Germline PHOX2B mutations are responsible for
Congenital Central Hypoventilation Syndrome
(CCHS). The vast majority of mutations is represented
by in frame triplet duplications of a sequence stretch
coding for 20 Alanine residues in exon 3, also known
as polyalanine (polyAla) expansions or PARM
(Polyalanine repeats mutation). The duplication length
is variable, starting from 12 bp up to 39 bp, thus
leading from +4 Ala up to +13 Ala expansions (Amiel
et al., 2003; Sasaki et al., 2003; Weese-Mayer et al.,
2003; Matera et al., 2004; Trochet et al., 2008a).
Ninety percent of constitutive (germinal) mutations
detected in CCHS patients are represented by polyAla
expansions. Among these, 75% have arisen de novo
while 25% is inherited from one parent (Bachetti et al.,
2011; Meguro et al., 2012).
In addition, germline PHOX2B missense, frameshift,
nonsense non polyAla mutations (NPARMs) have been
detected in a small fraction of mainly syndromic
patients
characterized
by
CCHS+other
neurocristophaties such as neuroblastoma (NB) and/or
Hirschsprung's disease (HSCR) (Trochet et al., 2005;
Matera et al., 2004). A few specific missense PHOX2B
mutations have been detected in isolated NB and/or
HSCR, as reported in Table 1.
In frame deletions within the polyAla stretch have been
identified in healthy subjects, but also in association
with schizophenia (Toyota et al., 2004).
Localisation
PHOX2B is localized within the nuclear compartment.
Function
PHOX2B is a transcription factor essential for the
development of autonomic neural crest derivatives
(Pattyn et al., 1999).
It controls the development of motoneurons (Pattyn et
al., 2000) and drives a somatic-to-visceral switch in
cranial sensory pathways (D'Autréaux et al., 2011).
PHOX2B regulates the transcriptional expression of
several genes: TH (Lo et al., 1999), DBH (Adachi et
al., 2000), PHOX2A (Flora et al., 2011), PHOX2B
itself (Cargnin et al., 2005), RET (Bachetti et al.,
2005a), TLX-2 (Borghini et al., 2006), ALK (Bachetti
et al., 2010), SOX10 (Nagashimada et al., 2012),
Hand1 (Vincentz et al., 2012), SCG2 (Wen et al.,
2007), MSX1 (Revet et al., 2008).
CREB-binding protein (CREBBP/CBP) interacts with
PHOX2B and serves as its coactivator to mediate
synergistic trans-activation (Wu et al., 2009).
Using a yeast two-hybrid screening, TRIM11 was
isolated as an additional PHOX2B interacting protein
(Hong et al., 2008).
Homology
The amino acid sequence of the human PHOX2B is
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
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PHOX2B (paired-like homeobox 2b)
Bachetti T, Ceccherini I
Table 1: NPARMS and PARMS mutations of PHOX2B in human disease. Legend: NB neuroblastoma, TSNS tumor sympathetic
nervous system, CCHS congenital central hypoventilation syndrome, LO-CHS late onset central hypoventialtion syndrome, NF1
neurofibromatosis type 1, (?) undetermined associations.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
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PHOX2B (paired-like homeobox 2b)
Bachetti T, Ceccherini I
Localization of mutations within the PHOX2B gene. In the figure some PARMS (yellow) and NPARMS (black) PHOX2B mutations are
shown (see also Weese-Mayer et al., 2010).
Additional dysfunction of the autonomous nervous
system, such as HSCR, NB, ocular defects, cardiac
rythm alterations, etc., may be found in association
with the especially largest polyAla expansions (WeeseMayer et al., 2010).
Disease
Congenital Central Hypovention Syndrome (CCHS).
Prognosis
Congenital central hypoventilation syndrome (CCHS)
is characterized by alveolar hypoventilation and
autonomic dysregulation.
It is a life-long, still untreatable disease.
Oncogenesis
Among PARMs, only subjects with the 20/29 and
20/33 genotypes have been identified to have tumors of
neural
crest
origin
(ganglioneuromas
and
ganglioneuroblastomas).
No children with genotypes 20/24 to 20/28 have been
identified with tumors of neural crest origin (WeeseMayer et al., 2010).
Somatic
No CCHS patient has ever been proven to be a somatic
mosaic for PHOX2B mutation; however, somatic and
therefore germline mosaicism has been demonstrated in
a proportion of CCHS parents (Parodi et al., 2008;
Bachetti et al., 2011; Bachetti et al., 2013).
Somatic PHOX2B mutations have been identified in
NB cell lines and NB tumor samples as reported in the
Table 1.
Note
There is a clear correlation between types of PHOX2B
mutations and clinical manifestations. Indeed, while the
vast majority of PHOX2B mutations identified in
isolated Congenital Central Hypoventilation Syndrome
(CCHS) are PARMs (Polyalanine repeats mutation),
those present in HSCR-NB (Hirschsprung's diseaseneuroblastoma) associated CCHS are non-PARMs
(NPARM), namely either missense mutations or
nucleotide deletions/insertions causing frameshifts of
the open reading frame.
Moreover, inherited and de novo missense and
frameshift mutations in exons 2 and 3 of the PHOX2B
gene have been detected in both sporadic (NB) and
syndromic (NB+CCHS) cases (Weese-Mayer et al.,
2010; Bachetti et al., 2005b), thus suggesting that
PHOX2B may play a role in isolated NB pathogenesis.
Table 1 reports PHOX2B mutations detected so far,
with detailed description of the nucleotide and
aminoacid changes. Associated phenotypes are also
annotated.
NPARMS: non polyAla repeat
mutations, either germline or somatic
(i.e. missense, nonsense, indels and
loss of the stop codon mutations)
Note
These mutations, listed in Table 1, include missense,
nonsense, loss of stop codon and small indels
mutations.
Disease
Neuroblastoma and/or Hirschsprung's disease (either
sporadic or in association with CCHS).
Implicated in
PARMs (from +4 to +13 polyAla
expansions)
Neuroblastoma
Note
In neuroblastoma cell lines and tumor samples,
PHOX2B expression has turned out to be much higher
than in normal tissues (Longo et al., 2008). Moreover,
LOH in about 10% of the tumors and rare aberrant CpG
Note
A correlation between the length of the expanded tract
and the severity of the CCHS phenotype has already
been reported (Matera et al., 2004; Weese-Mayer et al.,
2010).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
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PHOX2B (paired-like homeobox 2b)
Bachetti T, Ceccherini I
Benailly HK, Lapierre JM, Laudier B, Amiel J, Attié T, De
dinucleotide methylation of 500 bp of PHOX2B
promoter region have been reported as NB associated
molecular event (De Pontual et al., 2007).
Blois MC, Vekemans M, Romana SP. PMX2B, a new
candidate gene for Hirschsprung's disease. Clin Genet. 2003
Sep;64(3):204-9
Breakpoints
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. Molecular
analysis of congenital central hypoventilation syndrome. Hum
Genet. 2003 Dec;114(1):22-6
Note
A 5-Mb deletion at chromosome 4p12-p13 that
included the PHOX2B gene was found in a 16-monthold girl with developmental delay, severe hypotonia,
facial dysmorphism, and short-segment Hirschsprung
disease
thus
suggesting
that
PHOX2B
haploinsufficiency may predispose to colonic
aganglionosis (Benailly et al,. 2003).
Interestingly, other cytogenetic interstitial deletions,
spanning from 0.29 to 2.6 Mb across the PHOX2B
locus, have been detected in patients affected with
atypical disorders, apparently sharing a loss of
function/haploinsufficiency pathogenic mechanism,
namely apparent-life threatening event including,
Hirschsprung
disease,
transient
neonatal
hypoventilation
and
dysmorphic
features.
Neuroblastoma did not develop in any of these cases
(Jennings et al., 2012).
Weese-Mayer DE, Berry-Kravis EM, Zhou L, Maher BS,
Silvestri JM, Curran ME, Marazita ML. Idiopathic congenital
central hypoventilation syndrome: analysis of genes pertinent
to early autonomic nervous system embryologic development
and identification of mutations in PHOX2b. Am J Med Genet A.
2003 Dec 15;123A(3):267-78
Matera I, Bachetti T, Puppo F, Di Duca M, Morandi F,
Casiraghi GM, Cilio MR, Hennekam R, Hofstra R, Schöber JG,
Ravazzolo R, Ottonello G, Ceccherini I. PHOX2B mutations
and polyalanine expansions correlate with the severity of the
respiratory phenotype and associated symptoms in both
congenital and late onset Central Hypoventilation syndrome. J
Med Genet. 2004 May;41(5):373-80
Mosse YP, Laudenslager M, Khazi D, Carlisle AJ, Winter CL,
Rappaport E, Maris JM. Germline PHOX2B mutation in
hereditary neuroblastoma. Am J Hum Genet. 2004
Oct;75(4):727-30
Samad OA, Geisen MJ, Caronia G, Varlet I, Zappavigna V,
Ericson J, Goridis C, Rijli FM. Integration of anteroposterior
and dorsoventral regulation of Phox2b transcription in cranial
motoneuron
progenitors
by
homeodomain
proteins.
Development. 2004 Aug;131(16):4071-83
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This article should be referenced as such:
Trochet D, Mathieu Y, Pontual Ld, Savarirayan R, Munnich A,
Brunet JF, Lyonnet S, Goridis C, Amiel J. In Vitro studies of
non poly alanine PHOX2B mutations argue against a loss-offunction mechanism for congenital central hypoventilation.
Hum Mutat. 2009 Feb;30(2):E421-31
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11)
Bachetti T, Ceccherini I. PHOX2B (paired-like homeobox 2b).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(11):740-745.
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