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Gene Section
Review
PAX3 (paired box gene 3 (Waardenburg
syndrome 1))
Eun Hyun Ahn, Frederic G Barr
University of Pennsylvania, School of Medicine,Dept of Pathology and Laboratory Medicine, 506 Stellarchance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA
Published in Atlas Database: July 2006
Online updated version: http://AtlasGeneticsOncology.org/Genes/PAX3ID70ch2q35.html
DOI: 10.4267/2042/38353
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Expression
Identity
Hugo: PAX3
Other names: CDHS; HUP2;
MGC120382;
MGC120383;
MGC134778; WS1; WS3; HGNC8617
Location: 2q35-2q36.1
Based on experiments in the mouse, Pax3 is expressed
in the spinal cord and selected regions of the brain.
Pax3 is expressed in the neural crest and is involved in
development of neural crest derivatives including
spinal ganglia, melanocytes and Schwann cells. Pax3
expression is also detected in somite compartments that
give rise to embryonic skeletal muscle progenitors, and
in cells that give rise to skeletal muscle compartments
of the developing limb buds. In addition, Pax3 (as well
as Pax7 ) is also expressed in a proliferating population
without skeletal muscle specific markers that reside
within limb and trunk muscles throughout later
development; and a subset of adult muscles
subsequently contain Pax3-expressing satellite cells.
MGC120381;
MGC120384;
DNA/RNA
Description
The PAX3 gene extends approximately 100 kb and
consists of 10 exons.
Transcription
In human tissues and tumors, seven alternatively
spliced transcripts have been described. The abundant
transcripts, which have been studied in neural-related
tumor specimens and cell lines, appear to consist of the
first eight or nine exons (PAX3c and PAX3d). In
addition, there is also frequent alternative splicing at
the 5¹ end of exon 3 in human tissues and tumors that
results in inclusion or exclusion of a single codon
encoding a glutamine residue.
Localisation
Nucleus.
Function
PAX3 is a transcription factor characterized by three
highly converved motifs in the N-terminal region: a
paired box DNA binding domain, an intervening
octapeptide of unclear function, and a homeobox DNA
binding domain. The C-terminal region contains a
proline-, serine- and threonine-rich transactivation
domain.
Based on the studies of the mutant Pax3 alleles in the
mouse (Splotch phenotype) as well as studies of
patients with mutant PAX3 genes (see below), Pax3 is
postulated to have a crucial role in the development of
the early neural structures, derivatives of the neural
crest, and skeletal musculature. In these developmental
processes, there is evidence that the transcriptional
function of Pax3 impacts at four biological activities:
Protein
Description
479 amino acids, 53.0 kDa (8 exon form, PAX3c) or
484 amino acids, 53.5 kDa (9 exon form, PAX3d). The
isoform containing the variable glutamine residue at the
exon 3/4 junction is referred to as Q+, while the
isoform lacking the Q is designated as Q-.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
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PAX3 (paired box gene 3 (Waardenburg syndrome 1))
Ahn EH, Barr FG
1. proliferation
2. apoptosis
3. differentiation
4. motility
Implicated in
Alveolar Rhabdomyosarcoma (ARMS)
Homology
PAX3 shares homology through the conserved paired
box with eight other members of the PAX gene family.
In particular, within the PAX gene family, PAX3 and
PAX7 constitute a subfamily characterized by a paired
box, intervening octapeptide and complete homeobox
as well as homology between the C-terminal
transcriptional activation domains.
Mutations
Germinal
Germ-line sequence changes involving the PAX3 gene
are found in Waardenburg syndrome type I and type
III, a non-neoplastic autosomal dominant disorder
characterized by hearing loss and pigmentary
abnormalities. The majority of these alterations are
nucleotide substitutions resulting in missense
mutations, usually in the regions encoding the paired
box or homeobox. A smaller number of base
substitutions at splicing sites and small deletions and
insertions, which usually alter the reading frame, have
also been reported. Finally, there have also been several
cases of large deletions and other rearrangements of
chromosome 2.
Somatic
The PAX3 gene is rearranged by the characteristic and
recurrent acquired chromosomal translocation t(2;13)(q35;q14) - in the myogenic soft tissue cancer
alveolar rhabdomyosarcoma. As a result of this 2;13
translocation, portions of the PAX3 gene are
juxtaposed with portions of the FKHR (also called
FOXO1A) gene on chromosome 13. In particular, the
5' region of PAX3 including the first seven exons is
joined to the 3' region of FKHR including its last two
exons. Though the reciprocal chimeric gene is also
generated, this PAX3-FKHR chimeric gene is more
consistent and highly expressed, and results in
expression of a fusion protein consisting of the intact
PAX3 N-terminal DNA binding domain fused inframed to the intact FKHR C-terminal transcriptional
activation domain. This fusion protein functions as an
aberrant transcription factor. In rare cases of alveolar
rhabdomyosarcoma, PAX3 is fused to alternative Cterminal partners - MLLT7 (AFX, FOXO4) and
NCOA1.
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
a) Diagram of t(2;13)(q35;q14) and t(1;13)(p36;q14)
chromosomal translocations generating PAX3-FKHR and
PAX7-FKHR fusions.
b) Generation of chimeric genes by the t(2;13)(q35;q14)
translocation in ARMS. The exons of the wild-type and fusion
genes are shown as boxes above each map and the
translocation breakpoint distributions are shown as line
segments below the map of the wild-type genes.
c) Comparison of wild-type and fusion products associated with
the 2;13 and 1;13 translocations. The paired box, octapeptide,
homeobox and fork head domain are indicated as open boxes,
and transcriptional domains (DNA binding domain, DBD;
transcriptional activiation domain, TAD; transcriptional
inhibitory domain, TID) are shown as solid bars. The sites
phosphorylated by Akt are indicated by stars, and the
alternative splice in the paired box is shown by an arrowhead.
The vertical dash line indicates the translocation fusion point.
{Reproduced from: Barr (2001) Oncogene 20: 5736- 5746}
254
PAX3 (paired box gene 3 (Waardenburg syndrome 1))
Ahn EH, Barr FG
target genes and ultimately contributes to tumourigenic
behavior.
Disease
ARMS is one subtype of a family of pediatric soft
tissue tumors that is related to the skeletal muscle
lineage.
In
contrast
to
the
embryonal
rhabdomyosarcoma (ERMS), the other major subtype
in this family, ARMS often occurs in adolescents and
young adults, with primary tumors located in the
vicinity of skeletal muscle, such as in the extremities
and trunk.
Prognosis
In contrast to the favorable outcome in most cases of
ERMS, ARMS is associated with an unfavorable
prognosis. In the IRS-IV clinical trial, the three year
failure-free survival rate was 66% for patients
presenting without metastatic disease and 16% for
patients presenting with metastatic disease (compared
to 83% and 37% for non-metastatic and metastatic
ERMS, respectively). This unfavorable prognosis in
ARMS is related to the propensity for early and wide
dissemination, often involving bone marrow, and to
poor response to chemotherapy.
Cytogenetics
Chromosomal
studies
identified
nonrandom
chromosomal translocations that distinguish the
majority of ARMS tumors from ERMS and other
pediatric solid tumors. The t(2;13)(q35;q14)
translocation is the most prevalent and the
t(1;13)(p36;q14) is identified in a smaller subset of
cases.
Hybrid/Mutated Gene
The 2;13 or 1;13 chromosome translocation juxtapose
the PAX3 gene on chromosome 2 or the PAX7 gene on
chromosome 1 with the FKHR (FOXO1A) gene on
chromosome 13 to generate two chimeric genes. These
chimeric genes are transcribed to generate chimeric
transcripts, of which the PAX3-FKHR and PAX7FKHR transcripts are the most highly and consistently
expressed of the pair of potential products. Based on
RT-PCR assays for these chimeric transcripts,
approximately 60% of ARMS cases express PAX3FKHR and thus contain the t(2;13), 20% express
PAX7-FKHR and thus contain the t(1;13), and 20% are
fusion-negative.
Oncogenesis
The PAX3-FKHR and PAX7-FKHR chimeric genes
encode fusion proteins that contain the intact DNA
binding domain of PAX3 or PAX7 in the N-terminal
region fused in frame with a C-terminal FKHR
(FOXO1A) segment containing the transactivation
domain. The chromosomal changes in ARMS result in
high level expression, potent transcriptional activity,
and constitutive nuclear localization of the PAX3FKHR or PAX7-FKHR fusion products. The end result
is exaggerated activity at multiple biological levels that
converges to inappropriate activation of PAX3/PAX7
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
Waardenburg syndrome (type I et III)
Disease
Waardenburg syndrome (WS) is an inherited
autosomal-dominant
disorder
characterized
by
sensorineural hearing loss (of varying severity),
dystopia canthorum (lateral displacement of inner
corners of eye), and pigmentary disturbances of the
eye, skin and hair. It is a common cause of inherited
deafness in infants. Depending on additional
symptoms, WS is classified into four types, WS1, WS2,
WS3, and WS4, with only WS1 and WS3 being
associated with PAX3 mutations. Deletions, insertion,
base pair substitution, or dominant point mutations of
PAX3 cause WS1 and WS3. WS3 (Klein-Waardenburg
syndrome) is similar to WS1 but WS3 is also
characterized by musculoskeletal abnormalities, usually
involving the upper limbs. It should be noted that WS3
is often associated with deletions of the long arm of
chromosome 2 involving multiples genes including
PAX3 whereas WS1 is generally is associated with
mutations within the PAX3 gene. WS2 is heterogenous,
being caused by mutations in the MITF gene in some
but not all affected families. WS4 is caused by
mutations in the EDN3, EDNRB, or SOX10 ID genes.
Craniofacial-deafness-hand syndrome
(CDHS)
Disease
Craniofacial-deafness-hand syndrome is inherited as an
autosomal dominant mutation. CDHS shows clinical
characteristics of the absence or hypoplasia of the nasal
bones, profound sensorineural deafness, a small and
short nose with slitlike nares, hypertelorism, short
palpebral fissures, and limited movement at the wrist
and ulnar deviations of the fingers. A missense
mutation (Asn47Lys) in the paired domain (exon 2) of
PAX3 was detected in a family of three (a mother and
two children) first reported with this syndrome.
Breakpoints
Xq13 (MLLT7)
2q35 (PAX3)
13q14 (FOXO1A)
2p23 (NCOA1)
PAX3 and partners. Editor 08/2005.
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PAX3 (paired box gene 3 (Waardenburg syndrome 1))
Ahn EH, Barr FG
the Pax3 homeodomain recognition helix but not the Pax3
paired-box DNA binding domain. Mol Cell Biol 1999;19:594601.
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This article should be referenced as such:
Ahn EH, Barr FG. PAX3 (paired box gene 3 (Waardenburg
syndrome 1)). Atlas Genet Cytogenet Oncol Haematol.2006;
10(4):253-256.
Lam PY, Sublett JE, Hollenbach AD, Roussel MF. The
oncogenic potential of the Pax3-FKHR fusion protein requires
Atlas Genet Cytogenet Oncol Haematol. 2006;10(4)
256