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|Mutation Type||critical splice donor site (1 bp from exon)|
|Coordinate||78,122,590 bp (GRCm38)|
|Base Change||C ⇒ T (forward strand)|
|Gene Name||paired box 3|
|Chromosomal Location||78,101,267-78,197,134 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]
PHENOTYPE: Effects on homozygotes for mutations in this gene vary in severity and include embryonic to perinatal death, malformations of neural tube, spinal ganglia, heart, vertebral column, hindbrain and limb musculature. Heterozygotes have white belly spots and variable spotting on the back and extremeties. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000004994] [ENSMUSP00000084320]|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Local Stock||Live Mice|
|Last Updated||2016-05-13 3:09 PM by Peter Jurek|
|Record Created||2015-01-14 3:38 PM by Kimberly Hawkins|
The Widget phenotype was identified among N-ethyl-N-nitrosourea (ENU)-induced mice of the pedigree R2473, some of which exhibited variable white spotting of the fur (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 62 mutations. A mutation in Pax3 was presumed to be causative because the Widget belted phenotype mirrors that of other Pax3 alleles (see MGI). The mutation in Pax3 is a G to A transition at base pair 78,122,590 (v38) on chromosome 1, or base pair 74,927 in the GenBank genomic region NC_000067 within the donor splice site of intron 6. The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in skipping of the 166-nucleotide exon 6 (out of 9 total exons), resulting in a frame-shift and coding of 60 aberrant amino acids followed by a premature stop codon.
Genomic numbering corresponds to NC_000067. The donor splice site of intron 6, which is destroyed by the Widget mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Paired box (PAX) 3 [PAX3; alternatively, melanocyte specific factor (MSF)] is a member of the PAX family of transcription factors (1). The paired domain (PD; amino acids 34-159) and homeodomain (HD; amino acids 219-281) of PAX3 are both DNA-binding domains that can act independently or together to bind target genes [Figure 2; (2-6;6-8)]. For example, the PD is required for PAX3 binding to the Tyrp1 and Dct promoters, while both the HD and PD are required for binding to the Mitf promoter (5). The structure of the highly conserved human PAX3 HD in complex with DNA has been solved [Figure 3; PDB:3CMY; (9)]. The PAX3 HD folds into a prototypical HD fold of three α-helices (α1, α2, and α3), connected by short loops, and an extended N-terminal arm which is disordered in the absence of DNA (9). Upon interaction with DNA, the arm inserts into the major groove to interact with bases in both strands of the DNA as well as with the sugar-phosphate backbone. Serine 50 is essential for specifying the DNA sequence PAX3 will bind. Ser50 binds DNA that has two inverted TAAT motifs separated by either two (P2) or three (P3) base pairs (10). Two HDs from adjacent PAX3 molecules bind to DNA in a head-to-head arrangement. Helices α1 and α2 are arranged in an antiparallel fashion relative to each other and perpendicular to α3, which fits into the major groove. PAX3 also has an octapeptide motif (HSIDGILS; amino acids 186-193) and a C-terminal transcription activation (TA) domain (amino acids 282-484). The octapeptide may function as a binding motif for a DNA methylation or demethylation factor (7;8). The TA domain modulates the DNA binding specificity of PAX3 (11). PAX3 function may be regulated by phosphorylation and ubiquitination; Ser205 was identified as a site of phosphorylation on PAX3 (12;13).
Human PAX3 undergoes alternative splicing to generate multiple transcripts [Figure 4 and Table 1; (6;14-17)]. The multiple protein isoforms differ in structure and the activities of the paired, homeodomain, and transactivation domains (14;18;19). Mouse Pax3 only has one documented isoform.
Pax3 is expressed during early embryogenesis and development (6). Pax3 is expressed starting at approximately embryonic day (E)8.5 in the dorsal neural tube, developing hindbrain, mesencephalon, and prosencephalon (6;27;28). Pax3 is expressed in the presomitic mesoderm and throughout the epithelial somite, before expression is restricted to the dermomyotome (29). Pax3 expression persists as melanoblasts develop and migrate from the neural crest and as the melanocytes localize in developing hair follicles (30). Pax3 expression is lost in neurons when maturing neurons exit the ventricular zone and migrate through the intermediate zone. Pax3 has not been detected in the adult mouse. Pax3 downregulation during differentiation of neural crest precursors is essential for proper cranial development. Persistent Pax3 expression in neural crest derivatives results in cleft palate, ocular defect, malformation of the sphenoid bone, and perinatal lethality (31).
The PAX protein family regulates pattern formation, morphogenesis, cellular differentiation, and organogenesis by activating (or repressing) genes that encode secreted proteins, cell surface receptors, cell cycle regulators, and transcription factors.A list of select PAX3 targets and there respective functions in the above-described developmental processes are described in Table 2 (49). PAX3 is essential for normal development of the peripheral nervous system, the trigeminal (cranial nerve V), superior (IX), and jugular (X) ganglia as well as the frontal, ophthalmic, and spinal accessory nerves (32;33).
PAX3 controls cardiovascular development. PAX3 is essential for cardiac outflow tract septation in the mouse (34). Mice with homozygous mutations in Pax3 exhibit persistent truncus arteriosus whereby a single vessel emerging from the embryonic heart does not divide into the proximal aorta and the pulmonary artery. Double outlet right ventricle, a less-severe cardiovascular disorder, is also sometimes observed in which the truncus arteriosus is septated, but the vessels emerge from the right ventricle and a ventribular septal defect allows for outlet of blood from the left ventricle (35). The Pax3 mutant mice can also display thinning of the compact layer of the embryonic heart and defects in excitation-contraction coupling due to decreased inward calcium current (34). Defects in cardiovascular development are proposed to be due abnormal cardiac neural crest cell migration or function.
In the muscular system, PAX3 is essential for limb muscle precursor migration, but not for differentiation (36); PAX3 is not necessary for trunk muscle development (37). Newly formed somites are a grouping of epithelial cells that differentiate into sclerotome and dermomyotome upon signals from the ventral midline (37;38). The dermamyotome subsequently forms the dermis and muscle. Skeletal muscles in vertebrates are derived from two bilateral rows of somites on either side of the neural tube. Axial muscles are derived from the medial portion of the somite, while the limb muscles develop from the lateral somite (39). Precursors of limb muscles are derived from the lateral portion of the dermomytomes immediately adjacent to the limb buds. The cells in the limb bud subsequently differentiate and fuse to form primary myotubes of limb muscles. PAX3 and PAX7 are upstream regulators of myogenesis (36;37;40). PAX3 is expressed in myogenic precursor cells that will migrate from the somite to become the musculature of the abdominal walls and limbs (37). PAX3 expression marks migrating myogenic progenitor cells that have not activated myogenic determination genes.
During melanocyte development in the embryo, PAX3 and SOX10 (mutated in Dalmatian) are both required for the expression of Mitf, which is required for melanoblast survival after migration from the dorsal neural tube to the migration staging area [Figure 5; (41-43)]. The melanoblast population is derived from a much larger number of neural crest progenitors with melanoblasts migrating axially as well as laterally (44). Most melanoblasts migrate from the cervical region of the embryo and different cell dispersion mechanisms may operate in the head and trunk regions. Three distinct phases occur in trunk melanoblast development: a primary proliferative phase, followed by migration, leading to a second phase of proliferation by the dispersed cells. PAX3, SOX10, MITF, and LEF1 bind directly to the Dct promoter, which encodes an enzyme necessary for melanin pigment production in melanocytes (45-48). PAX3 and MITF share the same binding site within the Dct promoter and compete for occupancy (46). Expression of Tyr (see the record for ghost) and Tyrp1 (see the record for chi), additional melanin-generated enzymes in pigment cells, is induced a few days later.
Mutations in PAX3 are linked to craniofacial-deafness-hand syndrome [OMIM: #122880; (66;67)] and alveolar rhabdomyosarcoma 2 [OMIM: #268220; (68)] as well as Waardenburg syndrome (WS) type 1 [WS1; OMIM: #193500; (69)] and WS type 3 (WS3; alternatively, Klein-Waardenburg syndrome; OMIM: #148820) (70;71)]. Patients with craniofacial-deafness-hand syndrome exhibit absence or hypoplasia of the nasal bones, sensorineural deafness, small or short noses with slit-like nares, hypertelorism, short palpebral fissures, and reduced movement at the wrist. Alveolar rhapdomyosarcomas are caused by chromosomal translocations that encode either a PAX3-FKHR(FOXO1A) or PAX7-FKHR fusion protein that subsequently acts as a strong transcriptional activator of transcription factors and signaling components that affect myogenesis and transform myoblast and fibroblast cell lines in culture [reviewed in (29;72)]. The PAX3/FKHR(FOXO1A) fusion protein is able to activate expression of Pdgfar (platlet-derived growth factor alpha receptor); PAX3 alone does not regulate expression of Pdgfar (73). WS is an autosomal dominant condition causes variable degrees of deafness, dystopia canthorum (i.e., lateral displacement of the eyes), pigment defects (e.g., white forelock and differently colored eyes), and limb muscle hypoplasia (WS3 only).
White-spotting mutants are a subclass of coat color mutants in mice. These mutants exhibit white spots that include belly spots, head spots, belts spanning the caudal trunk region, piebald spotting and peppering. Unlike color variations in mice which are typically due to alterations in melanin production, distribution, or deposition into hair and/or skin, white-spotting mutants are often the result of improper melanoblast development or survival. The lack of pigment in the adult reflects the absence of mature melanocytes in that area due to defects at various stages of melanocyte development including proliferation, survival, migration, invasion of the integument, hair follicle entry and melanocyte stem cell renewal (74;75). White-spotted mutants have been ascribed to a variety of genes including ones encoding the transcription factors MITF and SOX10, the KIT receptor tyrosine kinase (mutated in Casper and Pretty2), a G-protein coupled receptor and its ligand (EDNRB (mutated in gus-gus) and endothelin-3 respectively), a transmembrane protein (Mucolipin 3) as well as ADAMTS-20 (mutated in splotch2), an ECM associated metalloprotease (74;75).
A spontaneous white belly spot phenotype was observed in a mouse, designated as Splotch, and attributed to a spontaneous splice acceptor site mutation in Pax3 (76;77). Homozygous Splotch mice are embryonic lethal by embryonic day (E) 14 due to neural tube closure defects in the lumbo-sacral area (i.e., spina bifida), absence (or reduction in size) of the dorsal root ganglia, exencephaly, abnormal formation of the cardiac outflow tract, and absent limb musculature (37). Heterozygous Splotch mice are viable and exhibit variable white belly spotting. Another Splotch allele, Splotch-delayed, results in a missense mutation within the paired domain and results in a less severe phenotype than observed in Splotch mice (i.e., only the spina bifida phenotype) and the mice survive until shortly after birth (78-80). Several other Splotch alleles have also been identified including Splotch4H (a large deletion in Pax3) and Splotch2H (an intragenic deletion) (77;81-83). Each of these mutants disply variable white belly spotting in the heterozygote. Two ENU-induced Pax3 mutants (Pax3wbs and Pax3Sp-1Xzg) exhibit variable white belly spotting in heterozygous mice (58;84). The Pax3wbs phenotype was linked to a missense mutation at base pair 319 in exon 2, which caused a premature stop codon at amino acid 107 (58). Homozygous Pax3wbs mice were embryonic lethal by E14.5 (58), similar to the Splotch mice (76). Similar to other Pax3 mutants, heterozygous Widget mice exhibit white belly spotting; the phenotype(s) in homozygous mice were not examined. Pigment defects in Pax3 mutants are attributed to reduced melanoblast numbers, not in defects through the migratory pathway (85).
|Primers||Primers cannot be located by automatic search.|
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|Science Writers||Anne Murray|
|Authors||Kimberly Hawkins and Jamie Russell|
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