Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PAX3
SNOMEDCT: 1010606009, 237918004, 702362004;
Cytogenetic location: 2q36.1 Genomic coordinates (GRCh38): 2:222,199,887-222,298,998 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.1 | Craniofacial-deafness-hand syndrome | 122880 | Autosomal dominant | 3 |
| Rhabdomyosarcoma 2, alveolar | 268220 | Somatic mutation | 3 | |
| Waardenburg syndrome, type 1 | 193500 | Autosomal dominant | 3 | |
| Waardenburg syndrome, type 3 | 148820 | Autosomal dominant; Autosomal recessive | 3 |
Based on amino acid sequence homology and common genomic exon/intron organization (Goulding et al., 1991), Burri et al. (1989) suggested that the human homolog of the mouse Pax3 gene is the HUP2 gene. Goulding et al. (1991) found that the product of the mouse Pax3 gene is a DNA-binding protein expressed during early neurogenesis. The HuP2 sequence contains 3 exons, which Tassabehji et al. (1992) designated exons 2, 3, and 4 because of their correspondence with exons 2, 3, and 4 of the mouse Pax3 gene, which has 5 exons. Tassabehji et al. (1992) found that the HuP2 sequence showed 92% nucleotide homology and 100% amino acid homology with the mouse Pax3 sequence over amino acids 2 to 121.
Tsukamoto et al. (1994) cloned PAX3 by 5-prime and 3-prime RACE of an adult cerebellum cDNA library. They identified 2 alternatively spliced isoforms, which they called PAX3A and PAX3B. The deduced PAX3A and PAX3B transcription factors contain 215 and 206 amino acids, respectively. RT-PCR detected high PAX3B expression in esophagus and stomach, with moderate levels in cerebellum, liver, and pancreas. PAX3B was not detected in lung, ovary, uterus, and cardiac muscle. PAX3A was expressed only in cerebellum, esophagus, and skeletal muscle.
Barber et al. (1999) cloned PAX3 from a skeletal muscle cDNA library. They also cloned mouse Pax3. Barber et al. (1999) identified several alternatively spliced isoforms in adult skeletal muscle and in mouse embryos, including 1 that shares significant evolutionary conservation between quail, mouse, and human.
Macina et al. (1995) determined that the PAX3 gene contains 8 exons and spans more than 100 kb. Analysis of the intronic translocation breakpoint region associated with alveolar rhabdomyosarcoma (268220) revealed a pair of inverted Alu repeats and a pair of inverted (GT)n-rich microsatellite repeats. The 5-prime region contains a microsatellite, putative CAAT, TATA, and CAP sites, and several binding sites for AP1 (see 165160) and SP1 (189906).
Barber et al. (1999) determined that the PAX3 gene contains 10 exons.
By analysis of an inversion breakpoint associated with Waardenburg syndrome type 1 (WS1; 193500), Tsukamoto et al. (1992) and Ishikiriyama (1993) mapped the PAX3 gene to chromosome 2q35.
Bondurand et al. (2000) showed that SOX10 (602229), in synergy with PAX3, strongly activates MITF (156845) expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in Waardenburg syndrome (see 193500) could explain the auditory/pigmentary symptoms of this disease.
Mutations in the MITF and PAX3 genes, encoding transcriptions factors, are responsible for Waardenburg syndrome 2A (WS2A; 193510) and WS1 (193500)/WS3 (148820), respectively. Tachibana et al. (1996) showed that MITF transactivates the gene for tyrosinase (see 606933), a key enzyme for melanogenesis, and is critically involved in melanocyte differentiation. Absence of melanocytes affects pigmentation in the skin, hair, and eyes, and hearing function in the cochlea. Therefore, hypopigmentation and hearing loss in WS2A are likely to be the results of an anomaly of melanocyte differentiation caused by MITF mutations. Watanabe et al. (1998) showed that PAX3 transactivates the MITF promoter. They further showed that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain failed the recognize and transactivate the MITF promoter. These results provided evidence that PAX3 directly regulates MITF, and suggested that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1.
Ridgeway and Skerjanc (2001) showed that expression of Pax3 induced myogenesis in a mouse pluripotent stem cell line. Pax3 induced expression of the transcription factor Six1 (601205), its cofactor Eya2 (601654), and the transcription factor Mox1 (600147), prior to inducing expression of MyoD (159970) and myogenin (159980). Expression of dominant-negative Pax3 resulted in loss of expression of Six1, Eya2, and endogenous Pax3, as well as downregulation of Mox1 expression. Pax3 expression had no effect on cardiogenesis in this cell line. Ridgeway and Skerjanc (2001) concluded that Pax3 controls a cascade of transcriptional events that are necessary and sufficient for skeletal myogenesis.
The Sox10 and Pax3 transcription factors can directly regulate both MITF and RET (164761) in a synergistic fashion. Lang and Epstein (2003) showed that Pax3 and Sox10 can physically interact; this interaction contributes to synergistic activation of a conserved RET enhancer, and it explains why Sox10 mutants that cannot bind DNA still retain the ability to activate this enhancer in the presence of Pax3. However, in the context of the MITF gene, Pax3 and Sox10 must each bind independently to DNA in order to achieve synergy. These observations appear to explain the phenotype in the mild form of Yemenite deaf-blind syndrome caused by a specific SOX10 mutation (602229.0005) in the HMG box that abrogates DNA binding without disrupting association with PAX3.
Pritchard et al. (2003) identified an alternatively spliced isoform of mouse Pax3 produced by skipping exon 8. Deletion of exon 8 removes most of the Pax3 transcriptional activation domain. Pritchard et al. (2003) demonstrated that this isoform is transcriptionally inactive, but it can inhibit the activity of the full-length protein.
Relaix et al. (2005) identified a new cell population that expresses the transcription factors Pax3 and Pax7 (167410) but no skeletal muscle-specific markers. These cells are maintained as a proliferating population in embryonic and fetal muscles of the trunk and limbs throughout development. Using a stable green fluorescent protein (GFP) reporter targeted to Pax3, Relaix et al. (2005) demonstrated that they constitute resident muscle progenitor cells that subsequently become myogenic and form skeletal muscle. Late in fetal development, these cells adopt a satellite cell position characteristic of progenitor cells in postnatal muscle. In the absence of both Pax3 and Pax7, further muscle development is arrested and only the early embryonic muscle of the myotome forms. Cells failing to express Pax3 or Pax7 die or assume a nonmyogenic fate. Relaix et al. (2005) concluded that this resident Pax3/Pax7-dependent progenitor cell population constitutes a source of myogenic cells of prime importance for skeletal muscle formation.
Lang et al. (2005) described the molecular details of a nodal point in adult melanocyte stem cell differentiation in which PAX3 simultaneously functions to initiate a melanogenic cascade while acting downstream to prevent terminal differentiation. PAX3 activates expression of MITF and at the same time competes with MITF for occupancy of an enhancer required for expression of dopachrome tautomerase (191275), an enzyme that functions in melanin synthesis. PAX3-expressing melanoblasts are thus committed but undifferentiated until PAX3-mediated repression is relieved by activated beta-catenin (see 116806). Lang et al. (2005) concluded that a stem cell transcription factor can both determine cell fate and simultaneously maintain an undifferentiated state, leaving a cell poised to differentiate in response to external stimuli.
In mice, de Morree et al. (2019) demonstrated that variation in muscle stem cell activation rate among different muscles (for example, limb versus diaphragm muscles) is determined by the levels of the transcription factor Pax3. De Morree et al. (2019) showed that Pax3 levels are controlled by alternative polyadenylation of its transcript, which is regulated by the small nucleolar RNA U1 (SNRNP70; 180740). Isoforms of the Pax3 mRNA that differed in their 3-prime UTRs were differentially susceptible to regulation by microRNA miR206 (611599), which resulted in varying levels of the Pax3 protein in vivo. De Morree et al. (2019) concluded that their findings highlighted a previously unrecognized mechanism of the homeostatic regulation of stem cell fate by multiple RNA species.
PAX3/FKHR Fusion Protein
Fredericks et al. (1995) demonstrated expression of a 97-kD PAX3/FKHR (FOXO1A; 136533) fusion protein in a t(2;13)-positive rhabdomyosarcoma cell line (see CYTOGENETICS section) and verified that a single polypeptide contained epitopes derived from each protein. The fusion protein was localized to the nucleus in these cells, as was wildtype PAX3 in cells lacking the translocation. They found that DNA binding of the fusion protein was significantly impaired relative to that of PAX3 despite the fact that the 2 proteins had identical PAX DNA-binding domains. However, the fusion protein was a much more potent transcriptional activator than PAX3. Thus, the fusion protein may function as an oncogenic transcription factor by enhancing activation of normal PAX3 target genes.
Sublett et al. (1995) found that the PAX3/FKHR hybrid protein binds DNA in vitro in a sequence-specific manner and transactivates the expression of artificial reporter genes, suggesting that its aberrant expression could subvert the transcriptional programs that normally control the growth, differentiation, and survival of primitive myogenic precursors in vivo.
Using a retroviral vector, Scheidler et al. (1996) introduced the PAX3/FKHR fusion gene into chicken embryo fibroblasts. Expression of the PAX3/FKHR protein in these cells led to transformation: the cells became enlarged, grew tightly packed and in multiple layers, and acquired the ability for anchorage-independent growth.
The PAX3/FKHR chimeric gene possesses transforming properties. To investigate the actions of these transcription factors, Khan et al. (1999) introduced both PAX3 and PAX3/FKHR into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a mouse cDNA microarray containing 2,225 elements. They found that PAX3/FKHR but not PAX3 activated a myogenic transcription program including the induction of transcription factors Myod (159970), myogenin (159980), Six1 (601205), and Slug (602150), as well as a battery of genes involved in several aspects of muscle function.
Roeb et al. (2007) found that myoblasts from transgenic mice expressing PAX3/FOXO1 under control of the PAX3 promoter were unable to complete myogenic differentiation because of an inability to upregulate p57(Kip2) (CDKN1C; 600856) transcription. This defect was caused by reduced levels of the transcriptional activator Egr1 (128990) resulting from a direct, destabilizing interaction with PAX3/FOXO1. Neither PAX3 nor FOXO1 shared the ability to regulate p57(Kip2) transcription.
Tsukamoto et al. (1992) cloned and characterized an inversion breakpoint of the inv(2)(q35q37.3) paracentric inversion reported by Ishikiriyama et al. (1989) in a child with Waardenburg syndrome type 1. Genomic cosmid clones containing the HUP2 gene were isolated from a library constructed from the patient's DNA. One of the clones contained the inversion breakpoint and revealed signals at both 2q35 and 2q37 by fluorescence in situ hybridization, indicating that the HUP2 gene had been disrupted by the inversion. The results suggested that the gene is situated at the more proximal breakpoint 2q35 because one cosmid clone, presumably derived from the normal allele, hybridized only to 2q35.
PAX3/FKHR Fusion Gene
A frequent finding in alveolar rhabdomyosarcomas is the translocation t(2;13)(q35;q14). Barr et al. (1993) determined that the PAX3 gene is affected by the t(2;13) translocation associated with alveolar rhabdomyosarcoma. The rearrangement breakpoints occurred within an intron downstream of the paired box and homeodomain-encoding regions. Galili et al. (1993) isolated the chromosome 13 gene that is fused with PAX3 and identified it as a member of the forkhead domain family, which encodes transcription factors containing a conserved DNA-binding motif related to the Drosophila region-specific homeotic gene 'forkhead.' They referred to the gene as FKHR (FOXO1A; 136533) for 'forkhead in rhabdomyosarcoma.' Thus, disruption of the PAX3 gene can cause either neoplasia or congenital malformation. Other genes that are implicated in both neoplasia and congenital anomalies include the oncogene GLI3 (165240), the oncogene RET (164761), and the tumor suppressor gene WT1 (607102).
Tassabehji et al. (1992) identified variations in the PAX3 gene in 6 of 17 unrelated patients with Waardenburg syndrome type 1 (WS1; 193500), using primers to amplify exons followed by testing for heteroduplex formation on polyacrylamide gels. No variants were seen in any exon in 50 normal controls. In 3 families that were tested, the variant was found to be familial in 2 and apparently de novo in the third. The variant bands showed perfect linkage to WS in the families studied. One family was found to have a heterozygous 18-bp deletion in the central region of exon 2, resulting in loss of amino acids 29 to 34 (606597.0001).
Simultaneously and independently, Baldwin et al. (1992) identified a heterozygous mutation in the HuP2 gene (P50L; 606597.0002) in affected members of a large Brazilian family with Waardenburg syndrome type 1 reported by da-Silva (1991). There were 49 affected persons in 6 generations, and more than 78% of the affected individuals had hearing loss.
Baldwin et al. (1995) described 10 additional mutations in the PAX3 gene in families with WS type 1. Eight of these mutations were in a region of PAX3 where only 1 mutation had previously been described. Taken together with previously reported mutations, these mutations covered essentially the entire PAX3 gene. All but 1 of the mutations were 'private;' only 1 mutation had been reported in 2 apparently unrelated families. Preliminary screening for mutations was performed with conformation-sensitive gel electrophoresis (CSGE), as described by Ganguly et al. (1993). Baldwin et al. (1995) also cataloged 16 previously reported mutations and 5 chromosomal abnormalities affecting the 2q35 region that were associated with WS.
Among 24 unrelated individuals with WS1 mutations, Farrer et al. (1994) found that no 2 had the same point mutation in the protein-coding region of PAX3 nor did any of them have a change in the same codon.
In each of 2 families with WS type 1, Wildhardt et al. (1996) described the causative PAX3 mutation. One mutation was an insertion in the paired box domain resulting in a protein termination within the paired box. The second mutation was a single-basepair substitution producing an arg271-to-cys amino acid change in the homeobox region.
In the 'Splotch-delayed' mouse, mutation in the Pax3 paired domain (G9R) abrogates the DNA-binding activity of both the paired domain and the homeodomain, suggesting that they may functionally interact. To investigate this possibility further, Fortin et al. (1997) analyzed the DNA binding properties of additional point mutations in the PAX3 paired domain and homeodomain that occur in Waardenburg syndrome patients. Within the paired domain, 7 of 10 mutations were found to abrogate DNA binding by the paired domain. Remarkably, these 7 mutations also affected DNA binding by the homeodomain, causing either a complete loss, a reduction, or an increase in DNA-binding activity. In addition, the effect of paired domain mutations occurred at the level of monomer formation by the homeodomain, while the dimerization potential of this domain seemed unaffected in mutants where it could be analyzed. One mutation in the homeodomain also abrogated DNA binding by the paired domain. The observation that independent mutations in either domain can affect DNA binding by the other in the intact PAX3 protein strongly suggests that the 2 domains are not functionally independent but bind DNA through cooperative interactions.
Tassabehji et al. (1995) reported the results of screening for mutations in the PAX3 and MITF genes (156845) in 134 families or individuals with auditory-pigmentary syndromes, such as Waardenburg syndrome or probable neural cristopathies. PAX3 mutations were found in 20 of 25 families with definite WS1 and 1 of 2 with WS3 (148820), but in none of 23 with definite type WS2 (see 193510) or 36 with other neural cristopathies. The latter category included 12 with Hirschsprung disease plus pigmentary disturbances (WS4; see 277580). They concluded that about 20% of cases of WS2 are caused by mutations in MITF.
Zlotogora et al. (1995) reported a large kindred in which many individuals had Waardenburg syndrome type 1 associated with a heterozygous mutation in the PAX3 gene (S84F; 606597.0009). However, there was 1 child, born of consanguineous parents, who had a severe phenotype consistent with WS type 3 (148820): this patient was found to be homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Since all Pax3 mutations in mice lead to severe neural tube defects and intrauterine or neonatal death, the survival of the homozygote in this case and the absence of neural tube defects were unexpected.
In 2 unrelated Chinese patients with Waardenburg syndrome type 1, Chen et al. (2010) identified 2 different heterozygous mutations in the PAX3 gene (606597.0015 and 606597.0016, respectively). Zhang et al. (2012) performed in vitro functional expression studies showed that the mutant proteins had decreased or abolished ability to transactivate the MITF promoter.
The work of Bosher and Hallpike (1966) on an animal analog, deaf white cats, suggested that destruction of the inner ear mechanism occurs in the first days of extrauterine life and was correlated with an inability to regulate properly the constitution of the endolymphatic fluid. The cat, like man, may escape deafness in one or both ears. If more of the factors that lead to retention of hearing were known, deafness might be preventable.
Motohashi et al. (1994) pointed out that melanocytes are a normal component of the inner ear, including the stria vascularis. There are 3 known mutations in the mouse which lead to a deficiency of melanocytes in mast cells: white dominant spotting (W), Steel (Sl), and microphthalmia (mi). All 3 mutants have a thin stria vascularis, without melanocyte-like intermediate cells, and severe impairment of hearing. Thus, the absence of intermediate cells or melanocytes causes severe hearing loss. The absence of melanin has little influence on hearing acuity because albino mice without melanin have no impairment of hearing.
Other genes in the 9q34 band have homologs on mouse chromosome 2. In the mouse, the 'lethal-spotted' (ls) mutation, which results not only in spotting but also in failure of the entire ganglia to colonize the gut, is located on chromosome 2. Jacobs-Cohen et al. (1987) found that in lethal spotting piebald (ls/ls) mice, who develop megacolon, the terminal 2 mm of intestine does not become colonized by neural crest cells, resulting in aganglionosis. Neural crest cells transplanted from areas around the neural tube (primary explants) or foregut (secondary explants) did not colonize the terminal portions of the hindgut. These findings suggested that the nonneuronal components are abnormal, preventing migration of normal neural crest derivatives into the bowel wall.
Epstein et al. (1991) studied a deletion of mouse chromosome 1 that involved the 'splotch' locus. The murine equivalent of the ALPP gene was included in the deletion, thus supporting the notion that 'splotch' is the equivalent of WS1. Furthermore, Epstein et al. (1991) mapped the paired box gene Pax3 to a region near or at the Sp locus on mouse chromosome 1 and found Pax3 to be deleted in mice heterozygous for a splotch allele. In another allelic variant of splotch, they found deletion of 32 nucleotides in the Pax3 mRNA transcript and gene. The deletion was located within the paired homeodomain of Pax3 and was predicted to create a truncated protein as a result of a newly created termination codon at the deletion breakpoint. The splotch mutation is associated in the mouse with spina bifida and exencephaly. The findings were interpreted to indicate that Pax3 plays a key role in normal neural development. Moase and Trasler (1992) reviewed the subject of the splotch locus in mouse mutants. Steel and Smith (1992) found that, unlike individuals with Waardenburg syndrome, the splotch mouse has normal hearing. They suggested that the difference in expression of the genes in the 2 species may result from different parts of the gene being mutated or from modifying influences as yet undefined.
Epstein et al. (1993) demonstrated that in the original, spontaneously arising Sp allele, a complex mutation in the PAX3 gene had occurred, including an A-to-T transversion at the invariant 3-prime AG splice acceptor of intron 3. This mutation abrogated the normal splicing of intron 3, resulting in the generation of 4 aberrantly spliced mRNA transcripts. Two of the transcripts made use of cryptic 3-prime splice sites within the downstream exon, generating small deletions which disrupted the reading frame of the transcripts. A third aberrant splicing event resulted in the deletion of exon 4, while a fourth retained intron 3. None of these mutations would be expected to result in functional PAX3 proteins.
Asher et al. (1996) stated that over 50 human PAX3 mutations leading to hearing, craniofacial, limb, and pigmentation anomalies had been identified. Variability in penetrance and expressivity is observed in humans with PAX3 mutations and in mice with 'splotch' mutations. In mice with certain 'splotch' mutations, influence of the genetic background and sex of the individual on penetrance and expressivity is demonstrable. Asher et al. (1996) described a murine model for Waardenburg syndrome variation and concluded that a minimum of 2 genes interact with the 'splotch' mutation to influence the craniofacial features of these mice. One of these genes may be either X-linked or sex-influenced, while the other is autosomal. They stated that these studies in mice may lead to the identification of genes that modify the expression of human PAX3 mutations.
Fleming and Copp (2000) exploited variations in the normal pattern of cranial neural tube closure (closure 2) among inbred mouse strains. Strains with a more caudal location of cranial neural tube closure (e.g., DBA/2) were relatively resistant to neural tube defects (NTDs), whereas strains with a rostrally positioned closure 2 (e.g., NZW) exhibited increased susceptibility to NTDs. The authors back-crossed the 'splotch' (Sp2H) mutant gene onto both the DBA/2 and NZW backgrounds. After transfer to the DBA/2 background, the frequency of cranial NTDs was reduced significantly in Sp2H homozygotes, confirming a protective effect of caudal closure 2. In contrast, Sp2H homozygotes on the NZW background had a persistently high frequency of cranial NTDs. The frequency of spina bifida was not altered in either backcross, emphasizing the specificity of this genetic effect for cranial neurulation only. The authors concluded that variation in the pattern of cranial neural tube closure is a genetically determined factor influencing susceptibility to cranial NTDs.
Lagutina et al. (2002) generated mice carrying a Pax3-Fkhr knockin allele. Despite low expression of this allele, heterozygous offspring of Pax3-Fkhr chimeric mice showed developmental abnormalities, including intraventricular septum defects, tricuspid valve insufficiency, and diaphragm defects, which caused congestive heart failure leading to perinatal death. Heterozygotes also displayed malformations of some, but not all, hypaxial muscles. However, neither newborn heterozygous pups nor their chimeric parents showed any signs of malignancy. Lagutina et al. (2002) concluded that the Pax2-Fkhr allele causes lethal developmental defects in knockin mice but is insufficient to cause muscle tumors.
Relaix et al. (2003) found that mice expressing Pax3/Fkhr displayed developmental defects, including ectopic delamination and inappropriate migration of muscle precursor cells. These events resulted from overexpression of Met (164860), leading to constitutive activation of Met signaling. The gain-of-function phenotype was also characterized by overactivation of MyoD (159970).
In a kindred with Waardenburg syndrome type 1 (193500), Tassabehji et al. (1992) demonstrated a heterozygous deletion of 18 bp from the central region of exon 2 of the PAX3 gene. This resulted in loss of amino acids 29 to 34 of the paired domain. The deleted sequence ran between 2 directly repeated GGCCC sequences.
In affected members of a Brazilian family with Waardenburg syndrome type 1 (193500) reported by da-Silva (1991), Baldwin et al. (1992) identified a heterozygous G-to-A transition 64 bases downstream from the 5-prime end of exon 2. This changed codon CCG (proline) to CTG (leucine) in the sense strand. Amino acid residue 50 was thought to be involved (Milunsky, 1992), thus resulting in a pro50-to-leu (P50L) substitution. Baldwin et al. (1992) noted that there were 49 affected persons in 6 generations, and more than 78% of the affected individuals had hearing loss. All 26 affected members of the family were heterozygous for the mutation, whereas all 34 unaffected members and 50 control subjects were homozygous for the wildtype allele. Baldwin et al. (1992) did not detect the P50L mutation in 17 unrelated WS1 families.
In an Indonesian family with Waardenburg syndrome type 1 (193500), Morell et al. (1992) identified a 14-bp deletion in the paired domain encoded by exon 2 of the PAX3 gene. The frameshift mutation resulted in a premature termination codon in exon 3. The gene product was a truncated protein lacking most of the paired domain and all of the predicted homeodomain. The deletion started with the last 2 nucleotides of codon 158 and extended through codon 162 of the paired box. Morell et al. (1992) discussed whether the phenotypic effects of the mutation are due to haploinsufficiency of the product protein or to a transdominant negative effect.
In a family with Waardenburg syndrome type 1 (193500), designated WS.06, Tassabehji et al. (1993) demonstrated a frameshift mutation in the PAX3 gene. The deletion of the last nucleotide in codon 63 in exon 2 led to premature termination, with amino acid residue 75 corresponding to the beginning of exon 3.
In a family with Waardenburg syndrome type 1 (193500), designated WS.11, Tassabehji et al. (1993) demonstrated a 2-bp deletion in exon 4 of the PAX3 gene that removed one of a tandemly repeated pair of CA dinucleotides. The deletion in exon 4 presumably led to premature termination in exon 5, abolishing the homeodomain. In this family and in 2 others, Tassabehji et al. (1993) used the ARMS method, the amplification refractory mutation system (Newton et al., 1989), to confirm that affected family members had the mutation and that no unaffected family member was carrying the alteration.
This mutation is designated 556delCA based on the sequencing of Hoth et al. (1993) (see also Tassabehji et al., 1995).
This variant, originally reported as a GLY48ALA substitution by Tassabehji et al. (1993) has been reclassified as a GLY81ALA substitution based on the sequencing of Hoth et al. (1993) (see Tassabehji et al., 1995).
Tassabehji et al. (1993) found a GGC-to-GCC transversion in the PAX3 gene, resulting in a gly-to-ala substitution, in a family (WS.15) presumed to have Waardenburg syndrome type 2 (193510) with normal inner canthal distance. However, although 1 individual by measurement said to have an inner canthal distance at the 65th percentile, the photograph (their Figure 4) certainly suggested dystopia canthorum. The affected individual I-2 had a W index of 2.21 but was the only member of the family with a value over 2.07, which is the threshold recommended by the Waardenburg Consortium. The family reported by Tassabehji et al. (1993) was later considered by Tassabehji et al. (1995) to have Waardenburg syndrome type 1 (193500).
Reynolds et al. (1995) reviewed a collection of 26 WS1 and 8 WS2 families and concluded that the W-index as a means of discriminating between affected WS1 and WS2 individuals 'may be problematic' because (1) ranges of W-index scores of affected and unaffected individuals overlapped considerably within both WS1 and WS2 families, and (2) a considerable number of both affected and unaffected WS2 individuals exhibited W-index scores consistent with dystopia canthorum. This classification of families might have implications for risk assessment of deafness, since WS2 families had been shown to have greater incidence of deafness.
'Splotch' is an established mouse model for neural tube defects (NTD). Furthermore, in the human, neural tube defects are occasionally associated with Waardenburg syndrome (Carezani-Gavin et al., 1992; Chatkupt et al., 1993). Hol et al. (1995) screened the PAX3 gene in 39 patients with familial NTD, using single-strand conformation analysis. One patient with lumbosacral meningomyelocele was found to have a 5-bp deletion in exon 5, approximately 55 bp upstream of the conserved homeodomain. The deletion of CAA (gln) and TC caused a frameshift with a stop codon almost immediately after the mutated site; the frameshift led to the insertion of an arg residue before the creation of the stop codon. The patient was found to show mild signs of WS1 (193500). Varying signs of this syndrome were found to cosegregate with the mutation in the family. The results supported the hypothesis that mutations in the gene for PAX3 can also predispose to NTD. It is noteworthy that whereas homozygous Splotch mouse embryos can have NTD, in the heterozygous state mutations of the PAX3 gene do not cause but seem to predispose to NTD in a strain-specific manner.
In affected members of a large kindred with Waardenburg syndrome type 1 (193500), Zlotogora et al. (1995) identified a heterozygous mutation in exon 2 of the PAX3 gene, resulting in a ser84-to-phe (S84F) substitution. However, there was 1 child, born of consanguineous parents, who had a severe phenotype consistent with WS type 3 (148820): this patient was found to be homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Since all Pax3 mutations in mice lead to severe neural tube defects and intrauterine or neonatal death, the survival of the homozygote in this case and the absence of neural tube defects were unexpected.
Craniofacial-deafness-hand syndrome (122880) was described by Sommer et al. (1983) in a mother and 2 children with absence or hypoplasia of the nasal bones, hypoplastic maxilla, small and sharp nose with thin nares, limited movement of the wrist, short palpebral fissures, ulnar deviation of the fingers, hypertelorism, and profound sensorineural deafness. Asher et al. (1996) demonstrated a PAX3 exon 2 missense mutation, asn47-to-lys (N47K), in the affected members of this family. The affected persons were heterozygous for the mutation. A missense mutation in the same codon, asn47-to-his (606597.0011), gave rise to Waardenburg syndrome type 3. CDHS is clinically distinct from WS3, since affected individuals in the former did not have either muscle or skeletal upper limb hypoplasia; and in families with WS3, a 'pursed' appearance of the mouth and hypoplasia or absence of the nasal bone have not been described.
In affected members of a family with Waardenburg syndrome type 3 (148820) studied by Goodman et al. (1982) and Sheffer and Zlotogora (1992), Milunsky et al. (1992) and Hoth et al. (1993) identified a heterozygous 352A-C transversion in exon 2 of the PAX3 gene, resulting in an asn47-to-his (N47H) substitution in the paired domain. In addition to telecanthus, blepharophimosis, and hearing loss, affected individuals had hypoplasia of the upper limbs.
Tekin et al. (2001) described a mother and son with typical clinical findings of WS type 3 (148820) segregating with a heterozygous 13-bp deletion in the paired domain in exon 3 of the PAX3 gene.
Wollnik et al. (2003) described a Turkish family in which both of the parents, who were consanguineous, were heterozygous for a 268T-C transition in the PAX3 gene, resulting in a tyr90-to-his (Y90H) substitution. The daughter was homozygous for the mutation and was determined to have type 3 Waardenburg syndrome (148820). Her eyebrows and eyelashes were completely white, the hair was blond, and the irides were blue. The skin was depigmented with spots of normal pigmentation on the upper part of the body. Other findings included relatively large head, small palpebral fissures, increased inner and outer-canthal distances, flexion deformities of wrists, and fingers with ulnar deviation and minimal webs between fingers.
In affected members of a family with Waardenburg syndrome type 1 (193500), Hoth et al. (1993) identified a heterozygous 380G-T transversion in exon 2 of the PAX3 gene, resulting in an arg56-to-leu (R56L) substitution. One of the affected individuals had a meningomyelocele. The family had been reported by Carezani-Gavin et al. (1992).
In a Chinese boy with Waardenburg syndrome type 1 (193500), Chen et al. (2010) identified a heterozygous 238C-G transversion in exon 2 of the PAX3 gene, resulting in a his80-to-asp (H80D) substitution in the paired domain. The mutant protein retained an intact homeodomain and transactivation domain. Zhang et al. (2012) performed in vitro functional expression studies in human cells, which showed that the H80D mutant protein was expressed and localized to the nucleus, but caused a dramatically reduced activation of MITF (156845) compared to wildtype PAX3. There was no dominant-negative effect of the mutant protein, and the mutant protein could still interact with SOX10 (602229), although it did not enhance the activity of SOX10 as much as wildtype. The findings were consistent with haploinsufficiency as a pathogenic mechanism. The patient had bilateral profound hearing loss, unilateral heterochromia irides, and dystopia canthorum.
In a Chinese boy with Waardenburg syndrome type 1 (193500), Chen et al. (2010) identified a heterozygous 1-bp deletion (556delC) in exon 4 of the PAX3 gene, resulting in a frameshift at premature termination at residue 192 (His186fsTer5). The mutant protein would lack the homeodomain and transactivation domain. Zhang et al. (2012) performed in vitro functional expression studies in human cells, which showed that the truncated protein was expressed and localized to both the nucleus and cytoplasm, but failed to activate MITF (156845). There was no dominant-negative effect of the mutant protein, consistent with haploinsufficiency as a pathogenic mechanism. The mutant protein was still able to interact with SOX10 (602229), but did not enhance its activity. The patient had bilateral profound hearing loss, bilateral heterochromia irides, and dystopia canthorum.
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