PAX3

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Species	Human	Mouse
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PAX3 is a gene within the PAX family, a group of transcription factors consisting of proteins binding to DNA sequences to control gene transcription. Pax3 is important in embryonic development because Pax3 is active in neural crest cells. In conjunction with Msx1, Pax3 guides the expression of Snail1 and Snail2 down-regulating adhesion molecules. This allows neural crest cells to become mesenchymal cells that migrate throughout the body and become bones and muscles around the face, the parasympathetic nervous system, and other structural components. As a result, mutations within Pax3 generally result in developmental malformations because neural crest cells cannot move to the necessary parts of the body to complete their function. Craniofacial-deafness-hand syndrome is an example of an autosomal dominant disease resulting from a missense mutation in exon2 of Pax3. This mutation results in replacing the amino acid asparagine with lysine, inhibiting the Pax3 protein from binding to the necessary DNA. Craniofacial-deafness-hand syndrome has distinctive symptoms, such as an underdeveloped nasal bone, a small mouth and upper-jaw, pursed lips, and wide spaced eyes with narrowed eye openings. Hearing loss and deformities in hand muscles are common. Hand abnormalities typically present themselves as angled and bent fingers. Depending on the severity, finger and hand movement can be limited. Despite these physical malformations, individuals have normal intelligence and an active life. Diagnosis involves genotyping and collaborative efforts from orthopedists, pediatricians, and ophthalmologists. While there are knockout models developed for Pax3, they focused on cancers rather than this syndrome.

PAX3 is a gene that belongs to the paired box (PAX) family of transcription factors. This gene was formerly known as splotch. PAX3 has been identified with ear, eye and facial development. Mutations in it can cause Waardenburg syndrome types 1 and 3. It is expressed in early embryonic phases in dermatomyotome of paraxial mesoderm which it helps to demarcate. In that way PAX3 contributes to early striated muscle development since all myoblasts are derived from dermatomyotome of paraxial mesoderm.

Alternative splicing results in transcripts encoding isoforms with different C-termini.

Role in rhabdomyosarcoma

A PAX3/FKHR fusion gene is often associated with the alveolar type of rhabdomyosarcoma, a kind of cancer arisen from striated muscle cells. Translocation between chromosomes 2 & 13 produce fusion protein PAX3/FKHR which serves as a tumor marker in this type of RMS.Also in ARMS expressing PAX3/FKHR increased risk of metastasis to bone marrow and hence increased rate of failure and death were seen.

Interactions

PAX3 has been shown to interact with MEOX1, MEOX2 and SOX10 as well as phosphatidylcholine transfer protein (PCTP). PAX3 has an important relationship with c-met in myogenesis; if PAX3 is mutated, c-met expression may be inhibited or prevented altogether resulting in a lack of lateral migration.

Further reading

• Moase CE, Trasler DG (1992). "Splotch locus mouse mutants: models for neural tube defects and Waardenburg syndrome type I in humans". J. Med. Genet. 29 (3): 145–51. doi:10.1136/jmg.29.3.145. PMC 1015886. PMID 1552554.
• Baldwin CT, Hoth CF, Macina RA, Milunsky A (1996). "Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature". Am. J. Med. Genet. 58 (2): 115–22. doi:10.1002/ajmg.1320580205. PMID 8533800.
• Blake J, Ziman MR (2003). "Aberrant PAX3 and PAX7 expression. A link to the metastatic potential of embryonal rhabdomyosarcoma and cutaneous malignant melanoma?". Histol. Histopathol. 18 (2): 529–39. PMID 12647804.
• Reddi KK (1976). "Human granulocyte ribonuclease". Biochem. Biophys. Res. Commun. 68 (4): 1119–25. doi:10.1016/0006-291X(76)90312-0. PMID 5077.
• Morell R, Friedman TB, Moeljopawiro S, et al. (1993). "A frameshift mutation in the HuP2 paired domain of the probable human homolog of murine Pax-3 is responsible for Waardenburg syndrome type 1 in an Indonesian family". Hum. Mol. Genet. 1 (4): 243–7. doi:10.1093/hmg/1.4.243. PMID 1303193.
• Carezani-Gavin M, Clarren SK, Steege T (1993). "Waardenburg syndrome associated with meningomyelocele". Am. J. Med. Genet. 42 (1): 135–6. doi:10.1002/ajmg.1320420127. PMID 1308353.
• Tassabehji M, Read AP, Newton VE, et al. (1992). "Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene". Nature. 355 (6361): 635–6. doi:10.1038/355635a0. PMID 1347148.
• Baldwin CT, Hoth CF, Amos JA, et al. (1992). "An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome". Nature. 355 (6361): 637–8. doi:10.1038/355637a0. PMID 1347149.
• Farrer LA, Grundfast KM, Amos J, et al. (1992). "Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium". Am. J. Hum. Genet. 50 (5): 902–13. PMC 1682585. PMID 1349198.
• Sheffer R, Zlotogora J (1992). "Autosomal dominant inheritance of Klein-Waardenburg syndrome". Am. J. Med. Genet. 42 (3): 320–2. doi:10.1002/ajmg.1320420312. PMID 1536170.
• Burri M, Tromvoukis Y, Bopp D, et al. (1989). "Conservation of the paired domain in metazoans and its structure in three isolated human genes". EMBO J. 8 (4): 1183–90. PMC 400932. PMID 2501086.
• Newton VE (1990). "Waardenburg's syndrome: a comparison of biometric indices used to diagnose lateral displacement of the inner canthi". Scandinavian audiology. 18 (4): 221–3. doi:10.3109/01050398909042198. PMID 2609099.
• Newton CR, Graham A, Heptinstall LE, et al. (1989). "Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS)". Nucleic Acids Res. 17 (7): 2503–16. doi:10.1093/nar/17.7.2503. PMC 317639. PMID 2785681.
• Sommer A, Young-Wee T, Frye T (1983). "Previously undescribed syndrome of craniofacial, hand anomalies, and sensorineural deafness". Am. J. Med. Genet. 15 (1): 71–7. doi:10.1002/ajmg.1320150109. PMID 6859126.
• Goodman RM, Lewithal I, Solomon A, Klein D (1982). "Upper limb involvement in the Klein-Waardenburg syndrome". Am. J. Med. Genet. 11 (4): 425–33. doi:10.1002/ajmg.1320110407. PMID 7091186.
• Tsukamoto K, Nakamura Y, Niikawa N (1994). "Isolation of two isoforms of the PAX3 gene transcripts and their tissue-specific alternative expression in human adult tissues". Hum. Genet. 93 (3): 270–4. doi:10.1007/BF00212021. PMID 7545913.
• Zlotogora J, Lerer I, Bar-David S, et al. (1995). "Homozygosity for Waardenburg syndrome". Am. J. Hum. Genet. 56 (5): 1173–8. PMC 1801439. PMID 7726174.
• Macina RA, Barr FG, Galili N, Riethman HC (1995). "Genomic organization of the human PAX3 gene: DNA sequence analysis of the region disrupted in alveolar rhabdomyosarcoma". Genomics. 26 (1): 1–8. doi:10.1016/0888-7543(95)80076-X. PMID 7782066.
• Lalwani AK, Brister JR, Fex J, et al. (1995). "Further elucidation of the genomic structure of PAX3, and identification of two different point mutations within the PAX3 homeobox that cause Waardenburg syndrome type 1 in two families". Am. J. Hum. Genet. 56 (1): 75–83. PMC 1801294. PMID 7825605.

External links

• GeneReviews/NCBI/NIH/UW entry on Waardenburg Syndrome Type I
• PAX3+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)