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.[1][2] 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.[1][3] 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.[4] This gene was formerly known as splotch.[5] PAX3 has been identified with ear, eye and facial development.[6] 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.
A PAX3/FKHRfusion gene is often associated with the alveolar type of rhabdomyosarcoma,[7] 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.
↑Begum S, Emami N, Emani N, et al. (March 2005). "Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR". Oncogene. 24 (11): 1860–72. doi:10.1038/sj.onc.1208315. PMID15688035.
↑ 8.08.1Stamataki D, Kastrinaki M, Mankoo BS, Pachnis V, Karagogeos D (June 2001). "Homeodomain proteins Mox1 and Mox2 associate with Pax1 and Pax3 transcription factors". FEBS Lett. 499 (3): 274–8. doi:10.1016/S0014-5793(01)02556-X. PMID11423130.
↑Lang D, Epstein JA (April 2003). "Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer". Hum. Mol. Genet. 12 (8): 937–45. doi:10.1093/hmg/ddg107. PMID12668617.
↑Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, Wegner M, Goossens M (August 2000). "Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome". Hum. Mol. Genet. 9 (13): 1907–17. doi:10.1093/hmg/9.13.1907. PMID10942418.
↑Kanno K, Wu MK, Agate DA, Fanelli BK, Wagle N, Scapa EF, Ukomadu C, Cohen DE (October 2007). "Interacting proteins dictate function of the minimal START domain phosphatidylcholine transfer protein/StarD2". J. Biol. Chem. 282 (42): 30728–36. doi:10.1074/jbc.M703745200. PMID17704541.
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. PMID8533800.
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. PMID12647804.
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. PMID1303193.
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. PMID1308353.
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. PMID1347148.
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. PMID1347149.
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. PMID2609099.
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. PMID6859126.
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. PMID7091186.
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. PMID7545913.
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. PMID7782066.