3cmy

Structural highlights

Disease

PAX3_HUMAN Defects in PAX3 are the cause of Waardenburg syndrome type 1 (WS1) [MIM:193500. WS1 is an autosomal dominant disorder characterized by wide bridge of nose owing to lateral displacement of the inner canthus of each eye (dystopia canthorum), pigmentary disturbances such as frontal white blaze of hair, heterochromia of irides, white eyelashes, leukoderma and sensorineural deafness. The syndrome shows variable clinical expression and some affected individuals do not manifest hearing impairment.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]} [:]^{[15] [16]} Defects in PAX3 are the cause of Waardenburg syndrome type 3 (WS3) [MIM:148820; also known as Klein-Waardenburg syndrome or Waardenburg syndrome with upper limb anomalies or white forelock with malformations. WS3 is a very rare autosomal dominant disorder, which shares many of the characteristics of WS1. Patients additionally present with musculoskeletal abnormalities. Defects in PAX3 are the cause of craniofacial-deafness-hand syndrome (CDHS) [MIM:122880. CDHS is thought to be an autosomal dominant disease which comprises absence or hypoplasia of the nasal bones, hypoplastic maxilla, small and short nose with thin nares, limited movement of the wrist, short palpebral fissures, ulnar deviation of the fingers, hypertelorism and profound sensory-neural deafness.^[17] Defects in PAX3 are a cause of rhabdomyosarcoma type 2 (RMS2) [MIM:268220. It is a form of rhabdomyosarcoma, a highly malignant tumor of striated muscle derived from primitive mesenchimal cells and exhibiting differentiation along rhabdomyoblastic lines. Rhabdomyosarcoma is one of the most frequently occurring soft tissue sarcomas and the most common in children. It occurs in four forms: alveolar, pleomorphic, embryonal and botryoidal rhabdomyosarcomas. Note=A chromosomal aberration involving PAX3 is found in rhabdomyosarcoma. Translocation (2;13)(q35;q14) with FOXO1. The resulting protein is a transcriptional activator. Note=A chromosomal aberration involving PAX3 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with NCOA1 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children.

Function

PAX3_HUMAN Probable transcription factor associated with development of alveolar rhabdomyosarcoma.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Paired box protein

References

1. ↑ Tassabehji M, Newton VE, Leverton K, Turnbull K, Seemanova E, Kunze J, Sperling K, Strachan T, Read AP. PAX3 gene structure and mutations: close analogies between Waardenburg syndrome and the Splotch mouse. Hum Mol Genet. 1994 Jul;3(7):1069-74. PMID:7981674
2. ↑ Tassabehji M, Read AP, Newton VE, Harris R, Balling R, Gruss P, Strachan T. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature. 1992 Feb 13;355(6361):635-6. PMID:1347148 doi:http://dx.doi.org/10.1038/355635a0
3. ↑ Morell R, Friedman TB, Moeljopawiro S, Hartono, Soewito, Asher JH Jr. 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. 1992 Jul;1(4):243-7. PMID:1303193
4. ↑ Baldwin CT, Hoth CF, Amos JA, da-Silva EO, Milunsky A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature. 1992 Feb 13;355(6361):637-8. PMID:1347149 doi:http://dx.doi.org/10.1038/355637a0
5. ↑ Tassabehji M, Read AP, Newton VE, Patton M, Gruss P, Harris R, Strachan T. Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2. Nat Genet. 1993 Jan;3(1):26-30. PMID:8490648 doi:http://dx.doi.org/10.1038/ng0193-26
6. ↑ Hoth CF, Milunsky A, Lipsky N, Sheffer R, Clarren SK, Baldwin CT. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I). Am J Hum Genet. 1993 Mar;52(3):455-62. PMID:8447316
7. ↑ Pierpont JW, Doolan LD, Amann K, Snead GR, Erickson RP. A single base pair substitution within the paired box of PAX3 in an individual with Waardenburg syndrome type 1 (WS1). Hum Mutat. 1994;4(3):227-8. PMID:7833953 doi:http://dx.doi.org/10.1002/humu.1380040310
8. ↑ Lalwani AK, Brister JR, Fex J, Grundfast KM, Ploplis B, San Agustin TB, Wilcox ER. 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. 1995 Jan;56(1):75-83. PMID:7825605
9. ↑ Baldwin CT, Hoth CF, Macina RA, Milunsky A. Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature. Am J Med Genet. 1995 Aug 28;58(2):115-22. PMID:8533800 doi:http://dx.doi.org/10.1002/ajmg.1320580205
10. ↑ Tassabehji M, Newton VE, Liu XZ, Brady A, Donnai D, Krajewska-Walasek M, Murday V, Norman A, Obersztyn E, Reardon W, et al.. The mutational spectrum in Waardenburg syndrome. Hum Mol Genet. 1995 Nov;4(11):2131-7. PMID:8589691
11. ↑ Pandya A, Xia XJ, Landa BL, Arnos KS, Israel J, Lloyd J, James AL, Diehl SR, Blanton SH, Nance WE. Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background? Hum Mol Genet. 1996 Apr;5(4):497-502. PMID:8845842
12. ↑ Soejima H, Fujimoto M, Tsukamoto K, Matsumoto N, Yoshiura KI, Fukushima Y, Jinno Y, Niikawa N. Three novel PAX3 mutations observed in patients with Waardenburg syndrome type 1. Hum Mutat. 1997;9(2):177-80. PMID:9067759 doi:<177::AID-HUMU11>3.0.CO;2-# 10.1002/(SICI)1098-1004(1997)9:2<177::AID-HUMU11>3.0.CO;2-#
13. ↑ Hol FA, Geurds MP, Cremers CW, Hamel BC, Mariman EC. Identification of two PAX3 mutations causing Waardenburg syndrome, one within the paired domain (M62V) and the other downstream of the homeodomain (Q282X). Hum Mutat. 1998;Suppl 1:S145-7. PMID:9452070
14. ↑ Carey ML, Friedman TB, Asher JH Jr, Innis JW. Septo-optic dysplasia and WS1 in the proband of a WS1 family segregating for a novel mutation in PAX3 exon 7. J Med Genet. 1998 Mar;35(3):248-50. PMID:9541113
15. ↑ Sotirova VN, Rezaie TM, Khoshsorour MM, Sarfarazi M. Identification of a novel mutation in the paired domain of PAX3 in an Iranian family with waardenburg syndrome type I. Ophthalmic Genet. 2000 Mar;21(1):25-8. PMID:10779847
16. ↑ Wollnik B, Tukel T, Uyguner O, Ghanbari A, Kayserili H, Emiroglu M, Yuksel-Apak M. Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome. Am J Med Genet A. 2003 Sep 15;122A(1):42-5. PMID:12949970 doi:http://dx.doi.org/10.1002/ajmg.a.20260
17. ↑ Asher JH Jr, Sommer A, Morell R, Friedman TB. Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome. Hum Mutat. 1996;7(1):30-5. PMID:8664898 doi:<30::AID-HUMU4>3.0.CO;2-T 10.1002/(SICI)1098-1004(1996)7:1<30::AID-HUMU4>3.0.CO;2-T