2l1g

Structural highlights

Disease

THAP1_HUMAN Defects in THAP1 are the cause of dystonia type 6 (DYT6) [MIM:602629. DYT6 is a primary torsion dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Dystonia type 6 is characterized by onset in early adulthood, cranial or cervical involvement in about half of the cases, and frequent progression to involve multiple body regions.[:]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]}

Function

THAP1_HUMAN DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression. Specifically binds the 5'-[AT]NTNN[GT]GGCA[AGT]-3' core DNA sequence and acts by modulating expression of pRB-E2F cell-cycle target genes, including RRM1. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. May also have pro-apoptopic activity by potentiating both serum-withdrawal and TNF-induced apoptosis.^{[18] [19] [20]}

Evolutionary Conservation

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

References

1. ↑ Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, Saunders-Pullman R. Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol. 2009 May;8(5):441-6. doi: 10.1016/S1474-4422(09)70081-X. Epub 2009, Apr 1. PMID:19345147 doi:10.1016/S1474-4422(09)70081-X
2. ↑ Bonetti M, Barzaghi C, Brancati F, Ferraris A, Bellacchio E, Giovanetti A, Ialongo T, Zorzi G, Piano C, Petracca M, Albanese A, Nardocci N, Dallapiccola B, Bentivoglio AR, Garavaglia B, Valente EM. Mutation screening of the DYT6/THAP1 gene in Italy. Mov Disord. 2009 Dec 15;24(16):2424-7. doi: 10.1002/mds.22861. PMID:19908325 doi:10.1002/mds.22861
3. ↑ Paisan-Ruiz C, Ruiz-Martinez J, Ruibal M, Mok KY, Indakoetxea B, Gorostidi A, Marti Masso JF. Identification of a novel THAP1 mutation at R29 amino-acid residue in sporadic patients with early-onset dystonia. Mov Disord. 2009 Dec 15;24(16):2428-9. doi: 10.1002/mds.22849. PMID:19908320 doi:10.1002/mds.22849
4. ↑ Fuchs T, Gavarini S, Saunders-Pullman R, Raymond D, Ehrlich ME, Bressman SB, Ozelius LJ. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet. 2009 Mar;41(3):286-8. doi: 10.1038/ng.304. Epub 2009 Feb 1. PMID:19182804 doi:10.1038/ng.304
5. ↑ Van Gerpen JA, Ledoux MS, Wszolek ZK. Adult-onset leg dystonia due to a missense mutation in THAP1. Mov Disord. 2010 Jul 15;25(9):1306-7. doi: 10.1002/mds.23086. PMID:20629133 doi:10.1002/mds.23086
6. ↑ Sohn AS, Glockle N, Doetzer AD, Deuschl G, Felbor U, Topka HR, Schols L, Riess O, Bauer P, Muller U, Grundmann K. Prevalence of THAP1 sequence variants in German patients with primary dystonia. Mov Disord. 2010 Sep 15;25(12):1982-6. doi: 10.1002/mds.23207. PMID:20669277 doi:10.1002/mds.23207
7. ↑ Groen JL, Ritz K, Contarino MF, van de Warrenburg BP, Aramideh M, Foncke EM, van Hilten JJ, Schuurman PR, Speelman JD, Koelman JH, de Bie RM, Baas F, Tijssen MA. DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation. Mov Disord. 2010 Oct 30;25(14):2420-7. doi: 10.1002/mds.23285. PMID:20687191 doi:10.1002/mds.23285
8. ↑ Xiao J, Zhao Y, Bastian RW, Perlmutter JS, Racette BA, Tabbal SD, Karimi M, Paniello RC, Wszolek ZK, Uitti RJ, Van Gerpen JA, Simon DK, Tarsy D, Hedera P, Truong DD, Frei KP, Dev Batish S, Blitzer A, Pfeiffer RF, Gong S, LeDoux MS. Novel THAP1 sequence variants in primary dystonia. Neurology. 2010 Jan 19;74(3):229-38. doi: 10.1212/WNL.0b013e3181ca00ca. PMID:20083799 doi:10.1212/WNL.0b013e3181ca00ca
9. ↑ Houlden H, Schneider SA, Paudel R, Melchers A, Schwingenschuh P, Edwards M, Hardy J, Bhatia KP. THAP1 mutations (DYT6) are an additional cause of early-onset dystonia. Neurology. 2010 Mar 9;74(10):846-50. doi: 10.1212/WNL.0b013e3181d5276d. PMID:20211909 doi:10.1212/WNL.0b013e3181d5276d
10. ↑ Lohmann K, Uflacker N, Erogullari A, Lohnau T, Winkler S, Dendorfer A, Schneider SA, Osmanovic A, Svetel M, Ferbert A, Zittel S, Kuhn AA, Schmidt A, Altenmuller E, Munchau A, Kamm C, Wittstock M, Kupsch A, Moro E, Volkmann J, Kostic V, Kaiser FJ, Klein C, Bruggemann N. Identification and functional analysis of novel THAP1 mutations. Eur J Hum Genet. 2012 Feb;20(2):171-5. doi: 10.1038/ejhg.2011.159. Epub 2011 Aug , 17. PMID:21847143 doi:10.1038/ejhg.2011.159
11. ↑ Cheng FB, Wan XH, Feng JC, Wang L, Yang YM, Cui LY. Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China. Eur J Neurol. 2011 Mar;18(3):497-503. doi: 10.1111/j.1468-1331.2010.03192.x. Epub, 2010 Sep 6. PMID:20825472 doi:10.1111/j.1468-1331.2010.03192.x
12. ↑ Cheng FB, Ozelius LJ, Wan XH, Feng JC, Ma LY, Yang YM, Wang L. THAP1/DYT6 sequence variants in non-DYT1 early-onset primary dystonia in China and their effects on RNA expression. J Neurol. 2012 Feb;259(2):342-7. doi: 10.1007/s00415-011-6196-5. Epub 2011 Jul, 29. PMID:21800139 doi:10.1007/s00415-011-6196-5
13. ↑ Song W, Chen Y, Huang R, Chen K, Pan P, Yang Y, Shang HF. Novel THAP1 gene mutations in patients with primary dystonia from southwest China. J Neurol Sci. 2011 Oct 15;309(1-2):63-7. doi: 10.1016/j.jns.2011.07.023. Epub, 2011 Aug 11. PMID:21839475 doi:10.1016/j.jns.2011.07.023
14. ↑ Schneider SA, Ramirez A, Shafiee K, Kaiser FJ, Erogullari A, Bruggemann N, Winkler S, Bahman I, Osmanovic A, Shafa MA, Bhatia KP, Najmabadi H, Klein C, Lohmann K. Homozygous THAP1 mutations as cause of early-onset generalized dystonia. Mov Disord. 2011 Apr;26(5):858-61. doi: 10.1002/mds.23561. Epub 2011 Mar 21. PMID:21425335 doi:10.1002/mds.23561
15. ↑ Jech R, Bares M, Krepelova A, Urgosik D, Havrankova P, Ruzicka E. DYT 6--a novel THAP1 mutation with excellent effect on pallidal DBS. Mov Disord. 2011 Apr;26(5):924-5. doi: 10.1002/mds.23599. Epub 2011 Mar 21. PMID:21425341 doi:10.1002/mds.23599
16. ↑ Clot F, Grabli D, Burbaud P, Aya M, Derkinderen P, Defebvre L, Damier P, Krystkowiak P, Pollak P, Leguern E, San C, Camuzat A, Roze E, Vidailhet M, Durr A, Brice A. Screening of the THAP1 gene in patients with early-onset dystonia: myoclonic jerks are part of the dystonia 6 phenotype. Neurogenetics. 2011 Feb;12(1):87-9. doi: 10.1007/s10048-010-0264-3. Epub 2010 Nov, 26. PMID:21110056 doi:10.1007/s10048-010-0264-3
17. ↑ LeDoux MS, Xiao J, Rudzinska M, Bastian RW, Wszolek ZK, Van Gerpen JA, Puschmann A, Momcilovic D, Vemula SR, Zhao Y. Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases. Parkinsonism Relat Disord. 2012 Jun;18(5):414-25. doi:, 10.1016/j.parkreldis.2012.02.001. Epub 2012 Feb 28. PMID:22377579 doi:10.1016/j.parkreldis.2012.02.001
18. ↑ Roussigne M, Cayrol C, Clouaire T, Amalric F, Girard JP. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies. Oncogene. 2003 Apr 24;22(16):2432-42. PMID:12717420 doi:10.1038/sj.onc.1206271
19. ↑ Cayrol C, Lacroix C, Mathe C, Ecochard V, Ceribelli M, Loreau E, Lazar V, Dessen P, Mantovani R, Aguilar L, Girard JP. The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes. Blood. 2007 Jan 15;109(2):584-94. Epub 2006 Sep 26. PMID:17003378 doi:10.1182/blood-2006-03-012013
20. ↑ Mazars R, Gonzalez-de-Peredo A, Cayrol C, Lavigne AC, Vogel JL, Ortega N, Lacroix C, Gautier V, Huet G, Ray A, Monsarrat B, Kristie TM, Girard JP. The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias. J Biol Chem. 2010 Apr 30;285(18):13364-71. doi: 10.1074/jbc.M109.072579. Epub, 2010 Mar 3. PMID:20200153 doi:10.1074/jbc.M109.072579