Genetic screening of THAP1 in primary dystonia patients of India.

THAP1; Apoptosis Regulatory Proteins; DNA-Binding Proteins; Dystonic Disorders; Genetic Testing/methods; Humans; India; Male; Mutation/genetics; Nuclear Proteins; Sequence Analysis, DNA; Indian population; Mutation; Primary dystonia; SNP

Abstract :

[en] BACKGROUND: Primary Dystonia is a common movement disorder manifested by dystonic symptoms only. DYT6, a major genetic factor, plays a significant role in primary pure dystonia pathogenesis. In this study we analyzed THAP1 (DYT 6) gene in primary pure dystonia patients, which has been widely studied in other populations but not in Indians. METHODS: The study cohort contained 227 index primary pure dystonia patients with the involvement of cervical region and 254 neurologically control individuals collected from East Indian population. All three exons of THAP1 and their flanking sequences, including exon-intron boundaries, were screened by PCR, DNA sequencing and/or RFLP analysis. RESULTS: A total of three nucleotide variants were detected, which include a reported missense mutation (c.427 A>G; p.Met143Val) in a juvenile onset generalized dystonia patient, a novel frameshift deletion mutation (c.208-209 ΔAA; p.K70VfsX15) in a juvenile onset cervical dystonia patient and a rare variant in 3' UTR of THAP1 (c.*157 T>C) in an adult-onset blepharospasm patient. In addition, two SNPs (rs71521601 and rs111989331) were detected both in the patients and controls with the major allele of the latter being significantly over represented in the patients. CONCLUSIONS: Our study suggests that the THAP1 is likely to have a causative role in the pathogenesis of Indian primary pure dystonia patients. Though the phenotypic spectrum is extensively diverse, the cervical involvement with dystonic tremor and speech problem is common amongst the patients harboring mutations.

Disciplines :

Genetics & genetic processes

Author, co-author :

Giri, Subhajit ; Université de Liège - ULiège > Stem Cells-Developmental Neurobiology

Naiya, Tufan

Equbal, Zaffar

Sankhla, Charulata Savant

Das, Shyamal Kumar

Ray, Kunal

Ray, Jharna

Language :

English

Title :

Genetic screening of THAP1 in primary dystonia patients of India.

Publication date :

2017

Journal title :

Neuroscience Letters

ISSN :

0304-3940

eISSN :

1872-7972

Publisher :

Elsevier, Netherlands

Volume :

637

Pages :

31-37

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 31 May 2020

Statistics

Number of views

48 (1 by ULiège)

Number of downloads

1 (1 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

[1] Defazio, G., Abbruzzese, G., Livrea, P., Berardelli, A., Epidemiology of primary dystonia. Lancet Neurol. 3 (2004), 673–678.
[2] Das, S.K., Banerjee, T.K., Biswas, A., Roy, T., Raut, D.K., Chaudhuri, A., et al. Community survey of primary dystonia in the city of Kolkata, India. Mov. Disord. 22 (2007), 2031–2036.
[3] Charlesworth, G., Bhatia, K.P., Wood, N.W., The genetics of dystonia: new twists in an old tale. Brain 136 (2013), 2017–2037.
[4] Charlesworth, G., Angelova, P.R., Bartolomé-Robledo, F., Ryten, M., Trabzuni, D., Stamelou, M., et al. Mutations in HPCA cause autosomal-recessive primary isolated dystonia. Am. J. Hum. Genet. 96 (2015), 657–665.
[5] Zech, M., Lam, D.D., Francescatto, L., Schormair, B., Salminen, A.V., Jochim, A., et al. Recessive mutations in the (3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. Am. J. Hum. Genet. 96 (2015), 883–893.
[6] Klein, C., Brin, M.F., de Leon, D., Limborska, S.A., Ivanova-Smolenskaya, I.A., Bressman, S.B., et al. De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia. Hum. Mol. Genet. 7 (1998), 1133–1136.
[7] Jamora, R.D., Tan, E.K., Liu, C.P., Kathirvel, P., Burgunder, J.M., Tan, L.C., DYT1 mutations amongst adult primary dystonia patients in Singapore with review of literature comparing East and West. J. Neurol. Sci. 247 (2006), 35–37.
[8] Naiya, T., Biswas, A., Neogi, R., Datta, S., Misra, A.K., Das, S.K., Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients. Acta Neurol. Scand. 114 (2006), 210–215.
[9] Fuchs, T., Gavarini, S., Saunders-Pullman, R., Raymond, D., Ehrlich, M.E., Bressman, S.B., Ozelius, L.J., Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat. Genet. 41 (2009), 286–288.
[10] Xiao, J., Zhao, Y., Bastian, R.W., Perlmutter, J.S., Racette, B.A., Tabbal, S.D., et al. Novel THAP1 sequence variants in primary dystonia. Neurology 74 (2010), 229–238.
[11] LeDoux, M.S., Xiao, J., Rudzińska, M., Bastian, R.W., Wszolek, Z.K., Van Gerpen, J.A., et al. Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases. Parkinsonism Relat. Disord. 18 (2012), 414–425.
[12] Muller, U., The monogenic primary dystonias. Brain 132 (2009), 2005–2025.
[13] Spatola, M., Wider, C., Overview of primary monogenic dystonia. Parkinsonism Relat. Disord. 18 (2012), S158–S161.
[14] Sengel, C., Gavarini, S., Sharma, N., Ozelius, L.J., Bragg, D.C., Dimerization of the DYT6 dystonia protein THAP1, requires residues within the coiled-coil domain. J. Neurochem. 118 (2011), 1087–1100.
[15] Cayrol, C., Lacroix, C., Mathe, C., Ecochard, V., Ceribelli, M., Loreau, E., et al. The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of pRB/E2F cell-cycle target genes. Blood 109 (2007), 584–594.
[16] Kaiser, F.J., Osmanoric, A., Rakovic, A., Erogullari, A., Uflacker, N., Braunholz, D., et al. The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Ann. Neurol. 68 (2010), 554–559.
[17] Gavarini, S., Cayrol, C., Fuchs, T., Lyons, N., Ehrlich, M.E., Girard, J.P., et al. Direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Ann. Neurol. 68 (2010), 549–553.
[18] Blanchard, A., Ea, V., Roubertie, A., Martin, M., Coquart, C., Claustres, M., et al. DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene. Hum. Mutat. 32 (2011), 1213–1224.
[19] Xiromerisiou, G., Houlden, H., Scarmeas, N., Stamelou, M., Kara, E., Hardy, J., et al. THAP1 mutations and dystonia phenotypes: genotype phenotype correlations. Mov. Disord. 27 (2012), 1290–1294.
[20] Dobričić, V.S., Kresojević, N.D., Svetel, M.V., Janković, M.Z., Petrović, I.N., Tomić, A.D., et al. Mutation screening of the DYT6/THAP1 gene in Serbian patients with primary dystonia. J. Neurol. 260 (2013), 1037–1042.
[21] Cheng, F.B., Ozelius, L.J., Wan, X.H., Feng, J.C., Ma, L.Y., Yang, Y.M., et al. THAP1/DYT6 sequence variants in non-DYT1 early-onset primary dystonia in China and their effects on RNA expression. J. Neurol. 259 (2012), 342–347.
[22] de Silva-Junior, F.P., dos Santos, C.O., Silva, S.M., Barbosa, E.R., Borges, V., Ferraz, H.B., et al. Novel THAP1 variants in Brazilian patients with idiopathic isolated dystonia. J. Neurol. Sci. 344 (2014), 190–192.
[23] Gajos, A., Golańska, E., Sieruta, M., Szybka, M., Liberski, P.P., Bogucki, A., High variability of clinical symptoms in a Polish family with a novel THAP1 mutation. Int. J. Neurosci. 125 (2015), 755–759.
[24] Fahn, S., Eldridge, R., Definition of dystonia and classification of the dystonic states. Adv. Neurol. 14 (1976), 1–5.
[25] Johns, M.B. Jr., Paulus-Thomas, J.E., Purification of human genomic DNA from whole blood using sodium perchlorate in place of phenol. Anal. Biochem. 180 (1989), 276–278.
[26] Söhn, A.S., Glöckle, N., Doetzer, A.D., Deuschl, G., Felbor, U., Topka, H.R., et al. Prevalence of THAP1 sequence variants in German patients with primary dystonia. Mov. Disord. 25 (2010), 1982–1986.
[27] Xiromerisiou, G., Dardiotis, E., Tsironi, E.E., Hadjigeorgiou, G., Ralli, S., Kara, E., et al. THAP1 mutations in a Greek primary blepharospasm series. Parkinsonism Relat. Disord. 19 (2013), 404–405.
[28] Sabogal, A., Lyubimov, A.Y., Corn, J.E., Berger, J.M., Rio, D.C., THAP proteins target specific DNA sites through bipartite recognition of adjacent major and minor grooves. Nat. Struct. Mol. Biol. 17 (2010), 117–123.
[29] Grundmann, K., Reischmann, B., Vanhoutte, G., Hübener, J., Teismann, P., Hauser, T.K., et al. Overexpression of human wildtype torsinA and human DeltaGAG torsinA in a transgenic mouse model causes phenotypic abnormalities. Neurobiol. Dis. 27 (2007), 190–206.
[30] Torres, G.E., Sweeney, A.L., Beaulieu, J.M., Shashidharan, P., Caron, M.G., Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. Proc. Natl. Acad. Sci. U. S. A. 101 (2004), 15650–15655.