Recent Advances in the Genetics of Dystonia

Overview

Journal Curr Neurol Neurosci Rep

Specialty Neurology

Date 2014 Jun 23

PMID 24952478

Citations 14

Authors

Jianfeng Xiao

Satya R Vemula

Mark S Ledoux

Affiliations

Soon will be listed here.

Abstract

Dystonia, a common and genetically heterogeneous neurological disorder, was recently defined as "a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both." Via the application of whole-exome sequencing, the genetic landscape of dystonia and closely related movement disorders is becoming exposed. In particular, several "novel" genetic causes have been causally associated with dystonia or dystonia-related disorders over the past 2 years. These genes include PRRT2 (DYT10), CIZ1 (DYT23), ANO3 (DYT24), GNAL (DYT25), and TUBB4A (DYT4). Despite these advances, major gaps remain in identifying the genetic origins for most cases of adult-onset isolated dystonia. Furthermore, model systems are needed to study the biology of PRRT2, CIZ1, ANO3, Gαolf, and TUBB4A in the context of dystonia. This review focuses on these recent additions to the family of dystonia genes, genotype-phenotype correlations, and possible cellular contributions of the encoded proteins to the development of dystonia.

Citing Articles

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Tremor in cervical dystonia.

Beylergil S, Mukunda K, Elkasaby M, Perlmutter J, Factor S, Baumer T Dystonia. 2024; 3.

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Prion-like domains drive CIZ1 assembly formation at the inactive X chromosome.

Sofi S, Williamson L, Turvey G, Scoynes C, Hirst C, Godwin J J Cell Biol. 2022; 221(4).

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Cerebellar Involvement in DYT-THAP1 Dystonia.

Nikolov P, Hassan S, Aytulun A, Hartmann C, Kohlhase J, Schnitzler A Cerebellum. 2019; 18(5):969-971.

PMID: 31367947 DOI: 10.1007/s12311-019-01062-0.

Maintenance of epigenetic landscape requires CIZ1 and is corrupted in differentiated fibroblasts in long-term culture.

Stewart E, Turner R, Newling K, Ridings-Figueroa R, Scott V, Ashton P Nat Commun. 2019; 10(1):460.

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References

de Carvalho Aguiar P, Sweadner K, Penniston J, Zaremba J, Liu L, Caton M . Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron. 2004; 43(2):169-75. DOI: 10.1016/j.neuron.2004.06.028. View

Ledoux M, Xiao J, Rudzinska M, Bastian R, Wszolek Z, van Gerpen J . Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases. Parkinsonism Relat Disord. 2012; 18(5):414-25. PMC: 3358360. DOI: 10.1016/j.parkreldis.2012.02.001. View

Saunders-Pullman R, Fuchs T, San Luciano M, Raymond D, Brashear A, Ortega R . Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites. Mov Disord. 2014; 29(6):812-8. PMC: 4013240. DOI: 10.1002/mds.25818. View

Ledoux M, Dauer W, Warner T . Emerging common molecular pathways for primary dystonia. Mov Disord. 2013; 28(7):968-81. PMC: 3838975. DOI: 10.1002/mds.25547. View

Liokatis S, Stutzer A, Elsasser S, Theillet F, Klingberg R, van Rossum B . Phosphorylation of histone H3 Ser10 establishes a hierarchy for subsequent intramolecular modification events. Nat Struct Mol Biol. 2012; 19(8):819-23. DOI: 10.1038/nsmb.2310. View

Veltman J, Brunner H . De novo mutations in human genetic disease. Nat Rev Genet. 2012; 13(8):565-75. DOI: 10.1038/nrg3241. View

Zhao Y, Xiao J, Gong S, Clara J, Ledoux M . Neural expression of the transcription factor THAP1 during development in rat. Neuroscience. 2012; 231:282-95. PMC: 3558550. DOI: 10.1016/j.neuroscience.2012.11.049. View

Huang F, Wang X, Ostertag E, Nuwal T, Huang B, Jan Y . TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing. Nat Neurosci. 2013; 16(9):1284-90. PMC: 4034143. DOI: 10.1038/nn.3468. View

Ledoux M . Non-Parkinson movement disorders: Five new things. Neurol Clin Pract. 2013; 3(1):22-29. PMC: 3613216. DOI: 10.1212/CPJ.0b013e318283ff2d. View

10.

Luo A, Cannon E, Wekesa K, Lyman R, Vandenbergh J, Anholt R . Impaired olfactory behavior in mice deficient in the alpha subunit of G(o). Brain Res. 2002; 941(1-2):62-71. DOI: 10.1016/s0006-8993(02)02566-0. View

11.

Hopfner F, Bungeroth M, Pendziwiat M, Tittmann L, Deuschl G, Schneider S . Rare variants in ANO3 are not a susceptibility factor in essential tremor. Parkinsonism Relat Disord. 2013; 20(1):134-5. DOI: 10.1016/j.parkreldis.2013.09.022. View

12.

Leandro-Garcia L, Leskela S, Landa I, Montero-Conde C, Lopez-Jimenez E, Leton R . Tumoral and tissue-specific expression of the major human beta-tubulin isotypes. Cytoskeleton (Hoboken). 2010; 67(4):214-23. DOI: 10.1002/cm.20436. View

13.

Fuchs T, Saunders-Pullman R, Masuho I, San Luciano M, Raymond D, Factor S . Mutations in GNAL cause primary torsion dystonia. Nat Genet. 2012; 45(1):88-92. PMC: 3530620. DOI: 10.1038/ng.2496. View

14.

Zech M, Gross N, Jochim A, Castrop F, Kaffe M, Dresel C . Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls. Mov Disord. 2013; 29(1):143-7. DOI: 10.1002/mds.25715. View

15.

Xiao J, Bastian R, Perlmutter J, Racette B, Tabbal S, Karimi M . High-throughput mutational analysis of TOR1A in primary dystonia. BMC Med Genet. 2009; 10:24. PMC: 2661056. DOI: 10.1186/1471-2350-10-24. View

16.

Caraballo R, Pavek S, Lemainque A, Gastaldi M, Echenne B, Motte J . Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am J Hum Genet. 2001; 68(3):788-94. PMC: 1274492. DOI: 10.1086/318805. View

17.

Heron S, Dibbens L . Role of PRRT2 in common paroxysmal neurological disorders: a gene with remarkable pleiotropy. J Med Genet. 2013; 50(3):133-9. DOI: 10.1136/jmedgenet-2012-101406. View

18.

Stamelou M, Charlesworth G, Cordivari C, Schneider S, Kagi G, Sheerin U . The phenotypic spectrum of DYT24 due to ANO3 mutations. Mov Disord. 2014; 29(7):928-34. PMC: 4150528. DOI: 10.1002/mds.25802. View

19.

Weber Y, Storch A, Wuttke T, Brockmann K, Kempfle J, Maljevic S . GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest. 2008; 118(6):2157-68. PMC: 2350432. DOI: 10.1172/JCI34438. View

20.

Hedera P, Xiao J, Puschmann A, Momcilovic D, Wu S, Ledoux M . Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia. BMC Neurol. 2012; 12:93. PMC: 3460747. DOI: 10.1186/1471-2377-12-93. View