Abstract
The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6–8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Fahn S (1988) Concept and classification of dystonia. Adv Neurol 50:1–8
Muller U (2009) The monogenic primary dystonias. Brain 132(Pt 8):2005–2025. doi:10.1093/brain/awp172
Albanese A, Asmus F, Bhatia KP, Elia AE, Elibol B, Filippini G, Gasser T, Krauss JK, Nardocci N, Newton A, Valls-Sole J (2011) EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 18(1):5–18. doi:10.1111/j.1468-1331.2010.03042.x
Kramer PL, Heiman GA, Gasser T, Ozelius LJ, de Leon D, Brin MF, Burke RE, Hewett J, Hunt AL, Moskowitz C et al (1994) The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-jews. Am J Hum Genet 55(3):468–475
Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, de Leon D, Brin MF, Raymond D, Corey DP, Fahn S, Risch NJ, Buckler AJ, Gusella JF, Breakefield XO (1997) The early-onset torsion dystonia gene (DYT1) encodes an atp-binding protein. Nat Genet 17(1):40–48. doi:10.1038/ng0997-40
Fuchs T, Gavarini S, Saunders-Pullman R, Raymond D, Ehrlich ME, Bressman SB, Ozelius LJ (2009) Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia. Nat Genet 41(3):286–288. doi:10.1038/ng.304
Bressman SB, de Leon D, Brin MF, Risch N, Burke RE, Greene PE, Shale H, Fahn S (1989) Idiopathic dystonia among Ashkenazi Jews: evidence for autosomal dominant inheritance. Ann Neurol 26(5):612–620. doi:10.1002/ana.410260505
Gerace L (2004) TorsinA and torsion dystonia: unraveling the architecture of the nuclear envelope. Proc Natl Acad Sci USA 101(24):8839–8840. doi:10.1073/pnas.0402441101
Giles LM, Chen J, Li L, Chin LS (2008) Dystonia-associated mutations cause premature degradation of torsinA protein and cell-type-specific mislocalization to the nuclear envelope. Hum Mol Genet 17(17):2712–2722. doi:10.1093/hmg/ddn173
Gonzalez-Alegre P, Paulson HL (2004) Aberrant cellular behavior of mutant torsinA implicates nuclear envelope dysfunction in DYT1 dystonia. J Neurosci 24(11):2593–2601. doi:10.1523/JNEUROSCI.4461-03.2004
Goodchild RE, Dauer WT (2004) Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Proc Natl Acad Sci USA 101(3):847–852. doi:10.1073/pnas.0304375101
Goodchild RE, Kim CE, Dauer WT (2005) Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron 48(6):923–932. doi:10.1016/j.neuron.2005.11.010
Granata A, Schiavo G, Warner TT (2009) TorsinA and dystonia: from nuclear envelope to synapse. J Neurochem 109(6):1596–1609. doi:10.1111/j.1471-4159.2009.06095.x
Naismith TV, Heuser JE, Breakefield XO, Hanson PI (2004) TorsinA in the nuclear envelope. Proc Natl Acad Sci USA 101(20):7612–7617. doi:10.1073/pnas.0308760101
Nery FC, Zeng J, Niland BP, Hewett J, Farley J, Irimia D, Li Y, Wiche G, Sonnenberg A, Breakefield XO (2008) TorsinA binds the kash domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton. J Cell Sci 121(Pt 20):3476–3486. doi:10.1242/jcs.029454
Vander Heyden AB, Naismith TV, Snapp EL, Hodzic D, Hanson PI (2009) Lull1 retargets torsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. Mol Biol Cell 20(11):2661–2672. doi:10.1091/mbc.E09-01-0094
Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, Saunders-Pullman R (2009) Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study. Lancet Neurol 8(5):441–446. doi:10.1016/S1474-4422(09)70081-X
Cayrol C, Lacroix C, Mathe C, Ecochard V, Ceribelli M, Loreau E, Lazar V, Dessen P, Mantovani R, Aguilar L, Girard JP (2007) The THAP-zinc finger protein THAP1 regulates endothelial cell proliferation through modulation of prb/e2f cell-cycle target genes. Blood 109(2):584–594. doi:10.1182/blood-2006-03-012013
Gavarini S, Cayrol C, Fuchs T, Lyons N, Ehrlich ME, Girard JP, Ozelius LJ (2010) Direct interaction between causative genes of DYT1 and DYT6 primary dystonia. Ann Neurol 68(4):549–553. doi:10.1002/ana.22138
Kaiser FJ, Osmanoric A, Rakovic A, Erogullari A, Uflacker N, Braunholz D, Lohnau T, Orolicki S, Albrecht M, Gillessen-Kaesbach G, Klein C, Lohmann K (2010) The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Ann Neurol 68(4):554–559. doi:10.1002/ana.22157
Forsgren L, Holmgren G, Almay BG, Drugge U (1988) Autosomal dominant torsion dystonia in a Swedish family. Adv Neurol 50:83–92
Holmgren G, Ozelius L, Forsgren L, Almay BG, Holmberg M, Kramer P, Fahn S, Breakefield XO (1995) Adult onset idiopathic torsion dystonia is excluded from the DYT1 region (9q34) in a Swedish family. J Neurol Neurosurg Psychiatry 59(2):178–181
Blomstedt P, Hariz MI, Tisch S, Holmberg M, Bergenheim TA, Forsgren L (2009) A family with a hereditary form of torsion dystonia from northern Sweden treated with bilateral pallidal deep brain stimulation. Mov Disord 24(16):2415–2419. doi:10.1002/mds.22842
Nutt JG, Muenter MD, Aronson A, Kurland LT, Melton LJ 3rd (1988) Epidemiology of focal and generalized dystonia in rochester, minnesota. Mov Disord 3(3):188–194. doi:10.1002/mds.870030302
Defazio G (2010) The epidemiology of primary dystonia: current evidence and perspectives. Eur J Neurol 17(Suppl 1):9–14. doi:10.1111/j.1468-1331.2010.03053.x
Lichte B, Veh RW, Meyer HE, Kilimann MW (1992) Amphiphysin, a novel protein associated with synaptic vesicles. EMBO J 11(7):2521–2530
Olsson A, Lind L, Thornell LE, Holmberg M (2008) Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. Hum Mol Genet 17(11):1666–1672. doi:10.1093/hmg/ddn057
Acknowledgments
We thank the members of the family for their invaluable participation in the study. The work was supported by the Bachmann-Strauss Dystonia and Parkinson Foundation and the Swedish Research Council.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Norgren, N., Mattson, E., Forsgren, L. et al. A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3. Neurogenetics 12, 137–143 (2011). https://doi.org/10.1007/s10048-011-0274-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-011-0274-9