The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein

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Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen independently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.

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  1. 1

    Fahn, S. Concept and classification of dystonia. Adv. Neurol. 50, 1–8 (1988).

  2. 2

    Chutorian, A.M. Childhood dystonia. Acta Neuropediatr. 2, 33–45 (1996).

  3. 3

    Nutt, J.G., Muenter, M.D., Aronson, A., Kurland, L.T. & Melton, L.J. Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov. Disord. 3, 188–194 (1988).

  4. 4

    Bressman, S.B. et al. Dystonia in Ashkenazi Jews: clinical characterization of a founder mutation. Ann. Neurol. 36, 771–777 (1994).

  5. 5

    Greene, P., Kang, U.J. & Fahn, S. Spread of symptoms in idiopathic torsion dystonia. Mov. Disord. 10, 143–152 (1995).

  6. 6

    Zeman, W. & Dyken, P. Dystonia musculorum deformans: clinical, genetic and patho-anatomical studies. Psychiatr. Neurol. Neurochir. 10, 77–121 (1967).

  7. 7

    Korczyn, A.D. et al. Torsion dystonia in Israel. Ann. Neurol. 8, 387–391 (1980).

  8. 8

    Eldridge, R. The torsion dystonia: literature review; genetic and clinical studies. Neurology 20, 1–78 (1970).

  9. 9

    Ozelius, L.J. et al. Strong allelic association between the torsion dystonia gene (DYT1) and loci on chromosome 9q34 in Ashkenazi Jews. Am. J. Hum. Genet. 50, 619–628 (1992).

  10. 10

    Risch, N.J. et al. Segregation analysis of idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance. Am. J. Hum. Genet. 46, 533–538 (1990).

  11. 11

    Risch, N. et al. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nature Genet. 9, 152–159 (1995).

  12. 12

    Bressman, S.B. et al. Idiopathic dystonia among Ashkenazi Jews: evidence for autosomal dominant inheritance. Ann. Neurol. 26, 612–620 (1989).

  13. 13

    Ozelius, L. et al. Human gene for torsion dystonia located on chromosome 9q32-q34. Neuron 2, 1427–1434 (1989).

  14. 14

    Kramer, P.L. et al. Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-q34. Ann. Neurol. 27, 114–120 (1990).

  15. 15

    Kramer, P.L. et al. The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia (ITD) in non-Jews. Am. J. Hum. Gen. 55, 468–475 (1994).

  16. 16

    Ozelius, L.J. et al. Fine localization of the torsion dystonia gene (DYT1) on human chromosome 9q34: YAC map and linkage disequilibrium. Genome Res. 7, 483–494 (1997).

  17. 17

    Buckler, A.J. et al. Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. Natl. Acad. Sci. USA 88, 4005–4009 (1991).

  18. 18

    Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).

  19. 19

    Frohman, M.A., Dush, M.K. & Martin, G.R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc Natl. Acad. Sci. USA 85, 8998–9002 (1988).

  20. 20

    Kozak, M. An analysis of 5′-noncoding sequences upstream from 699 vertebrate messenger RNAs. Nucleic Acids Res. 15, 8125–8148 (1987).

  21. 21

    Almasy, L. et al. Idiopathic torsion dystonia linked to chromosome 8 markers in a family of German Mennonite origin. Neurology (in the press).

  22. 22

    Schirmer, E.C., Glover, J.R., Singer, M.A. & Lindquist, S. HSP100/Clp proteins: a common mechanism explains diverse functions. Trends Biochem. Sci. 21, 289–296 (1996).

  23. 23

    Perier, F., Radeke, C.M., Raab-Graham, K.F. & Vandenberg, C.A. Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant: identification of a mammalian member of the Clp/HSP104 family. Gene 152, 157–163 (1995).

  24. 24

    Parsell, D.A. & Lindquist, S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu. Rev. Genet. 27, 437–496 (1993).

  25. 25

    Walker, J.E., Sarasti, M., Runswick, M.S. & Gay, N.S. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1, 945–950 (1982).

  26. 26

    Confalonieri, F. & Duguet, M. A 200–amino acid ATPase module in search of a basic function. Bioessays 17, 639–650 (1995).

  27. 27

    Missiakas, D., Schwager, F., Betton, J.-M., Georgopoulos, C. & Raina, J. Identification and characterization of HS1V HS1U (CIpQ ClpY) proteins involved in overall proteolysis of misfolded proteins in Escherichia coli. EMBO J. 15, 5899–6909 (1996).

  28. 28

    Akiyama, Y., Shirai, Y. & Ito, K. Involvement of FtsH in protein assembly into and through the membrane. J. Biol. Chem. 269, 5225–5229 (1994).

  29. 29

    Boyd, D. & Beckwith, J. The role of charged amino acids in the localization of secreted and membrane proteins. Cell 62, 1031–1033 (1990).

  30. 30

    Grosson, G.L., Esteban, J., McKenna-Yasek, D., Gusella, J.F. & Brown, R.H. Hypokalemic periodic paralysis mutations: confirmation of mutation and analysis of founder effect. Neurol. Disord. 6, 27–31 (1995).

  31. 31

    Fontaine, B. et al. Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31–32 in three European families. Nature Genet. 6, 267–272 (1994).

  32. 32

    Bellus, G.A. et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am. J. Hum. Genet. 56, 368–373 (1995).

  33. 33

    Watkins, H. et al. Independent origin of identical beta cardiac myosin heavy-chain mutations in hypertrophic cardiomyopathy. Am. J. Hum. Genet. 53, 1180–1185 (1993).

  34. 34

    Gusella, J.F., Persichetti, F. & MacDonald, M.E. The genetic defect causing Huntington's disease: repeated in other contexts? Mol. Med. 3, 238–246 (1997).

  35. 35

    Paulson, H.L. & Fishbeck, K.H. Trinucleotide repeats in neurogenetic disorders. Ann. Rev. Neurosci. 19, 79–107 (1996).

  36. 36

    Nygaard, T.G. et al. Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q. Nature Genet. 5, 386–391 (1993).

  37. 37

    Endo, K. et al. The gene for hereditary progressive dystonia with marked diurnalfluctuation maps to chromosome 14q. in Monographs in Neural Sciences: Age-Related Dopamine-Dependent Disorders (eds Segawa, M. & Nomura, Y.) 120–125 (Karger, New York, 1995).

  38. 38

    Ludecke, B., Dworniczak, B. & Bartholome, K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum. Genet. 95, 123–125 (1995).

  39. 39

    Knappskog, P.M., Glatmark, T., Mallet, J., Ludecke, B. & Bartholome, K. Recessively inherited L-dopa–responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum. Mol. Genet. 4, 1209–1212 (1995).

  40. 40

    Fink, J.K. et al. Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q. Am. J. Hum. Genet. 59, 140–145 (1996).

  41. 41

    Fouad, G.T., Servidei, S., Durcan, S., Bertini, E. & Ptácek, L.J. A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome 2q. Am. J. Hum. Genet. 59, 135–139 (1996).

  42. 42

    Leube, B. et al. Idiopathic torsion dystonia: assignment of a gene to chromosome 18p in a German family with adult onset, autosomal dominant inheritance and purely focal distribution. Hum. Mol. Genetics 5, 1673–1677 (1996).

  43. 43

    Wilhelmsen, K.D. et al. Genetic mapping of ‘lubag’ (X-linked dystonia-parkinsonism) is a Filipino kindred to the pericentromeric region of the X chromosomes. Ann. Neurol. 29, 124–131 (1991).

  44. 44

    Graeber, M.B., Kupke, K.G. & Muller, U. Delineation of the dystonia-parkinsonism syndrome locus in Xq13. Proc. Natl. Acad. Sci. USA 89, 8245–8248 (1992).

  45. 45

    Furukawa, Y., Mizuno, Y. & Narabayashi, H. Early-onset parkinsonism with dystonia: clinical and biochemical differences from hereditary progressive dystonia or dopa-responsive dystonia. Adv. Neurol. 69, 327–337 (1996).

  46. 46

    LeDoux, M.S., Lorden, J.F. & Meinzen-Derr, J. Selective elimination of cerebellar output in the genetically dystonic rat. Brain Res. 697, 91–103 (1995).

  47. 47

    Brown, A., Bernier, G., Mathieu, M., Rossant, J. & Kothary, R. The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1. Nature Genet. 10, 301–306 (1995).

  48. 48

    Nobrega, J.N., Richter, A., Burnham, W.M. & Loscher, W. Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of paroxysmal dystonia: a quantitative autoradiographic analysis. Neuroscience 64, 229–239 (1995).

  49. 49

    Nobrega, J.N., Richter, A., Tozman, N., Jiwa, D. & Loscher, W. Quantitative autoradiography reveals regionally selective changes in dopamine D1 and D2 receptor binding in the genetically dystonic hamster. Neuroscience 71, 927–937 (1996).

  50. 50

    Pratt, G.D., Richter, A., Mohler, H. & Loscher, W. Regionally selective and age-dependent alterations in benzodiazepine receptor binding in the genetically dystonic hamster. J. Neurochem. 64, 2153–2158 (1995).

  51. 51

    Hedreen, J.C., Zweig, R.M., DeLong, M.R., Whitehouse, P.J. & Price, D.L. Primary dystonias: a review of the pathology and suggestions for new directions of study. Adv. Neurol. 50, 123–132 (1988).

  52. 52

    Pooling, E.C. & Adams, R.D. The pathological anatomy of post-hemiplegic athetosis. Brain 98, 29–48 (1975).

  53. 53

    Bhatia, K.P. & Marsden, C.D. The behavioural and motor consequences of focal lesions of the basal ganglia in man. Brain 117, 859–876 (1994).

  54. 54

    Kulisevsky, J., Avilar, A., Rolg, C. & Escartin, A. Unilateral blepharospasm stemming from a thalamomesencephalic lesion. Mov. Disord. 8, 239–240 (1993).

  55. 55

    Christian, C.D. & Paulson, G. Severe motility disturbance after small doses of prochlorperazine. N. Engl. J. Med. 259, 828–830 (1958).

  56. 56

    Burke, R.E. et al. Tardive dystonia: late onset persistent dystonia caused by antipsychotic drugs. Neurology 32, 1335–1346 (1982).

  57. 57

    Tabaddor, K., Wolfson, L.I. & Sharpless, N.S. Diminished ventricular fluid dopamine metabolites in adult onset dystonia. Neurology 79, 1249–1253 (1978).

  58. 58

    Wolfson, L.I., Sharpless, N.S. & Thai, L.J. Diminished levels of ventricular fluid norpinephrine metabolite and somatostatin in childhood onset dystonia. Adv. Neurol. 50, 177–181 (1988).

  59. 59

    Brashear, A., Farlow, M.R., Butler, I.J., Kasarskis, E.J. & Dobysns, W.B. Variable phenotype of rapid-onset dystonia-parkinsonism. Mov. Disord. 11, 151–156 (1996).

  60. 60

    Gasser, T. et al. Haplotype analysis at the DYT1 locus in Ashkenazi Jewish patients with occupational hand dystonia. Mov. Disord. 11, 163–166 (1996).

  61. 61

    Bressman, S.B. et al. A study of idiopathic torsion dystonia in a non-Jewish family: evidence for genetic heterogeneity. Neurology 44, 283–287 (1994).

  62. 62

    Gusella, J. et al. Precise localization of human beta-globin gene complex on chromosome 11. Proc. Natl. Acad. Sci. USA 76, 5239–5242 (1979).

  63. 63

    Anderson, M. & Gusella, J. Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro (Rockville) 29, 856–858 (1984).

  64. 64

    Sambrook, J., Fritsch, E.F. & Maniatis, T. Extraction, purification and analysis of messanger RNA from eukaryotic cells, in Molecular Cloning: A Laboratory Manual. (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1989).

  65. 65

    Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J. & Rutter, W.J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18, 5294–5300 (1979).

  66. 66

    Newman, P.J. et al. Enzymatic amplification of platelet-specific messenger RNA using the polymerase chain reaction. J. Clin. Invest. 22, 739–743 (1988).

  67. 67

    van Dilla, M.A. & Deaven, L.L. Construction of gene libraries for each human chromosome. Cytometry 11, 208–218 (1990).

  68. 68

    Deaven, L.L. et al. Construction of human chromosome-specific DNA libraries from flow-sorted chromosomes. Cold Spring Harb. Symp. Quant Biol. 51, 159–167 (1986).

  69. 69

    McCormick, M.K. et al. Construction and characterization of a YAC library with a low frequency of chimeric clones from flow-sorted human chromosome 9. Genomics 18, 553–558 (1993).

  70. 70

    Murrell, J. et al. A 500-kilobase region containing the tuberous sclerosis locus (TSC1) in a 1.7-megabase YAC and cosmid contig. Genomics 25, 59–65 (1995).

  71. 71

    Feinberg, A.P. & Vogelstein, B. Addendum to ‘A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity’. Anal. Biochem. 137, 266–267 (1984).

  72. 72

    Apte, A.N. & Siebert, P.O. Anchor-ligated cDNA libraries: a technique for generating a cDNA library for the immediate cloning of the 5′ ends of mRNAs. Biotechniques 15, 890–893 (1993).

  73. 73

    Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).

  74. 74

    Hayashi, K. & Yandell, D.W. How sensitive is PCR-SSCP? Hum. Mutat. 2, 338–346 (1993).

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Correspondence to Laurie J. Ozelius.

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