Summary
The hereditary dystonias include a clinically heterogeneous group of movement disorders varying in symptoms, age of onset, and drug responsiveness. Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, has been implicated in dystonia because of increased serum levels of DBH in some patients, the influence of catecholaminergic drugs on the human phenotypes, and altered norepinephrine levels in several brain regions in dystonia patients and in genetically dystonic rodents. In addition, markers linked to the dystonia gene in two ethnic groups map close to the DBH locus on human chromosome 9q34. Here we evaluate the inheritance of restriction fragment length polymorphisms near the DBH gene in families with four subtypes of hereditary dystonia: Jewish and non-Jewish, early onset, generalized idiopathic torsion dystonia (ITD); dopa-responsive dystonia; and myoclonic dystonia. In all families, obligate recombination events were observed between the DBH and dystonia genes, thus excluding the DBH gene as the primary defect.
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References
Adams LM, Foote SL (1988) Possible involvement of brain noradrenergic neurons in dystonia. Adv Neurol 50:313–333
Anderson MA, Gusella JF (1984) Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro 29:856–858
Breakefield XO, Bressman SB, Kramer PL, Ozelius L, Moskowitz C, Tanzi R, Brin MF, Hobbs W, Kaufman D, Tobin A, Kidd KK, Fahn S, Gusella JF (1986) Linkage analysis in a family with dominantly inherited torsion dystonia: exclusion of the pro-opiomelanocortin and glutamic acid decarboxylase genes and other chromosomal regions using DNA polymorphisms. J Neurogenet 3:159–175
Bressman SB, Fahn S, Burke RE (1988) Paroxysmal nonkinesigenic dystonia. Adv Neurol 50:403–413
Bressman SB, Leon D de, Brin MF, et al (1989) Idiopathic dystonia among Ashkenazi Jews: evidence for autosomal dominant inheritance. Ann Neurol 26:612–620
Burke RE, Brin MF, Leon D de, Bressman SB, Fahn S (1989) Comparison of the clinical course of the Jewish and non-Jewish, juvenile-onset, familial torsion dystonias. Neurology 39:[Suppl] 188
Chakravarti A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, Kazaian HH (1984) Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet 36:1239–1258
Craig SP, Buckle VJ, Lamouroux A, Mallet J, Craig IW (1988) Localization of the human dopamine beta hydroxylase (DBH) gene to chromosome 9q34. Cytogenet Cell Genet 48:48–50
D'Amato T, Leboyer M, Malafosse A, Samolyk D, Lamouroux A, Junien C, Mallet J (1989) Two TaqI dimorphic sites at the human beta-hydroxylase locus. Nucleic Acids Res 17:5871
Davie AM (1979) The “singles” method for segregation analysis under ascertainment. Ann Hum Genet 42:507–512
De Yebenes JG, Vazques A, Martinez A, Mena MA, Rio RM del, de Felipe C, Rio J de (1988a) Biochemical findings in symptomatic dystonias. Adv Neurol 50:167–175
De Yebenes JG, Russell N, Fahn S (1988b) Intracerebral infusion of norepinephrine produces dystonia in the rat. Neurology 38:207
DeYebenes JG, Moskowitz C, Fahn S, Saint-Hilaire MH (1988c) Long-term treatment with levodopa in a family with autosomal dominant torsion dystonia. Adv Neurol 50:101–111
Ebstein RP, Freedman LS, Lieberman A, Park DH, Pasternack B, Goldstein M, Coleman M (1974) A familial study in serum dopamine-beta-hydroxylase levels in torsion dystonia. Neurology 24:684–687
Eldridge R (1970) The torsion dystonias: literature review: genetic and clinical studies. Neurology 20:1–78
Fahn S (1984) The varied clinical expressions of dystonia. Neurol Clin 2:541–554
Fahn S, Marsden CD, Calne DB (1987) Classification and investigation of dystonia. In: Marsden CD, Fahn S (eds) Movement disorders 2. Butterworths, Boston, pp 332–358
Feinberg AP, Vogelstein B (1983) A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6–13
Fletcher NA, Holt IJ, Harding AE, Nygaard TG, Mallet J, Marsden CD (1989) Tyrosine hydroxylase and levodopa responsive dystonia. J Neurol Neurosurg Psychiatry 52:112–114
Gusella J, Varsanyi-Breiner A, Kao FI, Jones C, Puck TT, Keys C, Orkin S, Housman D (1979) Precise localization of human beta-globin gene complex on chromosome 11. Proc Natl Acad Sci USA 76:5239–5242
Hornykiewicz O, Kish SJ, Becker LE, Farley I, Shannak K (1986) Brain neurotransmitters in dystonia musculorum deformans. N Engl J Med 315:347–353
Jankovic J, Svendsen CN, Bird ED (1987) Brain neurotransmitters in dystonia. N Engl J Med 316:278–279
Johnson W, Schwartz G, Barbeau A (1962) Studies on dystonia musculorum deformans. Arch Neurol 7:301–313
Kobayashi K, Kurosawa Y, Fujita K, Nagatsu T (1989) Human dopamine beta-hydroxylase gene: two mRNA types having different 3′-terminal regions are produced through alternative polyadenylation. Nucleic Acids Res 17:1089–1102
Kramer PL, de Leon D, Ozelius L, Risch N, Bressman SB, Brin MF, Schuback DE, Burke RE, Kwiatkowski DJ, Shale H, Gusella JF, Breakefield XO, Fahn S (1990) Dystonia gene in Ashkenazi Jewish population located on chromosome 9q32–34. Ann Neurol 27:114–120
Kurlan R, Behr J, Medved L, Shoulson I (1988) Myoclonus and dystonia: a family study. Adv Neurol 50:385–389
Kurland LT (1958) Epidemiology: incidence, geographic distribution and genetic considerations. In: Fields WS (ed) Pathogenesis and treatment of parkinsonism. Thomas, Springfield, Ill,pp 5–49
Kwiatkowski DJ, Nygaard TG, Schuback DE, Perman S, Bressman S, Burke RE, Brin M, Trugman J, Ozelius L, Breakefield XO, Fahn S, Kramer PL (1991) Highly polymorphic micro-satellite VNTR within the argininosuccinate synthetase locus excludes the DYT1 dystonia gene as a cause of dopa-responsive dystonia in a large kindred. Am J Hum Gen 48:121–128
Kyllerman M, Forsgren L, Sanner G, Holmgren G, Wählstrom J, Drugge U (1990) Alcohol responsive myoclonic dystonia in a large family: dominant inheritance and phenotypic variation. Move Disord 5:270–279
Lathrop GM, Lalouel J-M (1988) Efficient computations in multi-locus linkage analysis. Am J Hum Genet 3:129–136
Lathrop GM, Nakamura Y, O'Connell P, Leppert M, Woodward S, Lalouel J-M, White R (1988) A mapped set of genetic markers for human chromosome 9. Genomics 3:361–366
Lorden JF, Oltmans GA, Stratton S, Mays LE (1988) Neurophar-macological correlates of the motor syndrome of the genetically dystonic (dt) rat. Adv Neurol 50:277–297
Menkes JH, Wetterberg L, Ross SB, Yuwiler A (1987) Catechol-aminergic activity in idiopathic torsion dystonia. Neurology 37:779–783
Northrup H, Lathrop M, Lu S-Y, Daiger SP, Beaudet AL, O'Brien WE (1989) Multilocus linkage analysis with the human argininosuccinate synthetase gene. Genetics 5:442–444
Nygaard T, Trugman J, de Yebenes JG, Fahn S (1990) Dopa-responsive dystonia: the spectrum of clinical manifestations in a large North American family. Neurology 66:66–69
Ozelius L, Kramer PL, Moskowitz CB, Kwiatkowski DJ, Brin MF, Bressman SB, Schuback DE, Falk CT, Risch N, Leon D de, Burke RE, Haines J, Gusella JF, Fahn S, Breakefield XO (1989) Human gene for torsion dystonia located on chromosome 9q32-q34. Neuron 2:1427–1434
Pauls DL, Korczyn AD (1990) Complex segregation analysis of dystonia pedigrees suggests autosomal dominant inheritance. Neurology 40:1107–1110
Perry SE, Phillips JA, Robertson D (1990) fnuD II RFLP at the human dopamine-beta-hydroxylase (DBH) locus. Nucleic Acids Res 19:1162
Quinn NP, Rothwell JC, Thompson PD, Marsden CD (1988) Hereditary myclonic dystonia, hereditary torsion dystonia and hereditary essential myoclonus: an area of confusion. Adv Neurol 50:391–401
Risch N, Bressman SB, Leon D de, et al (1990) Segregation analysis of idiopathic torsion dystonia in Ashkenazi Jews suggests autosomal dominant inheritance. Am J Hum Genet 46:533–538
Schuback DE, Ozelius L, Hu G, Craft CM, Raese J, Breakefield XO, Hsu Y-PP (1990) RFLP for human dopamine beta-hydroxylase gene. Nucleic Acids Res 18:387
Segawa M, Hosaka A, Miyagawa F (1976) Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 14:215–233
Southern E (1979) Gel electrophoresis of restriction fragments. Methods Enzymol 68:152–176
Thomson G (1981) A review of theoretical aspects of HLA and disease associations. Theor Popul Biol 20:168–208
Wilson AF, Elston RC, Siervogel RM, Tran LD (1988) Linkage of a gene regulating dopamine-beta-hydroxylase activity and the ABO blood group locus. Am J Hum Genet 42:160–166
Wilson AF, Elston RC, Sellers TA, Bailey-Wilson JE, Gersting JM, Deen DK, Sorant AJM, Tran LD, Amos CI, Siervogel RM (1990) Stepwise oligogenic segregation and linkage analysis illustrated with dopamine-beta-hydroxylase activity. Am J Med Genet 35:425–432
Wooten GF, Eldridge R, Axelrod J, Stern RS (1973) Elevated plasma dopamine-beta-hydroxylase activity in autosomal dominant torsion dystonia. N Engl J Med 288:284–287
Zilber N, Korczyn AD, Kahana E, et al (1984) Inheritance of idiopathic torsion dystonia among Jews. J Med Genet 218:13–20
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Schuback, D., Kramer, P., Ozelius, L. et al. Dopamine beta-hydroxylase gene excluded in four subtypes of hereditary dystonia. Hum Genet 87, 311–316 (1991). https://doi.org/10.1007/BF00200910
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DOI: https://doi.org/10.1007/BF00200910