Nature Genetics
10, 61 - 66 (1995)
doi:10.1038/ng0595-61
Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutasePeter M. Andersen1, Peter Nilsson2, Veli Ala-Hurula3, Marja-Leena Keränen4, Ilkka Tarvainen5, Tuula Haltia6, Lotta Nilsson2, Michael Binzer1, Lars Forsgren1
& Stefan L. Marklund2
1Departments of Neurology, Umeå, University Hospital, S-901 85 Umeå, Sweden
2Clinical Chemistry, Umeå, University Hospital, S-901 85 Umeå, Sweden
3Department of Neurology, Centrallasarettet Kemi, SF-941 00 Kemi, Finland
4Department of Neurology, Lapin Keskussairaala, SF-961 01 Rovaniemi, Finland
5Department of Neurology, Mikkelin Keskussairaala, SF-501 00 Mikkeli, Finland
6Kauniala Sjukhus för krigsinvalider, SF-02700 Kauniainen, Finland Correspondence should be addressed to S.L.M. Recent reports have shown heterozygosity for some twenty different mutations in the CuZn−superoxide dismutase (CuZn−SOD) gene in familial amyotrophic lateral sclerosis (FALS), and analysed samples from patients have shown decreased enzymic activity. Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland. The erythrocyte CuZn−SOD activity is essentially normal. Our findings suggest that this CuZn−SOD mutation causes ALS by a gain of function rather than by loss, and that the Asp90Ala mutation is less detrimental than previously reported mutations.
REFERENCES
- Tandan, R. & Bradley, W.G. Amyotrophic lateral sclerosis Part 1. Clinical features, pathology, and ethical issues in management. Ann. Neurol. 18, 271−280 (1985). | PubMed | ISI | ChemPort |
- Rosen, D.R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59−62 (1993). | Article | PubMed | ISI | ChemPort |
- Ogasawara, M. et al. Mild ALS in Japan associated with novel SOD mutation. Nature Genet 5, 323−324 (1993). | PubMed | ISI |
- Rainero, I. et al. SOD1 missense mutation in an Italian family with ALS. Neurology 44, 347−349 (1994). | PubMed | ISI | ChemPort |
- Elshafey, A., Lanyon, W.O. & Conner, J.M. Identification of a new missense point mutation in exon 4 of the Cu/Zn superoxide dismutase gene in a family with amyotrophic lateral sclerosis. Hum. molec. Genet. 3, 363−364 (1994). | PubMed | ISI | ChemPort |
- Jones, C.T., Swingler, R.J. & Brock, D.J.H. Identification of a novel SOD1 mutation in an apparently sporadic amyotrophic lateral sclerosis patient and the detection of lle113Thr in three others. Hum. molec. Genet. 3, 649−650 (1994). | PubMed | ISI | ChemPort |
- Nakano, R. et al. A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. Biochem. Biophys. Res. Comms. 200, 695−703 (1994). | Article | ChemPort |
- Siddique, T., Deng, H.-X., Hentati, A., Hung, W.-Y., He, X.-X. & Mitsumoto, H. Identification of new mutations in famlial amyotrophic lateral sclerosis. Am. J. hum. Genet. 55, A1419 (1994).
- Tsuda, T. et al. Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis. Neuron 13, 727−736 (1994). | Article | PubMed | ISI | ChemPort |
- Pramatarova, A. et al. Identification of new mutations in the CuZn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis. Am. J. hum. Genet. 56, 592−596 (1995). | PubMed | ISI | ChemPort |
- Deng, H.-X. et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 261, 1047−1051 (1993). | PubMed | ISI | ChemPort |
- Robberecht, W. et al. Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis. J. Neurochem. 62, 384−387 (1994). | PubMed | ISI | ChemPort |
- Bowling, A.C., Schulz, J.B., Brown, R.H. & Beal, M.F. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J. Neurochem. 61, 2322−2325 (1993). | PubMed | ISI | ChemPort |
- Borchelt, D.R. et al. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc. natn. Acad. Sci. U.S.A. 91, 8292−8296 (1994). | ChemPort |
- Weisiger, R.A. & Fridovich, I. Mitochondrial superoxide dismutase. Site of synthesis and intramitochondrial localisation. J. biol. Chem. 248, 4793−4796 (1973). | PubMed | ISI | ChemPort |
- Marklund, S.L. Human copper-containing superoxide dismutase of high molecular weight. Proc. nafn. Acad. Sci. U.S.A. 79, 7634−7638 (1982). | ChemPort |
- Gumey, M.E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772−1775 (1994). | PubMed | ISI | ChemPort |
- McCord, J.M. & Fridovich, I. Superoxide dismutase, an enzymic function for erythrocuprein. J. biol. Chem. 244, 6049−6055 (1969). | PubMed | ISI | ChemPort |
- Levanon, D. et al. Architecture and anatomy of the chromosomal locus in human chromosome 21 encoding the Cu/Zn superoxide dismutase. EMBO J. 4, 77−84 (1985). | PubMed | ISI | ChemPort |
- Ohman, M. & Marklund, S.L. Plasma extracellular superoxide dismutase and erythrocyte Cu Zn-containing superoxide dismutase in alcoholics treated with disulfiram. Clin. Sci. 70, 365−369 (1986). | PubMed | ISI | ChemPort |
- Kurland, L.T. & Mulder, D.W. Epidemiological investigations of amyotrophic lateral sclerosis: 2 Familial aggregations indicative of dominant inheritance. Neurology 5, 182−196 & 249−268 (1955). | PubMed | ISI | ChemPort |
- Chio, A., Brignolio, F., Meineri, P. & Schiffer, D. Phenotypic and genotypic heterogeneity of dominantly inherited amyotrophic lateral sclerosis. Acta Neurol. Scand. 75, 277−282 (1987). | PubMed | ISI | ChemPort |
- Myllyla, V.V., Toivakka, E., Ala-Hurula, V., Hokkanen, E. & Emeryk-Szajewska, B. Juvenile amyotrophic lateral sclerosis: a report of two cases in a single family. Acta Neurol. Scand. 69, 170−177 (1979).
- Hentati, A. et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33−q35. Nature Genet. 7, 425−428 (1994). | Article | PubMed | ISI | ChemPort |
- Dumon, J., Macken, J. & de Barsy, T.H. Concordance for amyotrophic lateral sclerosis in a pair of dizygous twins of consanguineous parents. J. med. Genet. 8, 113−116 (1971). | PubMed | ISI | ChemPort |
- Beckman, G. Population studies in northern Sweden VI. Polymorphism of superoxide dismutase. Hereoditas 73, 305−309 (1973). | ChemPort |
- Beckman, G. & Pakarinen, A. Superoxide dismutase, a population study. Hum. Hereof. 23, 346−351 (1973). | ChemPort |
- Eriksson, A.W. Genetic polymorphisms in finno-ugrian populations. Israel J. med. Sci. 9, 1156−1170 (1973). | PubMed | ISI | ChemPort |
- Beckman, G., Beckman, L. & Nilsson, L.-O. Genetics of human superoxide dismutase. Heriditas 79, 43−46 (1975). | ChemPort |
- Själander, A. et al. Molecular characterisation of a missense mutation in the CuZn superoxide dismutase with normal enzyme activity. Hum. molec. Genet. (in the press).
- Forsgren, L., Almay, B.G., Holmgren, G. & Wall, S. Epidemiology of motor neuron disease in northern Sweden. Acta Neurol. Scand. 68, 20−29 (1983). | PubMed | ISI | ChemPort |
- Tainer, J.A., Getzoff, E.D., Beem, K.M., Richardson, J.S. & Richardson, D.L. Determination and analysis of the 2A structure of copper zinc superoxide dismutase. J. molec. Biol. 160, 181−217 (1982). | PubMed | ISI | ChemPort |
- Bordo, D., Djinovic, K. & Bolognesi, M. Conserved patterns in the CuZn superoxide dismutase family. J. molec. Biol. 238, 366−386 (1994). | Article | PubMed | ISI | ChemPort |
- Beckman, J.S., Larson, M., Smith, C.D. & Koppenol, W.H. ALS, SOD and peroxynitrite. Nature 364, 584 (1993). | Article | PubMed | ISI | ChemPort |
- Yim, M.B., Chock, P.B. & Stadtman, E.R. Enzyme function of copper. zinc superoxide dismutase as a free radical generator. J. biol. Chem. 268, 4099−4105 (1993). | PubMed | ISI | ChemPort |
- Swash, M. & Leigh, P.M. Criteria for diagnosis of familial amyotrophic lateral sclerosis. Neuromusc. Disord. 2, 7−9 (1992). | Article | PubMed | ChemPort |
- Marklund, S.L. Spectrophotometric study of spontaneous disproportionation of superoxide anion radical and sensitive direct assay for superoxide dismutase. J. biol. Chem. 251, 7504−7507 (1976). | PubMed | ISI | ChemPort |
- Marklund, S.L. Direct assay of superoxide dismutase with potassium superoxide. In Handbook of methods for oxygen radical research. (ed. Greenwald, R.A.) (CRC Press Inc., Boca Raton, 249−255 1985).
- Miettinen, O.S. Simple interval estimation of risk ratio. Am. J. Epidemiol. 100, 515−516 (1974). | ISI |
|
