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zinc superoxide dismutase (SOD1) gene mutations
Neuromuscular Disorders 10 (2000) 63±68 www.elsevier.com/locate/nmd
Amyotrophic lateral sclerosis: copper/zinc superoxide dismutase (SOD1) gene mutations Richard W. Orrell* University Department of Clinical Neurosciences, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK Received 16 June 1999; accepted 1 July 1999
Abstract Mutations of the SOD1 gene, encoding the enzyme copper/zinc superoxide dismutase, have been identi®ed in around 20% of patients with familial amyotrophic lateral sclerosis (ALS), and also in patients with apparently sporadic ALS. The table documents the mutations identi®ed and published to date, and references clinical and pathological descriptions of the patients and families with individual mutations. The table includes 63 different mutations of SOD1 at 43 codons, three intronic sites, and two in the 3 0 untranslated region. Most of the mutations are heterozygotes, with autosomal dominant inheritance, but a small number of individuals appear to be sporadic, or are homozygotes with autosomal dominant recessive inheritance. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Amyotrophic lateral sclerosis; SOD1; Genetics
1. Introduction Mutations of the SOD1 gene in amyotrophic lateral sclerosis (ALS) were ®rst identi®ed by Rosen et al. [47]. Around 5±10% of patients with ALS have other affected family members, and mutations of SOD1 are present in around 20% of these familial patients, and also in occasional apparently sporadic patients. This represents only 1±2% of all patients with ALS. A causal relationship has not been demonstrated for all the mutations reported, and the mechanism by which the mutations cause the disease has still to be clari®ed. Many of the mutations are at present unique to individual families. Reports of attempts to correlate genotype with phenotype have demonstrated that, for an individual, the severity of disease, as determined by time of onset or duration of disease, is generally dif®cult to predict on the basis of the SOD1 mutation [4,9,42]. Some mutations, however, appear to predict a more rapid course of disease, for example, Ala4Val, (which accounts for around 50% of mutations reported in the USA [9]). In Scandinavia, the ®nding of a homozygote form of the disease, also appears to have an Asp90A1a de®nable phenotype [3]. Otherwise in general the prognosis is similar to that of ALS in general, with median age at onset 46 years (range 24±72 years), and median duration of disease 3.0 years (range 0.3±20 years) * Tel.: 144-171-830-2387; fax: 144-171-431-1577. E-mail address: [email protected] (R.W. Orrell)
[42]. Penetrance is age dependent, and in families with autosomal dominant inheritance of the mutation, the disease may appear to skip several generations [40]. The clinical features of an individual patient with an SOD1 mutation are indistinguishable from those without an SOD1 mutation, although there is a tendency for the disease to commence in the limbs rather than the bulbar region. Molecular pathological studies may be expected to yield more detailed information on the pathogenesis of the disease. The reported number of patients is small. The pathology of ALS patients with SOD1 mutations has recently been investigated and reviewed by Ince et al. [21], focusing on the nature of neuronal inclusions, the signi®cance of which remains uncertain. The disease appears not to be caused by loss of SOD enzyme activity, but by gain of an as yet unknown toxic function, consistent with the predominant autosomal dominant pattern of inheritance. The major gene abnormalities in the other 80% of families with ALS, and the genetic contribution to the remainder of apparently sporadic ALS, representing around 98% of all patients with ALS, remain unknown. These are being explored by clinical molecular genetic studies, molecular pathological studies, studies of SOD1 patients and families, and studies of transgenic mouse models incorporating mutations of SOD1 found in human ALS. Linkage studies in both recessive and dominant forms of ALS have de®ned linkage in the recessive forms, e.g. ALS2 at 2q33
0960-8966/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0960-896 6(99)00071-1
GCC ! ACC
4
Leu-Phe Leu ! Val
TTG ! TTC TTG ! GTG
GGC -CGC AAT ! AGT GAC ! GCC
GAC ! GTC GGT ! AGT
85 86 90
90 93
Asp ! Val Gly ! Ser
Gly ! Arg Asn ! Ser Asp ! Ala
Asp ! Tyr
Gly ! Ser
GGT ! AGT
GAT ! TAT
Gly ! Asp His ! Arg His ! Arg His ! Gln
GGC ! GAC CAT ! CGT CAT ! CGT CAT ! CAG
76 Exon 4 84 84
41 43 46 48 Exon 3 72
s/m s/m
s/m s/m s/m
s/m s/m
s/m
s/m
s/m s/m s/m s/m
s/m s/m s/m
Gly ! Arg Leu ! Val Gly ! Ser
GGA ! AGA CTG ! GTG GGC ! AGC
s/m s/m s/m s/m s/m s/m s/m s/m
s/m
s/m
Nature /effect of mutation
s/u
Cys ! Phe Val ! Glu Leu ! Gln Val ! Met Val ! Gly Gly ! Ser Glu ! Lys Glu ! Gly
Ala ! Thr
Ala ! Val
Amino acid change
T!A
TGC ! TTT GTG ! GAG CTG ! CAG GTG ! ATG GTG ! GGG GGC ! AGC GAG ! AAG GAG ! GGG
GCC ! GTC
Exon 1 4
6 7 8 14 14 16 21 21 Intron 1 2108 bp Exon 2 37 38 41
Base change
Codon
Table 1 Gene table
AD AD AD AD AD AD Homo AD and S Homo AR and S Homo AD and S Homo S S AD AD
AD AD AD
AD AD AD AD AD AD AD AD
S
1 1 1 1 1 1 2 and 1 9 and 7 1 and 3 2 1 1 1
1 1 1
1 2 1 1 1 1 2 1
1
1 1 1 1 1 1 1 1
1 2
AD AD AD AD AD AD AD S S AD
27
Number of families reported
AD
Inheritance
UK USA Japan Japan USA Pakistan Belgium Sweden/Finland Sweden/Finland Finland UK Japan Japan
UK UK Denmark
USA USA USA Italy USA USA Japan UK
UK
Japan Japan Austria USA Sweden Japan UK France
Sweden Japan
USA
Country
C C C C
C C C
C C
C
C C C
C C C C C C C CP
CP
C C
C P C C P C C C
Clinical or pathological description
Shaw et al. (1998) Deng et al. (1995) Ohnishi et al. (1996) Aoki et al. (1995) Deng et al. (1993) Hayward et al. (1998) Robberecht et al. (1996) Andersen et al. (1996) Andersen et al. (1997) Andersen et al. (1997) Jackson et al. (1997) Morita et al. (1998) Kawata et al. (1997)
Orrell et al. (1997a) Shaw et al. (1998) Andersen et al. (1997)
Cudkowicz et al. (1997) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Rainero et al. (1994) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Abe et al. (1996) Shaw et al. (1996)
Ince et al. (1998)
Cudkowicz et al. (1997) Cudkowicz et al. (1998) Andersen et al. (1997) Nakano et al. (1994) Takahashi et al. (1994) Morita et al. (1996) Hirano et al. (1994) Bereznai et al. (1997) Deng et al. (1995) Andersen et al. (1997) Kawamata et al. (1997) Jones et al. (1995) Moulard et al. (1995)
Reference
[49] [11] [37] [5] [10] [15] [46] [3] [4] [4] [22] [34] [28]
[41] [49] [4]
[9] [9] [9] [45] [9] [9] [1] [50]
[21]
[9] [8] [4] [36] [53] [33] [17] [6] [11] [4] [26] [23] [35]
Ref no.
64 R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68
Asp ! Val Asp ! His Leu ! Gly, Gln, Arg, Trp, Lys, Stop Gly ! Gly, Gly, Gln, Arg, Trp, Lys, Stop Glu ! Asp, Stop Glu ! ± Ser ! Asn Asn ! Lys Leu ! Ser
CGC ! GGC GTG ! AAAACTG
A!G
GAT ! GTT GAC ! CAC TTC ! ±G
115 118
ins TGGG
insTT GAA ! ± AGT ! AAT AAC ! AAA TTG ! TCG
127
132 133 134 139 144
2 10 bp Exon 5 124 125 126
T!G
add Phe, Phe, Thr, s/it Gly, Pro, Stop add Phe, Leu, Gln s/i
GGA ! GTA ATC ! ACC ATT ! ACT
108 112 113
Intron 4 2 11 bp
Arg ! Gly Val ! Lys, Thr, Gly, Pro, Stop
GAT ! AAT GAT ! GGT ATC ! TTC CTC ! GTC
Gly ! Val Ile ! Thr Ile ! Thr
Asp ! Asn Asp ! Gly Ile ! Phe Leu -Val
i/mt d/d s/m s/m s/m
i/it
s/m s/m d/it
s/m i/it
s/m s/m s/m
s/m s/m s/m s/m
s/m s/m s/m s/m s/m s/m s/m
101 101 104 106
Gly ! Cys Gly ! Arg Gly ! Asp Gly ! Ala Gly ! Val Glu ! Lys Glu ! Gly
GGT ! TGT GGT ! CGT GGT ! GAT GGT ! GCT GGT ! GTT GAA ! AAA GAA -GGA
Nature /effect of mutation
93 93 93 93 93 100 100
Amino acid change
Base change
Codon
Table 1 (continued)
AD S AD AD AD
AD
AD AD AD
1 1 1 1 1
1
1 1 1
1
2 1 3 1 1 1 1 1 1 1 1 2 1 1 1 1 and 1 1 and 1 2 1 1
AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD and S AD and S S AD S
AD
1 1 1 1 1
Number of families reported
AD AD AD AD AD
Inheritance
UK USA Japan Canada USA
Denmark
USA UK Japan
USA
USA New Zealand UK UK UK UK Japan USA Japan UK USA USA Australia UK Canada Japan UK UK Germany UK
USA UK USA USA UK
Country
C
C C C
C
C C CP
C
C C C CP C C C C C C C C C CP CP CP CP C C C
C C C C C
Clinical or pathological description
Orrell et al. (1997b) Hosler et al. (1996) Watanabe et al. (1997) Pramatarova et al. (1995) Cudkowicz et al. (1997)
Andersen et al. (1997)
Hosler et al. (1996) Enayat et al. (1995) Kato et al. (1996)
Cudkowicz et al. (1997)
Siddique and Deng (1996)
Cudkowicz et al. (1997) Orrell et al. (1995a) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Hosler et al. (1996) Siddique and Deng (1996) Cudkowicz et al. (1997) Calder et al. (1995) Orrell et al. (1997b) Ince et al. (1996) Orrell et al. (1996) Orrell et al. (1997b) Abe et al. (1996) Cudkowicz et al. (1997) Kawamata et al. (1994) Orrell et al. (1997c) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Suthers et al. (1994) Orrell et al. (1995b) Rouleau et al. (1996) Kikugawa et al. (1997) Ince et al. (1998) Jackson et al. (1997) Kostrzewa et al. (1994) Jackson et al. (1997)
Reference
[42] [18] [54] [44] [9]
[4]
[18] [12] [24]
[9]
[51]
[9] [38] [9] [9] [18] [51] [9] [7] [42] [20] [20] [42] [1] [9] [25] [43] [9] [9] [52] [39] [48] [29] [21] [22] [30] [22]
Ref no.
R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68 65
TTG ! TTC GCT ! ACT TGT-CGT GTA ! GGA GTA ! ATA ATT ! ACT
ACC ! ATC
144 145 146 148 148 149
151 3 0 UTR bp726 bp 816±819
Variants Exon 1 10 Exon 3 59 Exon 5 139 140 153
Gly ! Gly
Ser ! Ser
Asn ! Asn Ala ! Ala Gln ! Gln
ACT ! AGC
AAC ! AAT GCT ! GCA CAA ! CAG
Thr ! Ile
Leu ! Phe Ala ! Thr Cys ! Arg Val ! Gly Val ! Ile Ile ! Thr
Amino acid change
GGC ! GGT
Polymorphisms Intron 2 Unknown Bgl II Intron 3 34 A!C
Deleted Deleted
Base change
Codon
Table 1 (continued)
d/u d/u
s/m
s/m s/m s/m s/m s/m s/m
Nature /effect of mutation
S
S
S S
AD
AD AD AD AD AD AD
Inheritance
1 1 1
1
1
1 1
1 1 1 1 1 1 1 1
Number of families reported
Scandinavia USA Scandinavia
USA
UK
UK UK
Canada USA Japan USA Japan Canada UK Germany
Country
CP CP
C C
C C
C
Clinical or pathological description
Andersen et al. (1997) Hosler et al. (1996) Andersen et al. (1997)
Hosler et al. (1996)
[4] [18] [4]
[18]
[22]
[13]
Esteban et al. (1994)
Jackson et al. (1997)
[32]
[21] [21]
[44] [9] [27] [9] [1] [44] [42] [31]
Ref no.
Levanon et al. (1985)
Ince et al. (1998) Ince et al. (1998)
Pramatarova et al. (1995) Cudkowicz et al. (1997) Kawamata et al. (1995) Cudkowicz et al. (1997) Abe et al. (1996) Pramatarova et al. (1995) Orrell et al. (1997b) Kostrzewa et al. (1996)
Reference
66 R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68
R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68
[19] and ALS5 at 15q15-22 [16]. Variants of the gene encoding the heavy neuro®lament subunit have been identi®ed in a small number of patients [2,14]. The SOD1 gene has 5 exons, and encodes a protein with 153 amino acids [32]. The active enzyme is homodimeric. Table 1 includes 63 different mutations of SOD1 at 43 codons, three intronic sites, and two in the 3 0 untranslated region (UTR). Most of the mutations are heterozygote, with autosomal dominant inheritance (AD), but a small number of individuals appear to be sporadic (S), or are homozygote (Homo) with autosomal recessive inheritance (AR). 2. Footnotes Table 1 includes key references, which especially relate to reports which include details of the clinical (C) or pathological (P) features of the patients. Many of the mutations were ®rst reported by Rosen et al. [47] and Deng et al. [10], but clinical details were not given at that time. The number of families reported is given where available, as an indication of the relative frequency of the mutations. The country of origin of the patient, or report, is given. This does not necessarily indicate the true frequency, country of origin, or ethnicity of the patient. The nature of the mutation ± base substitution (s), base insertion (i), base deletion (d), and predicted result of mutation ± missense/amino acid substitution (m), uncertain or unknown (u), amino acid insertion (i), and premature termination of protein (t). References [1] Abe K, Aoki M, Ikeda M, Watanabe M, Hirai S, Itoyama Y. Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations. J Neurol Sci 1996;136:101± 108. [2] Al-Chalabi A, Andersen PM, Nilsson P, et al. Deletions of the heavy neuro®lament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet 1999;8:157±164. [3] Andersen PM, Forsgren L, Binzer M, et al. Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. Brain 1996;119:1153±1172. [4] Andersen PM, Nilsson P, Keranen ML, et al. Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain 1997;120:1723±1737. [5] Aoki M, Abe K, Houi K, et al. Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel Cu/ Zn superoxide dismutase mutation. Ann Neurol 1995;37:676±679. [6] Bereznai B, Winkler A, Borasio GD, Gasser T. A novel SOD1 mutation in an Austrian family with amyotrophic lateral sclerosis. Neuromusc Disord 1997;7:113±116. [7] Calder VL, Domigan NM, George PM, Donaldson IM, Winterbourn CC. Superoxide dismutase (glu100gly) in a family with inherited motor neuron disease: detection of mutant superoxide dismutase activity and the presence of heterodimers. Neurosci Lett 1995;189:143±146. [8] Cudkowicz ME, McKennar-Yasek D, Chen C, Hedley-Whyte ET, Brown RH. Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc dismutase gene. Ann Neurol 1998;43:703±710.
67
[9] Cudkowicz ME, McKennar-Yasek D, Sapp PE, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol 1997;41:210±221. [10] Deng HX, Hentati A, Tainer JA, et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 1993;261:1047±1051. [11] Deng HX, Tainer JA, Mitsumoto H, et al. Two novel SOD1 mutations in patients with familial amyotrophic lateral sclerosis. Hum Mol Genet 1995;4:1113±1116. [12] Enayat ZE, Orrell RW, Claus A, et al. Two novel mutations in the gene for copper zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis. Hum Mol Genet 1995;4:1239±1240. [13] Esteban J, Rosen DR, Bowling AC, et al. Identi®cation of two novel mutations and a new polymorphism in the gene for Cu/Zn superoxide dismutase in patients with amyotrophic lateral sclerosis. Hum Mol Genet 1994;3:997±998. [14] Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien JP. Variants of the heavy neuro®lament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet 1994;3:1757±1761. [15] Hayward C, Brock DJH, Minns RA, Swingler RJ. Homozygosity for Asn86Ser mutation in the CuZn-superoxide dismutase gene produces a severe clinical phenotype in a juvenile onset case of familial amyotrophic lateral sclerosis. J Med Genet 1998;35:174±176. [16] Hentati A, Ouahchi K, Pericak-Vance MA, et al. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers. Neurogenetics 1998;2:55±60. [17] Hirano M, Fujii J, Nagai Y, et al. A new variant Cu/Zn superoxide dismutase (Val7Glu) deduced from lymphocyte mRNA sequences from Japanese patients with familial amyotrophic lateral sclerosis. Biochem Biophys Res Commun 1994;204:572±577. [18] Hosler BA, Nicholson GA, Sapp PC, et al. Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis. Neuromusc Disord 1996;6:361±366. [19] Hosler NA, Sapp PC, Berger R, et al. Re®ned mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus (ALS2) on chromosome 2q33. Neurogenetics 1998;2:34±42. [20] Ince PG, Shaw PJ, Slade JY, Jones C, Hudgson P. Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes. Acta Neuropathol 1996;92:395±403. [21] Ince PG, Tomkins J, Slade JY, Thatcher NM, Shaw PJ. Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of ®ve new cases, and comparison with previous reports and 73 sporadic cases of ALS. J Neuropathol Exp Neurol 1998;57:895±904. [22] Jackson M, Al-Chalabi A, Enayat ZE, Chioza B, Leigh PN, Morrison KE. Copper/zinc superoxide dismutase 1 and sporadic amyotrophic lateral sclerosis: analysis of 155 cases and identi®cation of a novel insertion mutation. Ann Neurol 1997;42:803±807. [23] Jones CT, Swingler RJ, Simpson SA, Brock DJH. Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients. J Med Genet 1995;32:290±292. [24] Kato S, Shimoda M, Watanabe Y, Nakashima K, Takahashi K, Ohama E. Familial amyotrophic lateral sclerosis with a two base pair deletion in superoxide dismutase 1 gene: multisystem degeneration with intracytoplasmic hyaline inclusions in astroctyes. J Neuropathol Exp Neurol 1996;55:1089±1101. [25] Kawamata J, Hasegawa H, Shimohama S, Kimura J, Tanaka S, Ueda K. Leu106Val (CTC-GTC) mutation of superoxide dismutase 1 gene in patient with familial amyotrophic lateral sclerosis in Japan. Lancet 1994;343:1501. [26] Kawamata J, Shimohama S, Takano S, Harada K, Ueda K, Kimura J. Novel G16S (GGC-AGC) mutation in the SOD1 gene in a patient with apparently sporadic young-onset amyotrophic lateral sclerosis. Hum Mutat 1997;9:356±358. [27] Kawamata J, Shimohama S, Hasegawa H, et al. Abstract of Eleventh
68
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[38] [39]
[40]
R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68 TMIN International Symposium, 1995 referenced in Siddique T, Denge, H.-X. Genetics of amyotrophic lateral sclerosis. Hum Mol Genet 1996;5:1465-1470. Kawata A, Kato S, Hayashi H, Hirai S. Prominent sensory and autonomic disturbances in familial amyotrophic lateral sclerosis with a Gly93Ser mutation in the SOD1 gene. J Neurol Sci 1997;153:82±85. Kikugawa K, Nakano R, Inuzuka T, et al. A missense mutation in the SOD1 gene in patients with amyotrophic lateral sclerosis from the Kii Peninsula and its vicinity. Japan. Neurogenetics 1997;1:113±115. Kostrzewa M, Burck-Lehmann U, Muller U. Autosomal dominant amyotrophic lateral sclerosis: a novel mutation in the Cu/Zn superoxide dismutase 1 gene. Hum Mol Genet 1994;3:2261±2262. Kostrzewa M, Damian MS, Muller U. Superoxide dismutase 1: identi®cation of a novel mutation in a case of familial amyotrophic lateral sclerosis. Hum Genet 1996;98:48±50. Levanon D, Lieman-Hurwitz J, Dafni N, et al. Architecture and anatomy of the chromosomal locus in human chromosome 21 encoding the Cu/Zn superoxide dismutase. EMBO J 1985;4:77±84. Morita M, Aoki M, Abe K, et al. A novel two-base mutation in the Cu/ Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis in Japan. Neurosci Lett 1996;205:79±82. Morita M, Abe K, Takahashi M, et al. A novel mutation Asp90Val in the SOD1 gene associated with Japanese familial ALS. Eur J Neurol 1998;5:389±392. Moulard B, Camu W, Brice DJ, et al. A previously undescribed mutation in the SOD1 gene in a French family with atypical ALS. 6th International Symposium on ALS/MND, 1995. Nakano R, Sato S, Inuzuka T, et al. A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. Biochem Biophys Res Commun 1994;200:695±703. Ohnishi A, Miyazaki S, Murai Y, Ueno S, Sakai H. Familial amyotrophic lateral sclerosis showing variable clinical courses with Leu84Val mutation of Cu/Zn superoxide dismutase. Clin Neurol 1996;36:485±487. Orrell R, deBelleroche J, Marklund S, Bowe F, Hallewell R. A novel SOD mutant and ALS. Nature 1995;374:504±505. Orrell RW, King AW, Hilton DA, et al. Familial amyotrophic lateral sclerosis with a point mutation of SOD1: intrafamilial heterogeneity of disease duration associated with neuro®brillary tangles. J Neurol Neurosurg Psychiatry 1995;59:266±270. Orrell RW, Habgood J, Rudge P, Lane RJM, deBelleroche JS. Dif®culties in distinguishing sporadic from familial amyotrophic lateral sclerosis. Ann Neurol 1996;39:810±812.
[41] Orrell RW, Marklund SL, deBelleroche JS. Familial ALS is associated with mutations in all exons of SOD1: a novel mutation in exon 3 (Gly72Ser). J Neurol Sci 1997;153:46±49. [42] Orrell RW, Habgood JJ, Gardiner I, et al. Clinical and functional investigation of 10 missense mutations and a novel frameshift insertion mutation of the gene for copper-zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis. Neurology 1997;48:746± 751. [43] Orrell RW, Habgood JJ, Shepherd DI, Donnai D, deBelleroche J. A novel mutation of SOD1 (Gly108Val) in familial amyotrophic lateral sclerosis. Eur J Neurol 1997;4:48±51. [44] Pramatarova A, Figlewicz DA, Krizus A, et al. Identi®cation of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis. Am J Hum Genet 1995;56:592±596. [45] Rainero I, Pinessi L, Tsuda T, et al. SOD1 missense mutation in an Italian family with ALS. Neurology 1994;44:347±349. [46] Robberecht W, Aguirre T, Van Den Bosch L, Tilkin P, Cassiman JJ, Matthijs G. D90A heterozygosity in the SOD1 gene is associated with familial and apparently sporadic amyotrophic lateral sclerosis. Neurology 1996;47:1336±1339. [47] Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59±62. [48] Rouleau GA, Clark AW, Rooke K, et al. SOD1 mutation is associated with accumulation of neuro®laments in amyotrophic lateral sclerosis. Ann Neurol 1996;39:128±131. [49] Shaw CE, Enayat ZE, Chioza BA, et al. Mutations in all ®ve exons of SOD-1 may cause ALS. Ann Neurol 1998;43:390±394. [50] Shaw CE, Enayat ZE, Powell JF, et al. Familial amyotrophic lateral sclerosis. Molecular pathology of a patient with a SOD1 mutation. Neurology 1997;49:1612±1616. [51] Siddique T, Deng HX. Genetics of amyotrophic lateral sclerosis. Hum Mol Genet 1996;5:1465±1470. [52] Suthers G, Laing N, Wilton S, Dorosz S, Waddy H. `Sporadic' motoneuron disease due to familial SOD1 mutation with low penetrance. Lancet 1994;334:1773. [53] Takahashi H, Makifuchi T, Nakano R, et al. Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene. Acta Neuropathol. 1994;88:185±188. [54] Watanabe M, Aoki M, Abe K, et al. A novel missense point mutation (S134N) of the Cu/Zn superoxide dismutase gene in a patient with familial motor neuron disease. Hum Mutat 1997;9:69±71.
Amyotrophic lateral sclerosis: copper/zinc superoxide dismutase (SOD1) gene mutations Richard W. Orrell* University Department of Clinical Neurosciences, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK Received 16 June 1999; accepted 1 July 1999
Abstract Mutations of the SOD1 gene, encoding the enzyme copper/zinc superoxide dismutase, have been identi®ed in around 20% of patients with familial amyotrophic lateral sclerosis (ALS), and also in patients with apparently sporadic ALS. The table documents the mutations identi®ed and published to date, and references clinical and pathological descriptions of the patients and families with individual mutations. The table includes 63 different mutations of SOD1 at 43 codons, three intronic sites, and two in the 3 0 untranslated region. Most of the mutations are heterozygotes, with autosomal dominant inheritance, but a small number of individuals appear to be sporadic, or are homozygotes with autosomal dominant recessive inheritance. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Amyotrophic lateral sclerosis; SOD1; Genetics
1. Introduction Mutations of the SOD1 gene in amyotrophic lateral sclerosis (ALS) were ®rst identi®ed by Rosen et al. [47]. Around 5±10% of patients with ALS have other affected family members, and mutations of SOD1 are present in around 20% of these familial patients, and also in occasional apparently sporadic patients. This represents only 1±2% of all patients with ALS. A causal relationship has not been demonstrated for all the mutations reported, and the mechanism by which the mutations cause the disease has still to be clari®ed. Many of the mutations are at present unique to individual families. Reports of attempts to correlate genotype with phenotype have demonstrated that, for an individual, the severity of disease, as determined by time of onset or duration of disease, is generally dif®cult to predict on the basis of the SOD1 mutation [4,9,42]. Some mutations, however, appear to predict a more rapid course of disease, for example, Ala4Val, (which accounts for around 50% of mutations reported in the USA [9]). In Scandinavia, the ®nding of a homozygote form of the disease, also appears to have an Asp90A1a de®nable phenotype [3]. Otherwise in general the prognosis is similar to that of ALS in general, with median age at onset 46 years (range 24±72 years), and median duration of disease 3.0 years (range 0.3±20 years) * Tel.: 144-171-830-2387; fax: 144-171-431-1577. E-mail address: [email protected] (R.W. Orrell)
[42]. Penetrance is age dependent, and in families with autosomal dominant inheritance of the mutation, the disease may appear to skip several generations [40]. The clinical features of an individual patient with an SOD1 mutation are indistinguishable from those without an SOD1 mutation, although there is a tendency for the disease to commence in the limbs rather than the bulbar region. Molecular pathological studies may be expected to yield more detailed information on the pathogenesis of the disease. The reported number of patients is small. The pathology of ALS patients with SOD1 mutations has recently been investigated and reviewed by Ince et al. [21], focusing on the nature of neuronal inclusions, the signi®cance of which remains uncertain. The disease appears not to be caused by loss of SOD enzyme activity, but by gain of an as yet unknown toxic function, consistent with the predominant autosomal dominant pattern of inheritance. The major gene abnormalities in the other 80% of families with ALS, and the genetic contribution to the remainder of apparently sporadic ALS, representing around 98% of all patients with ALS, remain unknown. These are being explored by clinical molecular genetic studies, molecular pathological studies, studies of SOD1 patients and families, and studies of transgenic mouse models incorporating mutations of SOD1 found in human ALS. Linkage studies in both recessive and dominant forms of ALS have de®ned linkage in the recessive forms, e.g. ALS2 at 2q33
0960-8966/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0960-896 6(99)00071-1
GCC ! ACC
4
Leu-Phe Leu ! Val
TTG ! TTC TTG ! GTG
GGC -CGC AAT ! AGT GAC ! GCC
GAC ! GTC GGT ! AGT
85 86 90
90 93
Asp ! Val Gly ! Ser
Gly ! Arg Asn ! Ser Asp ! Ala
Asp ! Tyr
Gly ! Ser
GGT ! AGT
GAT ! TAT
Gly ! Asp His ! Arg His ! Arg His ! Gln
GGC ! GAC CAT ! CGT CAT ! CGT CAT ! CAG
76 Exon 4 84 84
41 43 46 48 Exon 3 72
s/m s/m
s/m s/m s/m
s/m s/m
s/m
s/m
s/m s/m s/m s/m
s/m s/m s/m
Gly ! Arg Leu ! Val Gly ! Ser
GGA ! AGA CTG ! GTG GGC ! AGC
s/m s/m s/m s/m s/m s/m s/m s/m
s/m
s/m
Nature /effect of mutation
s/u
Cys ! Phe Val ! Glu Leu ! Gln Val ! Met Val ! Gly Gly ! Ser Glu ! Lys Glu ! Gly
Ala ! Thr
Ala ! Val
Amino acid change
T!A
TGC ! TTT GTG ! GAG CTG ! CAG GTG ! ATG GTG ! GGG GGC ! AGC GAG ! AAG GAG ! GGG
GCC ! GTC
Exon 1 4
6 7 8 14 14 16 21 21 Intron 1 2108 bp Exon 2 37 38 41
Base change
Codon
Table 1 Gene table
AD AD AD AD AD AD Homo AD and S Homo AR and S Homo AD and S Homo S S AD AD
AD AD AD
AD AD AD AD AD AD AD AD
S
1 1 1 1 1 1 2 and 1 9 and 7 1 and 3 2 1 1 1
1 1 1
1 2 1 1 1 1 2 1
1
1 1 1 1 1 1 1 1
1 2
AD AD AD AD AD AD AD S S AD
27
Number of families reported
AD
Inheritance
UK USA Japan Japan USA Pakistan Belgium Sweden/Finland Sweden/Finland Finland UK Japan Japan
UK UK Denmark
USA USA USA Italy USA USA Japan UK
UK
Japan Japan Austria USA Sweden Japan UK France
Sweden Japan
USA
Country
C C C C
C C C
C C
C
C C C
C C C C C C C CP
CP
C C
C P C C P C C C
Clinical or pathological description
Shaw et al. (1998) Deng et al. (1995) Ohnishi et al. (1996) Aoki et al. (1995) Deng et al. (1993) Hayward et al. (1998) Robberecht et al. (1996) Andersen et al. (1996) Andersen et al. (1997) Andersen et al. (1997) Jackson et al. (1997) Morita et al. (1998) Kawata et al. (1997)
Orrell et al. (1997a) Shaw et al. (1998) Andersen et al. (1997)
Cudkowicz et al. (1997) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Rainero et al. (1994) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Abe et al. (1996) Shaw et al. (1996)
Ince et al. (1998)
Cudkowicz et al. (1997) Cudkowicz et al. (1998) Andersen et al. (1997) Nakano et al. (1994) Takahashi et al. (1994) Morita et al. (1996) Hirano et al. (1994) Bereznai et al. (1997) Deng et al. (1995) Andersen et al. (1997) Kawamata et al. (1997) Jones et al. (1995) Moulard et al. (1995)
Reference
[49] [11] [37] [5] [10] [15] [46] [3] [4] [4] [22] [34] [28]
[41] [49] [4]
[9] [9] [9] [45] [9] [9] [1] [50]
[21]
[9] [8] [4] [36] [53] [33] [17] [6] [11] [4] [26] [23] [35]
Ref no.
64 R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68
Asp ! Val Asp ! His Leu ! Gly, Gln, Arg, Trp, Lys, Stop Gly ! Gly, Gly, Gln, Arg, Trp, Lys, Stop Glu ! Asp, Stop Glu ! ± Ser ! Asn Asn ! Lys Leu ! Ser
CGC ! GGC GTG ! AAAACTG
A!G
GAT ! GTT GAC ! CAC TTC ! ±G
115 118
ins TGGG
insTT GAA ! ± AGT ! AAT AAC ! AAA TTG ! TCG
127
132 133 134 139 144
2 10 bp Exon 5 124 125 126
T!G
add Phe, Phe, Thr, s/it Gly, Pro, Stop add Phe, Leu, Gln s/i
GGA ! GTA ATC ! ACC ATT ! ACT
108 112 113
Intron 4 2 11 bp
Arg ! Gly Val ! Lys, Thr, Gly, Pro, Stop
GAT ! AAT GAT ! GGT ATC ! TTC CTC ! GTC
Gly ! Val Ile ! Thr Ile ! Thr
Asp ! Asn Asp ! Gly Ile ! Phe Leu -Val
i/mt d/d s/m s/m s/m
i/it
s/m s/m d/it
s/m i/it
s/m s/m s/m
s/m s/m s/m s/m
s/m s/m s/m s/m s/m s/m s/m
101 101 104 106
Gly ! Cys Gly ! Arg Gly ! Asp Gly ! Ala Gly ! Val Glu ! Lys Glu ! Gly
GGT ! TGT GGT ! CGT GGT ! GAT GGT ! GCT GGT ! GTT GAA ! AAA GAA -GGA
Nature /effect of mutation
93 93 93 93 93 100 100
Amino acid change
Base change
Codon
Table 1 (continued)
AD S AD AD AD
AD
AD AD AD
1 1 1 1 1
1
1 1 1
1
2 1 3 1 1 1 1 1 1 1 1 2 1 1 1 1 and 1 1 and 1 2 1 1
AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD and S AD and S S AD S
AD
1 1 1 1 1
Number of families reported
AD AD AD AD AD
Inheritance
UK USA Japan Canada USA
Denmark
USA UK Japan
USA
USA New Zealand UK UK UK UK Japan USA Japan UK USA USA Australia UK Canada Japan UK UK Germany UK
USA UK USA USA UK
Country
C
C C C
C
C C CP
C
C C C CP C C C C C C C C C CP CP CP CP C C C
C C C C C
Clinical or pathological description
Orrell et al. (1997b) Hosler et al. (1996) Watanabe et al. (1997) Pramatarova et al. (1995) Cudkowicz et al. (1997)
Andersen et al. (1997)
Hosler et al. (1996) Enayat et al. (1995) Kato et al. (1996)
Cudkowicz et al. (1997)
Siddique and Deng (1996)
Cudkowicz et al. (1997) Orrell et al. (1995a) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Hosler et al. (1996) Siddique and Deng (1996) Cudkowicz et al. (1997) Calder et al. (1995) Orrell et al. (1997b) Ince et al. (1996) Orrell et al. (1996) Orrell et al. (1997b) Abe et al. (1996) Cudkowicz et al. (1997) Kawamata et al. (1994) Orrell et al. (1997c) Cudkowicz et al. (1997) Cudkowicz et al. (1997) Suthers et al. (1994) Orrell et al. (1995b) Rouleau et al. (1996) Kikugawa et al. (1997) Ince et al. (1998) Jackson et al. (1997) Kostrzewa et al. (1994) Jackson et al. (1997)
Reference
[42] [18] [54] [44] [9]
[4]
[18] [12] [24]
[9]
[51]
[9] [38] [9] [9] [18] [51] [9] [7] [42] [20] [20] [42] [1] [9] [25] [43] [9] [9] [52] [39] [48] [29] [21] [22] [30] [22]
Ref no.
R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68 65
TTG ! TTC GCT ! ACT TGT-CGT GTA ! GGA GTA ! ATA ATT ! ACT
ACC ! ATC
144 145 146 148 148 149
151 3 0 UTR bp726 bp 816±819
Variants Exon 1 10 Exon 3 59 Exon 5 139 140 153
Gly ! Gly
Ser ! Ser
Asn ! Asn Ala ! Ala Gln ! Gln
ACT ! AGC
AAC ! AAT GCT ! GCA CAA ! CAG
Thr ! Ile
Leu ! Phe Ala ! Thr Cys ! Arg Val ! Gly Val ! Ile Ile ! Thr
Amino acid change
GGC ! GGT
Polymorphisms Intron 2 Unknown Bgl II Intron 3 34 A!C
Deleted Deleted
Base change
Codon
Table 1 (continued)
d/u d/u
s/m
s/m s/m s/m s/m s/m s/m
Nature /effect of mutation
S
S
S S
AD
AD AD AD AD AD AD
Inheritance
1 1 1
1
1
1 1
1 1 1 1 1 1 1 1
Number of families reported
Scandinavia USA Scandinavia
USA
UK
UK UK
Canada USA Japan USA Japan Canada UK Germany
Country
CP CP
C C
C C
C
Clinical or pathological description
Andersen et al. (1997) Hosler et al. (1996) Andersen et al. (1997)
Hosler et al. (1996)
[4] [18] [4]
[18]
[22]
[13]
Esteban et al. (1994)
Jackson et al. (1997)
[32]
[21] [21]
[44] [9] [27] [9] [1] [44] [42] [31]
Ref no.
Levanon et al. (1985)
Ince et al. (1998) Ince et al. (1998)
Pramatarova et al. (1995) Cudkowicz et al. (1997) Kawamata et al. (1995) Cudkowicz et al. (1997) Abe et al. (1996) Pramatarova et al. (1995) Orrell et al. (1997b) Kostrzewa et al. (1996)
Reference
66 R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68
R.W. Orrell / Neuromuscular Disorders 10 (2000) 63±68
[19] and ALS5 at 15q15-22 [16]. Variants of the gene encoding the heavy neuro®lament subunit have been identi®ed in a small number of patients [2,14]. The SOD1 gene has 5 exons, and encodes a protein with 153 amino acids [32]. The active enzyme is homodimeric. Table 1 includes 63 different mutations of SOD1 at 43 codons, three intronic sites, and two in the 3 0 untranslated region (UTR). Most of the mutations are heterozygote, with autosomal dominant inheritance (AD), but a small number of individuals appear to be sporadic (S), or are homozygote (Homo) with autosomal recessive inheritance (AR). 2. Footnotes Table 1 includes key references, which especially relate to reports which include details of the clinical (C) or pathological (P) features of the patients. Many of the mutations were ®rst reported by Rosen et al. [47] and Deng et al. [10], but clinical details were not given at that time. The number of families reported is given where available, as an indication of the relative frequency of the mutations. The country of origin of the patient, or report, is given. This does not necessarily indicate the true frequency, country of origin, or ethnicity of the patient. The nature of the mutation ± base substitution (s), base insertion (i), base deletion (d), and predicted result of mutation ± missense/amino acid substitution (m), uncertain or unknown (u), amino acid insertion (i), and premature termination of protein (t). References [1] Abe K, Aoki M, Ikeda M, Watanabe M, Hirai S, Itoyama Y. Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations. J Neurol Sci 1996;136:101± 108. [2] Al-Chalabi A, Andersen PM, Nilsson P, et al. Deletions of the heavy neuro®lament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet 1999;8:157±164. [3] Andersen PM, Forsgren L, Binzer M, et al. Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. Brain 1996;119:1153±1172. [4] Andersen PM, Nilsson P, Keranen ML, et al. Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain 1997;120:1723±1737. [5] Aoki M, Abe K, Houi K, et al. Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel Cu/ Zn superoxide dismutase mutation. Ann Neurol 1995;37:676±679. [6] Bereznai B, Winkler A, Borasio GD, Gasser T. A novel SOD1 mutation in an Austrian family with amyotrophic lateral sclerosis. Neuromusc Disord 1997;7:113±116. [7] Calder VL, Domigan NM, George PM, Donaldson IM, Winterbourn CC. Superoxide dismutase (glu100gly) in a family with inherited motor neuron disease: detection of mutant superoxide dismutase activity and the presence of heterodimers. Neurosci Lett 1995;189:143±146. [8] Cudkowicz ME, McKennar-Yasek D, Chen C, Hedley-Whyte ET, Brown RH. Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc dismutase gene. Ann Neurol 1998;43:703±710.
67
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68
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