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Human Molecular Genetics Pages 2045-2050  

Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor
Introduction
Results
Discussion
Materials And Methods
   DNA and pedigree collection
   Diagnosis
   Initial genotyping
   Determination of founders
   Classical linkage analysis
Acknowledgements
References

Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor

Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor

Ammar Al-Chalabi*, Peter M. Andersen1, Barry Chioza, Christopher Shaw, Pak C. Sham, Wim Robberecht2, Gert Matthijs3, William Camu4, Stefan L. Marklund5, Lars Forsgren1, Guy Rouleau6, Nigel G. Laing7, P. V. Hurse7, Teepu Siddique8, P. Nigel Leigh and John F. Powell

Departments of Neuroscience and Clinical Neurosciences, Institute of Psychiatry and King's College School of Medicine and Dentistry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK, 1Department of Neurology, Umeå University, S-901 85 Umeå, Sweden, 2Department of Neurology, University Hospital Gasthuisberg, 3000 Leuven, Belgium, 3Center of Human Genetics, Leuven, Belgium, 4Service de Neurologie B, Hôpital Gui de Chauliac, 34295 Montpellier, Cedex 5, France, 5Department of Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden, 6Centre for Research in Neuroscience, McGill University, Montreal, Canada, 7Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia and 8Department of Neurology, Northwestern University, Evanston, IL, USA

Received May 12, 1998; Revised and Accepted September 2, 1998

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase (SOD1), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen. Experimental evidence suggests mutations act by a toxic gain of function but the mechanism is unknown. There are >60 known SOD1 mutations associated with ALS and all are dominant except for one in exon 4, a D90A substitution which is recessive. D90A pedigrees with dominant inheritance have now been reported and this apparent contradiction needs to be explained. We performed a worldwide haplotype study on 28 D90A pedigrees using six highly polymorphic microsatellite markers. We now show that all 20 recessive families share the same founder ([alpha] = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families ([alpha] = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation has been recessive. We propose a tightly linked protective factor which modifies the toxic effect of mutant SOD1 in recessive families.

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration in the cerebral cortex and spinal cord resulting in progressive paralysis and death from respiratory failure within 3-5 years (1,2). The incidence is 1-2/100 000 population/year with a prevalence of 5-7/100 000. The lifetime risk of developing the disease is ~1 in 1000. In 5-10% of cases there is a family history, usually suggesting autosomal dominant inheritance.

About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase (SOD1), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen (3). This enzyme is a homodimer with an electrostatic guidance channel leading to the active site containing copper and zinc atoms. The collective evidence suggests a toxic gain of function conferred by mutations (4,5). There is no obvious pattern to the mutation sites which result in disease and no correlation between genotype and phenotype in most cases. There are >60 known SOD1 mutations and all are dominant except for one in exon 4, an Asp->Ala substitution (D90A) which is recessive (6-8). A possible explanation for this is that the D90 residue lies on the periphery of SOD1 and has little influence on dimer interaction or catalytic site leading to a less toxic gain of function such that two mutations are required and the mutation appears recessive. However, D90A pedigrees with dominant inheritance have now been reported (6,9-11). A mutation with different modes of inheritance in different families is unique and this apparent contradiction needs to be explained. We hypothesize that the D90A mutation would normally have a dominant mode of inheritance in common with all other SOD1 mutations but that in recessive families, a tightly linked protective factor acts to reduce penetrance of the mutant allele. If this were the case, all recessive families should share a common founder regardless of geography, with at least one alternative founder for the dominant families.

In the present study we have genotyped members of dominant and recessive pedigrees for six closely linked polymorphic markers, five of which lie within 1 cM of SOD1. We have found a single founder for the recessive pedigrees and several for the dominant pedigrees. This finding strongly supports the hypothesis that D90A is a dominant mutation which has been modified by a tightly linked protective factor associated with the recessive haplotype.

RESULTS


Figure 1. Estimate of [alpha] and LOD score for index cases by linkage disequilibrium analysis. Black represents data for recessive pedigrees and grey dominant. The horizontal lines represent the support interval for the maximum LOD score for each group. The true position of the maximum LOD score has a 95% chance of falling in this region. White diamonds indicate the map position of the markers used. 265, D21S265; 263, D21S263; etc. The SOD1 gene lies closest to marker D21S223.


Figure 2. Graph to show log likelihood of being a sibling ibd (relatedness) for the index case of each family against every other family. Families have been grouped by relatedness and pattern of inheritance. The graph has been orientated such that x = y is in the midline.

We identified 28 families with ALS associated with the D90A SOD1 allele, of which 19 were Scandinavian, three were Belgian, three French and one each was from the USA, UK and Australia. These pedigrees contained 227 individuals from whom DNA and clinical data were available. (Pedigree structures and clinical information are found in refs 6-11.) Of these, 183 were unaffected and 44 had ALS. The unaffected individuals consisted of 103 heterozygous for D90A and 15 homozygous. Those with ALS consisted of nine heterozygous for D90A and 35 homozygous. All individuals carrying the D90A mutation were examined by a neurologist. We could identify eight dominant and 20 recessive pedigrees. The recessive families were from northern Sweden and Finland and from France, the USA and possibly Australia. The dominant families were from Finland, France, Belgium and the UK. All families maintained a consistent pattern of inheritance. No recessive pedigrees contained affected heterozygotes even though the oldest heterozygote from these pedigrees was >90 years of age and 24 were >70 (8). In dominant pedigrees, there were two patterns of inheritance, sporadic (five pedigrees) and familial (three pedigrees). In the sporadic cases, there was no apparent family history of ALS, suggesting reduced penetrance of the mutant allele or spontaneous mutation. In the remaining three families, there was clear autosomal dominant inheritance with affected members in each generation.

Two-point LOD scores of 7.15 were obtained for SOD1 for linkage to ALS at 0 = 0.0 with a recessive model. The possibility that there were other missense mutations of SOD1 with which D90A was in disequilibrium was excluded both by sequencing of all five exons and, in Scandinavian pedigrees, by red cell SOD1 protein analysis (12). A series of polymorphic markers flanking the SOD1 locus were also analysed in 41 pedigree samples as well as 48 controls from northern Sweden and Finland. Haplotypes are presented in Table 1. The order chosen (D21S265, D21S263, D21S223, SOD1, D21S63, D21S262, D21S261) was based on published data and a consensus of current publicly available maps (13-15). On examination of the haplotypes it was apparent that they fell into two groups, one consisting predominantly of haplotype x13maxx and recessive pedigrees, the other more variable and containing the dominant pedigrees. Linkage disequilibrium analysis (16) with all markers gave [alpha] = 0.999 for recessive pedigree index cases at marker D21S63 (LOD score 28.6; Fig. 1) occurring ~43 generations or 1000 years ago. The support interval for the LOD function is given by maximum LOD-1. In the dominant pedigree index cases, the support interval extended beyond the marker map. In the recessive pedigree index cases, the interval included markers D21S263, D21S223 and D21S63 (D21S223 is thought to be coincident with SOD1). In this region [alpha] varied from 0.887 to 1 (Fig. 1). For dominant pedigree index cases over the same region, [alpha] = 0.383-0.657 (LOD score 5.1 at D21S263). To visualize the founder effect graphically, log likelihood (z-axis) of any pair of index cases (x- and y-axes) being siblings ibd compared with unrelated was plotted using the four most informative markers (i.e. all except D21S265 and D21S261). This produced a matrix of the estimated relatedness of every family to every other family. Using such a system, any regions of high relatedness would cluster about a line connecting identical samples (x = y). An island of relatedness would potentially appear for each founder in the population. A single founder was obvious for recessive families from this test and provided visual confirmation that the most appropriate grouping was of recessive families versus dominant families (Fig. 2). Of the 20 recessive cases, two (a Scandinavian case and a French case) did not have the complete recessive haplotype. Of the eight dominant cases, at least one (Scandinavian) had the recessive haplotype and six did not. For the other case (Scandinavian), the phase is not known, but given a D90A allele frequency of 0.011 in this region of Scandinavia, the occurrence of ALS by a non-SOD1 mechanism in D90A heterozygotes might be expected (6,8).

Table 1. Genotypes for each index case
Country Sc Sc Sc Sc Sc Sc Sc Sc Sc Sc Sc Sc Sc Sc Sc US Sc Sc Sc UK Fr Fr Sc Au Be Fr Be Be
Rec/Dom R R R R R R R R R R R R R R D R R R R D R D D R? D D D D
Family 4 5 7 8 9 12 15 16 18 19 10 11 2 3 14 25 6 17 1 28 26 27 13 24 21 23 20 22
D21S265 44 14 84 85 37 55 77 34 45 26* 53* 33 43 45* 24 44 45* 43* 53 44 86 51 53* 34* 57* 34* 44 67
D21S263 11 11 11 11 11 11 11 11 11 11 11 11 11 13 13 [1-] 11 11 11 11 33 34 11 13* 37* 34* 79* 44
D21S223 33 33 33 33 33 33 33 33 33 33 33 33 35 33 33 33 35 35 33 33 33 33 35* 32* 42* 35* 32* 23
SOD1 mm mm mm mm mm mm mm mm mm mm mm mm mm mm mc mm mm mm mm mc* mm mc mc mc mc mc mc mc
D21S63 aa aa aa aa aa aa aa aa aa aa aa aa aa aa a7 aa a6* a3* 22 76 aa a6 a6* aa aa a7* a7* 14
D21S262 44 44 44 44 44 44 44 44 44 54 54 55 65 44 36 77 45* 26* 66 76 77 66 32* 44 46* 34* 67* 66
D21S261 22 22 22 22 22 22 22 22 22 22 22 22 23 22 22 22 22 22 22 34 22 25 22 22 22 25* 23* 22
For the Australian family, DNA is only available from unaffected heterozygotes. An asterisk denotes unknown phase. Square brackets denote a reconstructed haplotype. R, recessive; D, dominant; Sc, Scandinavian; Be, Belgian; Fr, French; Aus, Australian. a is allele 10. For SOD1, m is the D90A allele and c is the wild-type. The partial or complete x13maxx haplotype (where x represents any allele) is shown in bold where the phase is known.

DISCUSSION

We have shown a single founder for recessive ALS families with the D90A SOD1 mutation. Other than D90A, all mutations of SOD1 are consistently dominant, probably by a toxic gain of function (4,5). Despite the original reports of recessive D90A pedigrees, there are now three familial ALS pedigrees showing convincing autosomal dominant inheritance (6,9-11). Pedigrees of each type breed true, implying a familial factor which maintains the pattern of inheritance. The recessive families share a common founder while there are several for the dominant families, which suggests that on more than one occasion a new instance of the D90A mutation has resulted in dominant inheritance, whereas on only one occasion has it resulted in recessive inheritance. This implies that the mutation should be dominant by default (in common with all other SOD1 mutations) and that the recessive haplotype is linked to a modifying factor. Further evidence that this is the case is found in a different mutation of the same residue, D90V (Asp->Val), which is dominant (K.Abe, personal communication), as are five other SOD1 mutations found in Scandinavia. This makes the arguments that D90A is recessive because of its unimportant position in the SOD1 molecule or because of an environmental or unlinked modifying factor difficult to maintain.

Assuming a toxic gain of function, a double dose of mutant SOD1 would be expected to result in more severe disease. Indeed, an individual homozygous for the N86S (Asn->Ser) mutation of SOD1 with very severe disease has recently been reported from a consanguineous family (17). This mutation has previously only been associated with dominant inheritance and heterozygotes develop typical ALS in middle age. Like D90A, it is also in exon 4 and codes for an amino acid on the periphery of the molecule (18). However, this homozygous individual developed ALS at an exceptionally young age (13 years) with an extremely rapid progression, dying within 14 weeks. In contrast, homozygous individuals from recessive D90A families are more mildly affected than most ALS patients (8). In addition, the phenotype is very homogeneous with a predominantly lower motor neuron and lower limb form of ALS at onset, with most living longer than 10 years (7,11). This is unusal and most studies have failed to show phenotypic homogeneity for dominant SOD1 mutations even within families. There is a widely varying age of onset, site of onset, predominant pattern of motor neuron damage and disease progression (5,19,20). In keeping with this pattern for dominant ALS, the disease phenotype for the dominant D90A families also fails to show homogeneity. The two Scandinavian cases had bulbar onset, the UK case had mainly upper motor neuron involvement, while the Belgian and French cases showed a varied clinical presentation with intrafamilial heterogeneity and variable disease progression. Thus, the dominant D90A phenotype appears consistent with all other SOD1 mutations, while the recessive phenotype is mild, homogeneous and atypical.

It could be argued that the finding of recessive and dominant D90A ALS families is simply a consequence of the high frequency of D90A in the Scandinavian population (0.025) (21). If this explanation were true, it is difficult to explain why none of 121 heterozygous D90A relatives has developed ALS in these recessive families, even though some individuals are >90 years old, while in France and Belgium >50% of the heterozygotes in dominant families have ALS. Rather than the high allele frequency being an explanation for homozygosity in Scandinavia, the putative existence of a protective allele renders the heterozygotes disease free and explains both the high allele frequency and the homozygosity of ALS cases. The recessive haplotype is presumably of Scandinavian origin and worldwide regions of high D90A allele frequency correspond with Viking migration (22), as does the timing of the original mutation ~1000 years (43 generations) ago. Extrapolating from this, we would also expect other areas of apparently high D90A allele frequency, such as Westray in the Orkney Isles (0.015) (23), north east Iran (0.013) (24), Ramadi in Iraq (0.008) (25) or West Coast, Newfoundland (0.026) (26), to have the recessive Scandinavian haplotype.

Twelve of the 17 recessive Scandinavian families share the complete x13ma42 haplotype, which is likely to be the founding haplotype, and 18 of the 20 recessive families share x13maxx. Marker D21S265, which is most variable and first in the order quoted, is also the furthest from SOD1 and is 2.5 cM from the next marker. Several interpretations of the crossover and migration events leading to the observed haplotypes are possible and the simplest of these is shown in Figure 3. The French recessive and dominant haplotypes differ only at the D21S262 locus and are probably descendants of family 3 ancestors.


Figure 3. A model of migration and crossover events. Abbreviations are as for Table 1. The dotted vertical line separates dominant pedigrees from recessive, the horizontal separates Scandinavians from migrants or other nationals. Boxed alleles are putative crossovers or expansion/contractions. Solid arrows indicate descent. Dotted arrows indicate alternative interpretations. Cases with uncertain phase have been omitted as have data from distant marker D21S265 and the less informative marker D21S261

In conclusion, all recessive families have the same founder regardless of geography, families maintain a consistent inheritance pattern and recessive families tend to have milder disease. Of all SOD1 mutations, including D90A, only the D90A allele on the x13maxx background is recessive. This strongly supports the hypothesis that a disease modifying factor is transmitted with the x13maxx haplotype resulting in recessive disease. A tightly linked protective factor is the most likely candidate but a factor in strong linkage disequilibrium because of population effects cannot be ruled out. The nature of the modifying factor must await further studies at the genetic and protein level.

MATERIALS AND METHODS

DNA and pedigree collection

Genetic researchers in the field of ALS were contacted directly for DNA from D90A families with pedigree and clinical information where available. Groups with known involvement in ALS research from the European Familial ALS Consortium, the USA, Canada, South America, Australia, New Zealand, North Africa, Japan, Russia and workers known to have collected samples from Iraq and the Middle East, the Philippines and the Central African Republic were all contacted in person, by telephone or by fax, email or letter. In all, attempts were made to obtain information about possible D90A cases from 32 different groups worldwide.

Diagnosis

The diagnosis of ALS was made by a consultant neurologist after full investigation and according to the ICD-10 classification of disease. For unaffected typed relatives, neurological examination was performed to exclude subclinical phenotypes or early disease. Families were classified as dominant if heterozygotes with ALS existed or recessive if heterozygotes were never observed to have ALS. Patients with apparently sporadic ALS who were heterozygote were classified with the dominant families. Ethical approval was obtained in all collaborating centres.

Initial genotyping

Blood was taken after informed written consent. DNA was extracted from buffy coat cells. The presence of the D90A allele and absence of other mutations was determined by sequencing all five exons of SOD1 in every case. In all cases, the homozygosity or heterozygosity of cases was retested by restriction with CfoI and PAGE after amplification of exon 4 of SOD1 under standard PCR conditions in a central laboratory. All samples were then forwarded to a further laboratory for blind genotyping with six polymorphic closely linked markers. Marker order and map distance was estimated by consensus between published maps. Genotyping was performed with fluorescent labelled primers using standard published conditions for each marker. Markers used were D21S265, D21S263, D21S223, (SOD1), D21S63, D21S262 and D21S261 with genetic distances estimated as 2.5, 0.1, 0.2, 0.82, 0.82 and 0.47 cM between adjacent loci. Genotyping was performed using an ABI377 automated genotyper and analysed using the Genescan and Genotyper programs. In the majority of cases, genotyping was repeated at least once. From each family, the index case was genotyped at marker loci and SOD1. For samples heterozygous at more than one locus, further family members were genotyped to determine phase where possible. Information about SOD1 genotype on all available family members was collected for two-point linkage analysis. For control marker allele frequencies in linkage disequilibrium tests, unrelated Scandinavian controls from northern Sweden and Finland were also genotyped.

Determination of founders

The founder effect was determined by testing for linkage disequilibrium using the DISEQ program (16) for each group with an estimate of [alpha] (the proportion of different founders contributing to the observed marker groupings) and n (the number of generations ago the founder mutation first appeared). Support intervals for the LOD function were calculated as maximum LOD-1. The founder effect was then represented visually in the following way. Families were tested for relatedness by testing the hypothesis of true relationship being sibling ibd for each index case against every other index case and the result expressed as a log likelihood versus unrelated (27). Related families were then grouped. Although the program used was designed for use with a larger number of markers, its use in this instance provided a useful visual confirmation of the founder effect.

Classical linkage analysis

In order to confirm D90A as the causative mutation, classical linkage analysis was performed with full D90A pedigree information. Two-point LOD scores and multipoint linkage analysis were performed using the LINKAGE package of programs (28). Disease frequency was taken as 8/100 000 with penetrances 0.00001, 0.00001 and 0.04. D90A allele frequency was taken as 0.025. Marker frequencies were as published (14).

ACKNOWLEDGEMENTS

We are grateful to all patients and relatives who contributed samples to this study. We thank Karen Morrisson and Mandy Jackson who identified the D90A mutation in the UK samples. We thank Aleks Radunovic and all clinicians who contributed samples to the study. This work was supported by grants from the Medical Research Council (UK) and the Motor Neurone Disease Association of Great Britain to the King's Motor Neurone Disease Care and Research Centre, by the Council of Västerbotten, Sweden, the Swedish Natural Sciences Research Council, l'Association Française pour la Recherche sur la Sclerose Latérale Amyotophique, l'Association Française contre les Myopathies, the Amyotrophic Lateral Sclerosis Association and the Australian National Health and Research Council Project Grant 970104. At the time of this work A.A.C. was a Medical Research Council Clinical Training Fellow.

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*To whom correspondence should be addressed. Tel: +44 171 346 5172; Fax: +44 171 346 5190; Email: ammar@iop.bpmf.ac.uk

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M R Turner, A D Osei-Lah, A Hammers, A Al-Chalabi, C E Shaw, P M Andersen, D J Brooks, P N Leigh, and K R Mills
Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS
J. Neurol. Neurosurg. Psychiatry, September 1, 2005; 76(9): 1279 - 1285.
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 BrainHome page
M. R. Turner, A. Hammers, A. Al-Chalabi, C. E. Shaw, P. M. Andersen, D. J. Brooks, and P. N. Leigh
Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C]flumazenil PET
Brain, June 1, 2005; 128(6): 1323 - 1329.
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 Am J EpidemiolHome page
C. E. Sabel, P. J. Boyle, M. Loytonen, A. C. Gatrell, M. Jokelainen, R. Flowerdew, and P. Maasilta
Spatial Clustering of Amyotrophic Lateral Sclerosis in Finland at Place of Birth and Place of Death
Am. J. Epidemiol., May 15, 2003; 157(10): 898 - 905.
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 BrainHome page
T. M. Tikka, N. E. Vartiainen, G. Goldsteins, S. S. Oja, P. M. Andersen, S. L. Marklund, and J. Koistinaho
Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease
Brain, April 1, 2002; 125(4): 722 - 731.
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J. Jacobsson, P. A. Jonsson, P. M. Andersen, L. Forsgren, and S. L. Marklund
Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations
Brain, July 1, 2001; 124(7): 1461 - 1466.
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L. P. Rowland and N. A. Shneider
Amyotrophic Lateral Sclerosis
N. Engl. J. Med., May 31, 2001; 344(22): 1688 - 1700.
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M. Weber, A. Eisen, H. G. Stewart, and P. M. Andersen
Preserved slow conducting corticomotoneuronal projections in amyotrophic lateral sclerosis with autosomal recessive D90A CuZn-superoxide dismutase mutation
Brain, July 1, 2000; 123(7): 1505 - 1515.
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