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. Andersen; Barry Chioza; Christopher Shaw; Pak C. Sham; Wim Robberecht; Gert Matthijs; William Camu; Stefan L. Marklund; Lars Forsgren; Guy Rouleau; Nigel G. Laing; P. V. Hurse; Teepu Siddique; P. Nigel Leigh; John F. Powell

doi:10.1093/hmg/7.13.2045

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. Andersen, Barry Chioza, Christopher Shaw, Pak C. Sham, Wim Robberecht, Gert Matthijs, William Camu, Stefan L. Marklund, Lars Forsgren, Guy Rouleau, Nigel G. Laing, P. V. Hurse, Teepu Siddique, P. Nigel Leigh, John F. Powell

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

148 Scopus citations

Abstract

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 (a = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (a = 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.

Original language	English (US)
Pages (from-to)	2045-2050
Number of pages	6
Journal	Human molecular genetics
Volume	7
Issue number	13
DOIs	https://doi.org/10.1093/hmg/7.13.2045
State	Published - Dec 1998

Funding

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 Väster-botten, 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.

ASJC Scopus subject areas

Genetics(clinical)
Genetics
Molecular Biology

Access to Document

10.1093/hmg/7.13.2045

Cite this

Al-Chalabi, A., Andersen, P. M., Chioza, B., Shaw, C., Sham, P. C., Robberecht, W., Matthijs, G., Camu, W., Marklund, S. L., Forsgren, L., Rouleau, G., Laing, N. G., Hurse, P. V., Siddique, T., Leigh, P. N., & Powell, J. F. (1998). Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: Evidence for a linked protective factor. Human molecular genetics, 7(13), 2045-2050. https://doi.org/10.1093/hmg/7.13.2045

@article{cdb63f87461f4a4cb02462f7d5890000,

title = "Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: Evidence for a linked protective factor",

abstract = "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 (a = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (a = 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.",

author = "Ammar Al-Chalabi and Andersen, {Peter M.} and Barry Chioza and Christopher Shaw and Sham, {Pak C.} and Wim Robberecht and Gert Matthijs and William Camu and Marklund, {Stefan L.} and Lars Forsgren and Guy Rouleau and Laing, {Nigel G.} and Hurse, {P. V.} and Teepu Siddique and Leigh, {P. Nigel} and Powell, {John F.}",

note = "Funding Information: 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{\textquoteright}s Motor Neurone Disease Care and Research Centre, by the Council of V{\"a}ster-botten, Sweden, the Swedish Natural Sciences Research Council, l{\textquoteright}Association Fran{\c c}aise pour la Recherche sur la Sclerose Lat{\'e}rale Amyotophique, l{\textquoteright}Association Fran{\c c}aise 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.",

year = "1998",

month = dec,

doi = "10.1093/hmg/7.13.2045",

language = "English (US)",

volume = "7",

pages = "2045--2050",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "13",

}

Al-Chalabi, A, Andersen, PM, Chioza, B, Shaw, C, Sham, PC, Robberecht, W, Matthijs, G, Camu, W, Marklund, SL, Forsgren, L, Rouleau, G, Laing, NG, Hurse, PV, Siddique, T, Leigh, PN & Powell, JF 1998, 'Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: Evidence for a linked protective factor', Human molecular genetics, vol. 7, no. 13, pp. 2045-2050. https://doi.org/10.1093/hmg/7.13.2045

TY - JOUR

T1 - Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder

T2 - Evidence for a linked protective factor

AU - Al-Chalabi, Ammar

AU - Andersen, Peter M.

AU - Chioza, Barry

AU - Shaw, Christopher

AU - Sham, Pak C.

AU - Robberecht, Wim

AU - Matthijs, Gert

AU - Camu, William

AU - Marklund, Stefan L.

AU - Forsgren, Lars

AU - Rouleau, Guy

AU - Laing, Nigel G.

AU - Hurse, P. V.

AU - Siddique, Teepu

AU - Leigh, P. Nigel

AU - Powell, John F.

N1 - Funding Information: 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 Väster-botten, 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.

PY - 1998/12

Y1 - 1998/12

N2 - 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 (a = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (a = 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.

AB - 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 (a = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (a = 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.

UR - http://www.scopus.com/inward/record.url?scp=7844227669&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=7844227669&partnerID=8YFLogxK

U2 - 10.1093/hmg/7.13.2045

DO - 10.1093/hmg/7.13.2045

M3 - Article

C2 - 9817920

AN - SCOPUS:7844227669

SN - 0964-6906

VL - 7

SP - 2045

EP - 2050

JO - Human molecular genetics

JF - Human molecular genetics

IS - 13

ER -

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

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this