Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor
Identifieur interne : 002B28 ( Istex/Corpus ); précédent : 002B27; suivant : 002B29Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor
Auteurs : 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. PowellSource :
- Human Molecular Genetics [ 0964-6906 ] ; 1998-12.
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 (α = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (α = 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.
Url:
DOI: 10.1093/hmg/7.13.2045
Links to Exploration step
ISTEX:E5B0F2D12C41213D28DA3EA4D41BD9050F916C50Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor</title><author><name sortKey="Al Chalabi, Ammar" sort="Al Chalabi, Ammar" uniqKey="Al Chalabi A" first="Ammar" last="Al-Chalabi">Ammar Al-Chalabi</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ammar@iop.bpmf.ac.uk</mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ammar@iop.bpmf.ac.uk</mods:affiliation></affiliation></author><author><name sortKey="Andersen, Peter M" sort="Andersen, Peter M" uniqKey="Andersen P" first="Peter M." last="Andersen">Peter M. Andersen</name><affiliation><mods:affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Chioza, Barry" sort="Chioza, Barry" uniqKey="Chioza B" first="Barry" last="Chioza">Barry Chioza</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Shaw, Christopher" sort="Shaw, Christopher" uniqKey="Shaw C" first="Christopher" last="Shaw">Christopher Shaw</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Sham, Pak C" sort="Sham, Pak C" uniqKey="Sham P" first="Pak C." last="Sham">Pak C. Sham</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><affiliation><mods:affiliation>Department of Neurology, University Hospital Gasthuisberg, 3000 Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Matthijs, Gert" sort="Matthijs, Gert" uniqKey="Matthijs G" first="Gert" last="Matthijs">Gert Matthijs</name><affiliation><mods:affiliation>Center of Human Genetics, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Camu, William" sort="Camu, William" uniqKey="Camu W" first="William" last="Camu">William Camu</name><affiliation><mods:affiliation>Service de Neurologie B, Hôpital Gui de Chauliac, 34295 Montpellier, Cedex 5, France</mods:affiliation></affiliation></author><author><name sortKey="Marklund, Stefan L" sort="Marklund, Stefan L" uniqKey="Marklund S" first="Stefan L." last="Marklund">Stefan L. Marklund</name><affiliation><mods:affiliation>Department of Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Forsgren, Lars" sort="Forsgren, Lars" uniqKey="Forsgren L" first="Lars" last="Forsgren">Lars Forsgren</name><affiliation><mods:affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Rouleau, Guy" sort="Rouleau, Guy" uniqKey="Rouleau G" first="Guy" last="Rouleau">Guy Rouleau</name><affiliation><mods:affiliation>Centre for Research in Neuroscience, McGill University, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Laing, Nigel G" sort="Laing, Nigel G" uniqKey="Laing N" first="Nigel G." last="Laing">Nigel G. Laing</name><affiliation><mods:affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</mods:affiliation></affiliation></author><author><name sortKey="Hurse, P V" sort="Hurse, P V" uniqKey="Hurse P" first="P. V." last="Hurse">P. V. Hurse</name><affiliation><mods:affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</mods:affiliation></affiliation></author><author><name sortKey="Siddique, Teepu" sort="Siddique, Teepu" uniqKey="Siddique T" first="Teepu" last="Siddique">Teepu Siddique</name><affiliation><mods:affiliation>Department of Neurology, Northwestern University, Evanston, IL, USA</mods:affiliation></affiliation></author><author><name sortKey="Nigel Leigh, P" sort="Nigel Leigh, P" uniqKey="Nigel Leigh P" first="P." last="Nigel Leigh">P. Nigel Leigh</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Powell, John F" sort="Powell, John F" uniqKey="Powell J" first="John F." last="Powell">John F. Powell</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:E5B0F2D12C41213D28DA3EA4D41BD9050F916C50</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1093/hmg/7.13.2045</idno><idno type="url">https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">002B28</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">002B28</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor</title><author><name sortKey="Al Chalabi, Ammar" sort="Al Chalabi, Ammar" uniqKey="Al Chalabi A" first="Ammar" last="Al-Chalabi">Ammar Al-Chalabi</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ammar@iop.bpmf.ac.uk</mods:affiliation></affiliation><affiliation><mods:affiliation></mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ammar@iop.bpmf.ac.uk</mods:affiliation></affiliation></author><author><name sortKey="Andersen, Peter M" sort="Andersen, Peter M" uniqKey="Andersen P" first="Peter M." last="Andersen">Peter M. Andersen</name><affiliation><mods:affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Chioza, Barry" sort="Chioza, Barry" uniqKey="Chioza B" first="Barry" last="Chioza">Barry Chioza</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Shaw, Christopher" sort="Shaw, Christopher" uniqKey="Shaw C" first="Christopher" last="Shaw">Christopher Shaw</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Sham, Pak C" sort="Sham, Pak C" uniqKey="Sham P" first="Pak C." last="Sham">Pak C. Sham</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Robberecht, Wim" sort="Robberecht, Wim" uniqKey="Robberecht W" first="Wim" last="Robberecht">Wim Robberecht</name><affiliation><mods:affiliation>Department of Neurology, University Hospital Gasthuisberg, 3000 Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Matthijs, Gert" sort="Matthijs, Gert" uniqKey="Matthijs G" first="Gert" last="Matthijs">Gert Matthijs</name><affiliation><mods:affiliation>Center of Human Genetics, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Camu, William" sort="Camu, William" uniqKey="Camu W" first="William" last="Camu">William Camu</name><affiliation><mods:affiliation>Service de Neurologie B, Hôpital Gui de Chauliac, 34295 Montpellier, Cedex 5, France</mods:affiliation></affiliation></author><author><name sortKey="Marklund, Stefan L" sort="Marklund, Stefan L" uniqKey="Marklund S" first="Stefan L." last="Marklund">Stefan L. Marklund</name><affiliation><mods:affiliation>Department of Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Forsgren, Lars" sort="Forsgren, Lars" uniqKey="Forsgren L" first="Lars" last="Forsgren">Lars Forsgren</name><affiliation><mods:affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Rouleau, Guy" sort="Rouleau, Guy" uniqKey="Rouleau G" first="Guy" last="Rouleau">Guy Rouleau</name><affiliation><mods:affiliation>Centre for Research in Neuroscience, McGill University, Montreal, Canada</mods:affiliation></affiliation></author><author><name sortKey="Laing, Nigel G" sort="Laing, Nigel G" uniqKey="Laing N" first="Nigel G." last="Laing">Nigel G. Laing</name><affiliation><mods:affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</mods:affiliation></affiliation></author><author><name sortKey="Hurse, P V" sort="Hurse, P V" uniqKey="Hurse P" first="P. V." last="Hurse">P. V. Hurse</name><affiliation><mods:affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</mods:affiliation></affiliation></author><author><name sortKey="Siddique, Teepu" sort="Siddique, Teepu" uniqKey="Siddique T" first="Teepu" last="Siddique">Teepu Siddique</name><affiliation><mods:affiliation>Department of Neurology, Northwestern University, Evanston, IL, USA</mods:affiliation></affiliation></author><author><name sortKey="Nigel Leigh, P" sort="Nigel Leigh, P" uniqKey="Nigel Leigh P" first="P." last="Nigel Leigh">P. Nigel Leigh</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author><author><name sortKey="Powell, John F" sort="Powell, John F" uniqKey="Powell J" first="John F." last="Powell">John F. Powell</name><affiliation><mods:affiliation>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</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="1998-12">1998-12</date><biblScope unit="volume">7</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="2045">2045</biblScope><biblScope unit="page" to="2050">2050</biblScope></imprint><idno type="ISSN">0964-6906</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="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 (α = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (α = 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.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Ammar Al-Chalabi</name><affiliations><json:string>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</json:string><json:string>E-mail: ammar@iop.bpmf.ac.uk</json:string><json:null></json:null><json:string>E-mail: ammar@iop.bpmf.ac.uk</json:string></affiliations></json:item><json:item><name>Peter M. Andersen</name><affiliations><json:string>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</json:string></affiliations></json:item><json:item><name>Barry Chioza</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Christopher Shaw</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Pak C. Sham</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Wim Robberecht</name><affiliations><json:string>Department of Neurology, University Hospital Gasthuisberg, 3000 Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Gert Matthijs</name><affiliations><json:string>Center of Human Genetics, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>William Camu</name><affiliations><json:string>Service de Neurologie B, Hôpital Gui de Chauliac, 34295 Montpellier, Cedex 5, France</json:string></affiliations></json:item><json:item><name>Stefan L. Marklund</name><affiliations><json:string>Department of Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden</json:string></affiliations></json:item><json:item><name>Lars Forsgren</name><affiliations><json:string>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</json:string></affiliations></json:item><json:item><name>Guy Rouleau</name><affiliations><json:string>Centre for Research in Neuroscience, McGill University, Montreal, Canada</json:string></affiliations></json:item><json:item><name>Nigel G. Laing</name><affiliations><json:string>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</json:string></affiliations></json:item><json:item><name>P. V. Hurse</name><affiliations><json:string>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</json:string></affiliations></json:item><json:item><name>Teepu Siddique</name><affiliations><json:string>Department of Neurology, Northwestern University, Evanston, IL, USA</json:string></affiliations></json:item><json:item><name>P. Nigel Leigh</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>John F. Powell</name><affiliations><json:string>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</json:string></affiliations></json:item></author><arkIstex>ark:/67375/HXZ-783NH3HT-L</arkIstex><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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 (α = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (α = 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.</abstract><qualityIndicators><refBibsNative>true</refBibsNative><abstractWordCount>205</abstractWordCount><abstractCharCount>1327</abstractCharCount><keywordCount>0</keywordCount><score>8.315</score><pdfWordCount>3855</pdfWordCount><pdfCharCount>24607</pdfCharCount><pdfVersion>1.2</pdfVersion><pdfPageCount>6</pdfPageCount><pdfPageSize>595 x 842 pts (A4)</pdfPageSize></qualityIndicators><title>Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor</title><pmid><json:string>9817920</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>Human Molecular Genetics</title><language><json:string>unknown</json:string></language><issn><json:string>0964-6906</json:string></issn><eissn><json:string>1460-2083</json:string></eissn><publisherId><json:string>hmg</json:string></publisherId><volume>7</volume><issue>13</issue><pages><first>2045</first><last>2050</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>21S</json:string><json:string>1000</json:string><json:string>1998</json:string><json:string>86S</json:string></date><geogName></geogName><orgName><json:string>UK and Australia</json:string><json:string>Denmark Hill, London SE</json:string><json:string>Sweden, the Swedish Natural Sciences Research Council</json:string><json:string>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA</json:string><json:string>Australian National Health and Research Council Project Grant</json:string><json:string>Department of Neurology, Northwestern University, Evanston, IL, USA Received</json:string><json:string>Iraq and the Middle East, the Philippines</json:string><json:string>Finland, France, Belgium</json:string><json:string>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</json:string><json:string>France and Belgium</json:string><json:string>Medical Research Council Clinical Training Fellow</json:string><json:string>ALS Consortium, the USA, Canada, South America, Australia, New Zealand, North Africa, Japan, Russia and workers</json:string><json:string>Institute of Psychiatry and King</json:string><json:string>Sweden and Finland</json:string><json:string>Department of Clinical Chemistry, Umeå University</json:string><json:string>Motor Neurone Disease Care and Research Centre</json:string><json:string>France, the USA</json:string><json:string>Medical Research Council</json:string><json:string>UK</json:string></orgName><orgName_funder><json:string>Medical Research Council</json:string><json:string>UK</json:string></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Barry Chioza</json:string><json:string>Christopher Shaw</json:string><json:string>Peter M. Andersen</json:string><json:string>C. Sham</json:string><json:string>Guy Rouleau</json:string><json:string>P. Nigel</json:string><json:string>Karen Morrisson</json:string><json:string>William Camu</json:string><json:string>Stefan L. Marklund</json:string><json:string>P. V. Hurse</json:string><json:string>Mandy Jackson</json:string><json:string>Gert Matthijs</json:string><json:string>Aleks Radunovic</json:string><json:string>Gui de Chauliac</json:string><json:string>Lars Forsgren</json:string><json:string>Nigel G. Laing</json:string><json:string>K.Abe</json:string></persName><placeName><json:string>Montpellier</json:string><json:string>Central African Republic</json:string><json:string>Australia</json:string><json:string>UK</json:string><json:string>Montreal</json:string><json:string>Canada</json:string><json:string>ALS</json:string><json:string>LOD</json:string><json:string>Leuven</json:string><json:string>Iraq</json:string><json:string>France</json:string><json:string>Umeå</json:string><json:string>Sweden</json:string><json:string>Iran</json:string><json:string>Belgium</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>Department of Neurology, University Hospital Gasthuisberg, 3000</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-783NH3HT-L</json:string></ark><categories><wos><json:string>science</json:string><json:string>genetics & heredity</json:string><json:string>biochemistry & molecular biology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>biomedical research</json:string><json:string>genetics & heredity</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Genetics(clinical)</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Genetics</json:string><json:string>1 - Life Sciences</json:string><json:string>2 - Biochemistry, Genetics and Molecular Biology</json:string><json:string>3 - Molecular Biology</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - General Medicine</json:string></scopus><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string><json:string>neurologie</json:string></inist></categories><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1093/hmg/7.13.2045</json:string></doi><id>E5B0F2D12C41213D28DA3EA4D41BD9050F916C50</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://publisher-list.data.istex.fr">Oxford University Press</publisher><availability><licence><p>© 1998 Oxford University Press</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</p></availability><date>1998</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor</title><author xml:id="author-0000" corresp="yes"><persName><forename type="first">Ammar</forename><surname>Al-Chalabi</surname></persName><email>ammar@iop.bpmf.ac.uk</email><email>ammar@iop.bpmf.ac.uk</email><affiliation>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</affiliation><affiliation></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Peter M.</forename><surname>Andersen</surname></persName><affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Barry</forename><surname>Chioza</surname></persName><affiliation>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</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Christopher</forename><surname>Shaw</surname></persName><affiliation>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</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Pak C.</forename><surname>Sham</surname></persName><affiliation>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</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Wim</forename><surname>Robberecht</surname></persName><affiliation>Department of Neurology, University Hospital Gasthuisberg, 3000 Leuven, Belgium</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Gert</forename><surname>Matthijs</surname></persName><affiliation>Center of Human Genetics, Leuven, Belgium</affiliation></author><author xml:id="author-0007"><persName><forename type="first">William</forename><surname>Camu</surname></persName><affiliation>Service de Neurologie B, Hôpital Gui de Chauliac, 34295 Montpellier, Cedex 5, France</affiliation></author><author xml:id="author-0008"><persName><forename type="first">Stefan L.</forename><surname>Marklund</surname></persName><affiliation>Department of Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden</affiliation></author><author xml:id="author-0009"><persName><forename type="first">Lars</forename><surname>Forsgren</surname></persName><affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</affiliation></author><author xml:id="author-0010"><persName><forename type="first">Guy</forename><surname>Rouleau</surname></persName><affiliation>Centre for Research in Neuroscience, McGill University, Montreal, Canada</affiliation></author><author xml:id="author-0011"><persName><forename type="first">Nigel G.</forename><surname>Laing</surname></persName><affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</affiliation></author><author xml:id="author-0012"><persName><forename type="first">P. V.</forename><surname>Hurse</surname></persName><affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</affiliation></author><author xml:id="author-0013"><persName><forename type="first">Teepu</forename><surname>Siddique</surname></persName><affiliation>Department of Neurology, Northwestern University, Evanston, IL, USA</affiliation></author><author xml:id="author-0014"><persName><forename type="first">P.</forename><surname>Nigel Leigh</surname></persName><affiliation>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</affiliation></author><author xml:id="author-0015"><persName><forename type="first">John F.</forename><surname>Powell</surname></persName><affiliation>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</affiliation></author><idno type="istex">E5B0F2D12C41213D28DA3EA4D41BD9050F916C50</idno><idno type="ark">ark:/67375/HXZ-783NH3HT-L</idno><idno type="DOI">10.1093/hmg/7.13.2045</idno></analytic><monogr><title level="j">Human Molecular Genetics</title><title level="j" type="abbrev">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><idno type="publisher-id">hmg</idno><idno type="PublisherID-hwp">hmg</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="1998-12"></date><biblScope unit="volume">7</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="2045">2045</biblScope><biblScope unit="page" to="2050">2050</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><abstract><p>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 (α = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (α = 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.</p></abstract></profileDesc><revisionDesc><change when="1998-12">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><abbrev-journal-title>Human Molecular Genetics</abbrev-journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta>
<article-id pub-id-type="doi">10.1093/hmg/7.13.2045</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Recessive Amyotrophic Lateral Sclerosis Families with the D90A <italic>SOD1</italic> Mutation Share a Common Founder: Evidence for a Linked Protective Factor</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Al-Chalabi</surname><given-names>Ammar</given-names></name><xref rid="aff9" ref-type="aff"></xref><xref rid="COR1" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Andersen</surname><given-names>Peter M.</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chioza</surname><given-names>Barry</given-names></name><xref rid="aff9" ref-type="aff"></xref></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>Christopher</given-names></name><xref rid="aff9" ref-type="aff"></xref></contrib><contrib contrib-type="author"><name><surname>Sham</surname><given-names>Pak C.</given-names></name><xref rid="aff9" ref-type="aff"></xref></contrib><contrib contrib-type="author"><name><surname>Robberecht</surname><given-names>Wim</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Matthijs</surname><given-names>Gert</given-names></name><xref rid="aff3" ref-type="aff"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Camu</surname><given-names>William</given-names></name><xref rid="aff4" ref-type="aff"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Marklund</surname><given-names>Stefan L.</given-names></name><xref rid="aff5" ref-type="aff"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Forsgren</surname><given-names>Lars</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rouleau</surname><given-names>Guy</given-names></name><xref rid="aff6" ref-type="aff"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Laing</surname><given-names>Nigel G.</given-names></name><xref rid="aff7" ref-type="aff"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hurse</surname><given-names>P. V.</given-names></name><xref rid="aff7" ref-type="aff"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Siddique</surname><given-names>Teepu</given-names></name><xref rid="aff8" ref-type="aff"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nigel Leigh</surname><given-names>P.</given-names></name><xref rid="aff9" ref-type="aff"></xref></contrib><contrib contrib-type="author"><name><surname>Powell</surname><given-names>John F.</given-names></name><xref rid="aff9" ref-type="aff"></xref></contrib><aff id="aff9"><institution>Departments of Neuroscience and Clinical Neurosciences, Institute of Psychiatry and King's College School of Medicine and Dentistry</institution>, <addr-line>De Crespigny Park, Denmark Hill, London SE5 8AF, UK</addr-line></aff><aff id="aff1"><label><sup>1</sup></label><institution>Department of Neurology, Umeå University</institution>, <addr-line>S-901 85 Umeå, Sweden</addr-line></aff><aff id="aff2"><label><sup>2</sup></label><institution>Department of Neurology, University Hospital Gasthuisberg</institution>, <addr-line>3000 Leuven, Belgium</addr-line></aff><aff id="aff3"><label><sup>3</sup></label><institution>Center of Human Genetics</institution>, <addr-line>Leuven, Belgium</addr-line></aff><aff id="aff4"><label><sup>4</sup></label><institution>Service de Neurologie B, Hôpital Gui de Chauliac</institution>, <addr-line>34295 Montpellier, Cedex 5, France</addr-line></aff><aff id="aff5"><label><sup>5</sup></label><institution>Department of Clinical Chemistry, Umeå University</institution>, <addr-line>S-901 85 Umeå, Sweden</addr-line></aff><aff id="aff6"><label><sup>6</sup></label><institution>Centre for Research in Neuroscience, McGill University</institution>, <addr-line>Montreal, Canada</addr-line></aff><aff id="aff7"><label><sup>7</sup></label><institution>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia</institution>, <addr-line>Nedlands, WA 6001, Australia</addr-line></aff><aff id="aff8"><label><sup>8</sup></label><institution>Department of Neurology, Northwestern University</institution>, <addr-line>Evanston, IL, USA</addr-line></aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>To whom correspondence should be addressed. Tel: +44 171 346 5172; Fax: +44 171 346 5190; <email>ammar@iop.bpmf.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><month>12</month><year>1998</year></pub-date><volume>7</volume><issue>13</issue><fpage>2045</fpage><lpage>2050</lpage><history><date date-type="received"><day>12</day><month>05</month><year>1998</year></date><date date-type="accepted"><day>2</day><month>9</month><year>1998</year></date></history><copyright-statement>© 1998 Oxford University Press</copyright-statement><copyright-year>1998</copyright-year><abstract><p>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 <italic>SOD1</italic> 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 (α = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (α = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other <italic>SOD1</italic> 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 <italic>SOD1</italic> in recessive families.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Ammar</namePart><namePart type="family">Al-Chalabi</namePart><affiliation>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</affiliation><affiliation>E-mail: ammar@iop.bpmf.ac.uk</affiliation><affiliation></affiliation><affiliation>E-mail: ammar@iop.bpmf.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter M.</namePart><namePart type="family">Andersen</namePart><affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Barry</namePart><namePart type="family">Chioza</namePart><affiliation>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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher</namePart><namePart type="family">Shaw</namePart><affiliation>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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Pak C.</namePart><namePart type="family">Sham</namePart><affiliation>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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wim</namePart><namePart type="family">Robberecht</namePart><affiliation>Department of Neurology, University Hospital Gasthuisberg, 3000 Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gert</namePart><namePart type="family">Matthijs</namePart><affiliation>Center of Human Genetics, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William</namePart><namePart type="family">Camu</namePart><affiliation>Service de Neurologie B, Hôpital Gui de Chauliac, 34295 Montpellier, Cedex 5, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stefan L.</namePart><namePart type="family">Marklund</namePart><affiliation>Department of Clinical Chemistry, Umeå University, S-901 85 Umeå, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lars</namePart><namePart type="family">Forsgren</namePart><affiliation>Department of Neurology, Umeå University, S-901 85 Umeå, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Guy</namePart><namePart type="family">Rouleau</namePart><affiliation>Centre for Research in Neuroscience, McGill University, Montreal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nigel G.</namePart><namePart type="family">Laing</namePart><affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P. V.</namePart><namePart type="family">Hurse</namePart><affiliation>Australian Neuromuscular Research Institute, Department of Pathology, University of Western Australia, Nedlands, WA 6001, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Teepu</namePart><namePart type="family">Siddique</namePart><affiliation>Department of Neurology, Northwestern University, Evanston, IL, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P.</namePart><namePart type="family">Nigel Leigh</namePart><affiliation>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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John F.</namePart><namePart type="family">Powell</namePart><affiliation>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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">1998-12</dateIssued><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><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 (α = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (α = 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.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><titleInfo type="abbreviated"><title>Human Molecular Genetics</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>7</number></detail><detail type="issue"><caption>no.</caption><number>13</number></detail><extent unit="pages"><start>2045</start><end>2050</end></extent></part></relatedItem><identifier type="istex">E5B0F2D12C41213D28DA3EA4D41BD9050F916C50</identifier><identifier type="DOI">10.1093/hmg/7.13.2045</identifier><accessCondition type="use and reproduction" contentType="copyright">© 1998 Oxford University Press</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>© 1998 Oxford University Press</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/metadata/json</uri></json:item></metadata><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/E5B0F2D12C41213D28DA3EA4D41BD9050F916C50/annexes/gif</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002B28 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 002B28 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:E5B0F2D12C41213D28DA3EA4D41BD9050F916C50
|texte= Recessive Amyotrophic Lateral Sclerosis Families with the D90A SOD1 Mutation Share a Common Founder: Evidence for a Linked Protective Factor
}}
| This area was generated with Dilib version V0.6.33. |  |