A Wide Variety of Mutations in the Parkin Gene Are Responsible for Autosomal Recessive Parkinsonism in Europe
Identifieur interne : 003D14 ( Main/Exploration ); précédent : 003D13; suivant : 003D15A Wide Variety of Mutations in the Parkin Gene Are Responsible for Autosomal Recessive Parkinsonism in Europe
Auteurs : Nacer Abbas [France] ; Christoph B. Lücking [France] ; Sylvain Ricard [France] ; Alexandra Dürr [France] ; Vincenzo Bonifati [Italie] ; Giuseppe De Michele [Italie] ; Sandrine Bouley [France] ; Jenny R. Vaughan [Royaume-Uni] ; Thomas Gasser [Allemagne] ; Roberto Marconi [Italie] ; Emmanuel Broussolle [France] ; Christine Brefel-Courbon [France] ; Biswadjiet S. Harhangi [Pays-Bas] ; Ben A. Oostra [Pays-Bas] ; Edito Fabrizio [Italie] ; Georg A. Böhme [France] ; Laurent Pradier [France] ; Nick W. Wood [Royaume-Uni] ; Alessandro Filla [Italie] ; Giuseppe Meco [Italie] ; Patrice Denefle [France] ; Yves Agid [France] ; Alexis Brice [France]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 1999-04.
Descripteurs français
- Pascal (Inist)
- Wicri :
English descriptors
- KwdEn :
- Autosomal character, Binding Sites, Chromosome C6, Europe, Exons (genetics), Family Health, Family study, Female, Gene Deletion, Genes, Recessive (genetics), Genetics, Genotype, Human, Humans, Ligases, Male, Mutation, Parkinson Disease (genetics), Parkinson disease, Pedigree, Phenotype, Point Mutation, Polymorphism, Polymorphism, Genetic, Proteins (genetics), Recessive character, Ubiquitin-Protein Ligases.
- MESH :
- chemical , genetics : Proteins.
- chemical : Ligases, Ubiquitin-Protein Ligases.
- genetics : Exons, Genes, Recessive, Parkinson Disease.
- Binding Sites, Europe, Family Health, Female, Gene Deletion, Genotype, Humans, Male, Mutation, Pedigree, Phenotype, Point Mutation, Polymorphism, Genetic.
Abstract
Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110–166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202–203delAG, 255delA and 321–322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 ± 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.
Url:
DOI: 10.1093/hmg/8.4.567
Affiliations:
- Allemagne, France, Italie, Pays-Bas, Royaume-Uni
- Auvergne-Rhône-Alpes, Bavière, District de Haute-Bavière, Latium, Midi-Pyrénées, Occitanie (région administrative), Rhône-Alpes, Île-de-France
- Evry, Lyon, Munich, Paris, Rome, Toulouse, Vitry
- Hôpital de la Salpêtrière
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Le document en format XML
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Vaughan</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Neurology, Queen Square, London WC1N 3BG</wicri:regionArea><wicri:noRegion>London WC1N 3BG</wicri:noRegion></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Neurologische Klinik, Klinikum Großhadern, Ludwig-Maximilians-Universität, 81377 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Marconi, Roberto" sort="Marconi, Roberto" uniqKey="Marconi R" first="Roberto" last="Marconi">Roberto Marconi</name><affiliation wicri:level="1"><country xml:lang="fr">Italie</country><wicri:regionArea>Divisione di Neurologia, Ospedale Misericordia, 58100 Grosseto</wicri:regionArea><wicri:noRegion>58100 Grosseto</wicri:noRegion></affiliation></author><author><name sortKey="Broussolle, Emmanuel" sort="Broussolle, Emmanuel" uniqKey="Broussolle E" first="Emmanuel" last="Broussolle">Emmanuel Broussolle</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Hôpital Neurologique et Neurochirurgical Pierre Wertheimer, 69003 Lyon</wicri:regionArea><placeName><region type="region" nuts="2">Auvergne-Rhône-Alpes</region><region type="old region" nuts="2">Rhône-Alpes</region><settlement type="city">Lyon</settlement></placeName></affiliation></author><author><name sortKey="Brefel Courbon, Christine" sort="Brefel Courbon, Christine" uniqKey="Brefel Courbon C" first="Christine" last="Brefel-Courbon">Christine Brefel-Courbon</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Service de Pharmacologie-Centre d'Investigation Clinique, INSERM U455, CHU de Toulouse, 31073 Toulouse</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Harhangi, Biswadjiet S" sort="Harhangi, Biswadjiet S" uniqKey="Harhangi B" first="Biswadjiet S." last="Harhangi">Biswadjiet S. Harhangi</name><affiliation wicri:level="1"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Epidemiology and Biostatistics, Erasmus University Medical School, 3000 DR Rotterdam</wicri:regionArea><wicri:noRegion>3000 DR Rotterdam</wicri:noRegion></affiliation></author><author><name sortKey="Oostra, Ben A" sort="Oostra, Ben A" uniqKey="Oostra B" first="Ben A." last="Oostra">Ben A. Oostra</name><affiliation wicri:level="1"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Clinical Genetics, Erasmus University, 3015 GE Rotterdam</wicri:regionArea><wicri:noRegion>3015 GE Rotterdam</wicri:noRegion></affiliation></author><author><name sortKey="Fabrizio, Edito" sort="Fabrizio, Edito" uniqKey="Fabrizio E" first="Edito" last="Fabrizio">Edito Fabrizio</name><affiliation wicri:level="1"><country xml:lang="fr">Italie</country><wicri:regionArea>Dipartimento di Scienze Neurologiche, Università ‘La Sapienza’, 00185 Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Bohme, Georg A" sort="Bohme, Georg A" uniqKey="Bohme G" first="Georg A." last="Böhme">Georg A. Böhme</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>CNS Department, Rhône-Poulenc Rorer, 94400 Vitry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Vitry</settlement></placeName></affiliation></author><author><name sortKey="Pradier, Laurent" sort="Pradier, Laurent" uniqKey="Pradier L" first="Laurent" last="Pradier">Laurent Pradier</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>CNS Department, Rhône-Poulenc Rorer, 94400 Vitry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Vitry</settlement></placeName></affiliation></author><author><name sortKey="Wood, Nick W" sort="Wood, Nick W" uniqKey="Wood N" first="Nick W." last="Wood">Nick W. Wood</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Neurology, Queen Square, London WC1N 3BG</wicri:regionArea><wicri:noRegion>London WC1N 3BG</wicri:noRegion></affiliation></author><author><name sortKey="Filla, Alessandro" sort="Filla, Alessandro" uniqKey="Filla A" first="Alessandro" last="Filla">Alessandro Filla</name><affiliation wicri:level="1"><country xml:lang="fr">Italie</country><wicri:regionArea>Dipartimento di Scienze Neurologiche, Università Federico II, 80131 Naples</wicri:regionArea><wicri:noRegion>80131 Naples</wicri:noRegion></affiliation></author><author><name sortKey="Meco, Giuseppe" sort="Meco, Giuseppe" uniqKey="Meco G" first="Giuseppe" last="Meco">Giuseppe Meco</name><affiliation wicri:level="1"><country xml:lang="fr">Italie</country><wicri:regionArea>Dipartimento di Scienze Neurologiche, Università ‘La Sapienza’, 00185 Rome</wicri:regionArea><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></affiliation></author><author><name sortKey="Denefle, Patrice" sort="Denefle, Patrice" uniqKey="Denefle P" first="Patrice" last="Denefle">Patrice Denefle</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>Genomics Department, Rhône-Poulenc Rorer, 91006 Evry Cedex</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Evry</settlement></placeName></affiliation></author><author><name sortKey="Agid, Yves" sort="Agid, Yves" uniqKey="Agid Y" first="Yves" last="Agid">Yves Agid</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>INSERM U289, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName><orgName type="hospital" n="4">Hôpital de la Salpêtrière</orgName></affiliation></author><author><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><affiliation wicri:level="3"><country xml:lang="fr">France</country><wicri:regionArea>INSERM U289, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">France</country></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="1999-04">1999-04</date><biblScope unit="volume">8</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="567">567</biblScope><biblScope unit="page" to="574">574</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">412B31E79CBE22C542677230BC550D8192B1CE2E</idno><idno type="DOI">10.1093/hmg/8.4.567</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autosomal character</term><term>Binding Sites</term><term>Chromosome C6</term><term>Europe</term><term>Exons (genetics)</term><term>Family Health</term><term>Family study</term><term>Female</term><term>Gene Deletion</term><term>Genes, Recessive (genetics)</term><term>Genetics</term><term>Genotype</term><term>Human</term><term>Humans</term><term>Ligases</term><term>Male</term><term>Mutation</term><term>Parkinson Disease (genetics)</term><term>Parkinson disease</term><term>Pedigree</term><term>Phenotype</term><term>Point Mutation</term><term>Polymorphism</term><term>Polymorphism, Genetic</term><term>Proteins (genetics)</term><term>Recessive character</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Proteins</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Ligases</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Exons</term><term>Genes, Recessive</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Europe</term><term>Family Health</term><term>Female</term><term>Gene Deletion</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Mutation</term><term>Pedigree</term><term>Phenotype</term><term>Point Mutation</term><term>Polymorphism, Genetic</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Caractère autosomique</term><term>Caractère récessif</term><term>Chromosome C6</term><term>Etude familiale</term><term>Europe</term><term>Gène parkin</term><term>Génétique</term><term>Homme</term><term>Mutation</term><term>Parkinson maladie</term><term>Polymorphisme</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract">Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110–166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202–203delAG, 255delA and 321–322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 ± 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>France</li><li>Italie</li><li>Pays-Bas</li><li>Royaume-Uni</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Bavière</li><li>District de Haute-Bavière</li><li>Latium</li><li>Midi-Pyrénées</li><li>Occitanie (région administrative)</li><li>Rhône-Alpes</li><li>Île-de-France</li></region><settlement><li>Evry</li><li>Lyon</li><li>Munich</li><li>Paris</li><li>Rome</li><li>Toulouse</li><li>Vitry</li></settlement><orgName><li>Hôpital de la Salpêtrière</li></orgName></list><tree><country name="France"><region name="Île-de-France"><name sortKey="Abbas, Nacer" sort="Abbas, Nacer" uniqKey="Abbas N" first="Nacer" last="Abbas">Nacer Abbas</name></region><name sortKey="Agid, Yves" sort="Agid, Yves" uniqKey="Agid Y" first="Yves" last="Agid">Yves Agid</name><name sortKey="Bohme, Georg A" sort="Bohme, Georg A" uniqKey="Bohme G" first="Georg A." last="Böhme">Georg A. Böhme</name><name sortKey="Bouley, Sandrine" sort="Bouley, Sandrine" uniqKey="Bouley S" first="Sandrine" last="Bouley">Sandrine Bouley</name><name sortKey="Brefel Courbon, Christine" sort="Brefel Courbon, Christine" uniqKey="Brefel Courbon C" first="Christine" last="Brefel-Courbon">Christine Brefel-Courbon</name><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><name sortKey="Brice, Alexis" sort="Brice, Alexis" uniqKey="Brice A" first="Alexis" last="Brice">Alexis Brice</name><name sortKey="Broussolle, Emmanuel" sort="Broussolle, Emmanuel" uniqKey="Broussolle E" first="Emmanuel" last="Broussolle">Emmanuel Broussolle</name><name sortKey="Denefle, Patrice" sort="Denefle, Patrice" uniqKey="Denefle P" first="Patrice" last="Denefle">Patrice Denefle</name><name sortKey="Durr, Alexandra" sort="Durr, Alexandra" uniqKey="Durr A" first="Alexandra" last="Dürr">Alexandra Dürr</name><name sortKey="Lucking, Christoph B" sort="Lucking, Christoph B" uniqKey="Lucking C" first="Christoph B." last="Lücking">Christoph B. Lücking</name><name sortKey="Pradier, Laurent" sort="Pradier, Laurent" uniqKey="Pradier L" first="Laurent" last="Pradier">Laurent Pradier</name><name sortKey="Ricard, Sylvain" sort="Ricard, Sylvain" uniqKey="Ricard S" first="Sylvain" last="Ricard">Sylvain Ricard</name></country><country name="Italie"><region name="Latium"><name sortKey="Bonifati, Vincenzo" sort="Bonifati, Vincenzo" uniqKey="Bonifati V" first="Vincenzo" last="Bonifati">Vincenzo Bonifati</name></region><name sortKey="De Michele, Giuseppe" sort="De Michele, Giuseppe" uniqKey="De Michele G" first="Giuseppe" last="De Michele">Giuseppe De Michele</name><name sortKey="Fabrizio, Edito" sort="Fabrizio, Edito" uniqKey="Fabrizio E" first="Edito" last="Fabrizio">Edito Fabrizio</name><name sortKey="Filla, Alessandro" sort="Filla, Alessandro" uniqKey="Filla A" first="Alessandro" last="Filla">Alessandro Filla</name><name sortKey="Marconi, Roberto" sort="Marconi, Roberto" uniqKey="Marconi R" first="Roberto" last="Marconi">Roberto Marconi</name><name sortKey="Meco, Giuseppe" sort="Meco, Giuseppe" uniqKey="Meco G" first="Giuseppe" last="Meco">Giuseppe Meco</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Vaughan, Jenny R" sort="Vaughan, Jenny R" uniqKey="Vaughan J" first="Jenny R." last="Vaughan">Jenny R. Vaughan</name></noRegion><name sortKey="Wood, Nick W" sort="Wood, Nick W" uniqKey="Wood N" first="Nick W." last="Wood">Nick W. Wood</name></country><country name="Allemagne"><region name="Bavière"><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name></region></country><country name="Pays-Bas"><noRegion><name sortKey="Harhangi, Biswadjiet S" sort="Harhangi, Biswadjiet S" uniqKey="Harhangi B" first="Biswadjiet S." last="Harhangi">Biswadjiet S. Harhangi</name></noRegion><name sortKey="Oostra, Ben A" sort="Oostra, Ben A" uniqKey="Oostra B" first="Ben A." last="Oostra">Ben A. Oostra</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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