Serveur d'exploration autour de Joseph Jankovic

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Lrrk2 R1441G-related Parkinson's disease: evidence of a common founding event in the seventh century in Northern Spain

Identifieur interne : 000185 ( Pmc/Checkpoint ); précédent : 000184; suivant : 000186

Lrrk2 R1441G-related Parkinson's disease: evidence of a common founding event in the seventh century in Northern Spain

Auteurs : Ignacio Mata ; Carolyn Hutter ; María González ; Marian De ; Elena Lezcano ; Cecilia Huerta ; Marta Blazquez ; Renee Ribacoba ; Luis Guisasola ; Carlos Salvador ; Juan G ; Juan Zarranz ; Jon Infante ; Joseph Jankovic [États-Unis] ; Hao Deng ; Karen Edwards ; Victoria Alvarez ; Cyrus Zabetian

Source :

RBID : PMC:2821036

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene together represent the most common genetic determinant of Parkinson's disease (PD) identified to date. The vast majority of patients with LRRK2-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the LRRK2 region. Nine of the patients were of Basque origin and 20 were non-Basques. We inferred haplotypes using a Bayesian approach and utilized a maximum-likelihood method to estimate the age of the most recent common ancestor. Significant but incomplete allele sharing was observed over a distance of 6.0 Mb and a single, rare ten-marker haplotype 5.8 Mb in length was seen in all mutation carriers. We estimate that the most recent common ancestor lived 1,350 (95% CI, 1,020–1,740) years ago in approximately the seventh century. We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain.


Url:
DOI: 10.1007/s10048-009-0187-z
PubMed: 19308469
PubMed Central: 2821036


Affiliations:


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PMC:2821036

Le document en format XML

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<title xml:lang="en" level="a" type="main">Lrrk2 R1441G-related Parkinson's disease: evidence of a common founding event in the seventh century in Northern Spain</title>
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<name sortKey="Hutter, Carolyn M" sort="Hutter, Carolyn M" uniqKey="Hutter C" first="Carolyn" last="Hutter">Carolyn Hutter</name>
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<name sortKey="Gonzalez Fernandez, Maria C" sort="Gonzalez Fernandez, Maria C" uniqKey="Gonzalez Fernandez M" first="María" last="González">María González</name>
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<name sortKey="Edwards, Karen L" sort="Edwards, Karen L" uniqKey="Edwards K" first="Karen" last="Edwards">Karen Edwards</name>
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<name sortKey="Alvarez, Victoria" sort="Alvarez, Victoria" uniqKey="Alvarez V" first="Victoria" last="Alvarez">Victoria Alvarez</name>
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<name sortKey="Zabetian, Cyrus P" sort="Zabetian, Cyrus P" uniqKey="Zabetian C" first="Cyrus" last="Zabetian">Cyrus Zabetian</name>
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<div type="abstract" xml:lang="en">
<p id="P2">Mutations in the leucine-rich repeat kinase 2 (
<italic>LRRK2</italic>
) gene together represent the most common genetic determinant of Parkinson's disease (PD) identified to date. The vast majority of patients with
<italic>LRRK2</italic>
-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the
<italic>LRRK2</italic>
region. Nine of the patients were of Basque origin and 20 were non-Basques. We inferred haplotypes using a Bayesian approach and utilized a maximum-likelihood method to estimate the age of the most recent common ancestor. Significant but incomplete allele sharing was observed over a distance of 6.0 Mb and a single, rare ten-marker haplotype 5.8 Mb in length was seen in all mutation carriers. We estimate that the most recent common ancestor lived 1,350 (95% CI, 1,020–1,740) years ago in approximately the seventh century. We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain.</p>
</div>
</front>
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<journal-meta>
<journal-id journal-id-type="nlm-journal-id">9709714</journal-id>
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<journal-id journal-id-type="nlm-ta">Neurogenetics</journal-id>
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<title-group>
<article-title>Lrrk2 R1441G-related Parkinson's disease: evidence of a common founding event in the seventh century in Northern Spain</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Mata</surname>
<given-names>Ignacio F.</given-names>
</name>
<aff id="A1">Geriatric Research Education and Clinical Center S-182, Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108, USA</aff>
<aff id="A2">Department of Neurology, University of Washington, Seattle, WA, USA</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hutter</surname>
<given-names>Carolyn M.</given-names>
</name>
<aff id="A3">Department of Epidemiology, University of Washington, Seattle, WA, USA</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>González-Fernández</surname>
<given-names>María C.</given-names>
</name>
<aff id="A4">Servicio General de Investigación Genómica: Banco de ADN, Universidad del País Vasco, Vitoria-Gasteiz, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>de Pancorbo</surname>
<given-names>Marian M.</given-names>
</name>
<aff id="A5">Servicio General de Investigación Genómica: Banco de ADN, Universidad del País Vasco, Vitoria-Gasteiz, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lezcano</surname>
<given-names>Elena</given-names>
</name>
<aff id="A6">Unidad de trastornos del movimiento, Hospital de Cruces, Baracaldo, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Huerta</surname>
<given-names>Cecilia</given-names>
</name>
<aff id="A7">Genética Molecular-Instituto de Investigacion Nefrológica, Hospital Universitario Central de Asturias, Oviedo, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Blazquez</surname>
<given-names>Marta</given-names>
</name>
<aff id="A8">Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ribacoba</surname>
<given-names>Renee</given-names>
</name>
<aff id="A9">Servicio de Neurología, Hospital Alvarez-Buylla, Mieres, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Guisasola</surname>
<given-names>Luis M.</given-names>
</name>
<aff id="A10">Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Salvador</surname>
<given-names>Carlos</given-names>
</name>
<aff id="A11">Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gómez-Esteban</surname>
<given-names>Juan C.</given-names>
</name>
<aff id="A12">Unidad de trastornos del movimiento, Hospital de Cruces, Baracaldo, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Zarranz</surname>
<given-names>Juan J.</given-names>
</name>
<aff id="A13">Unidad de trastornos del movimiento, Hospital de Cruces, Baracaldo, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Infante</surname>
<given-names>Jon</given-names>
</name>
<aff id="A14">Servicio de Neurología, Hospital Universitario “Marqués de Valdecilla”, Universidad de Cantabria, Santander, Spain</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jankovic</surname>
<given-names>Joseph</given-names>
</name>
<aff id="A15">Department of Neurology, Baylor College of Medicine, Houston, TX, USA</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Deng</surname>
<given-names>Hao</given-names>
</name>
<aff id="A16">Department of Neurology, Baylor College of Medicine, Houston, TX, USA</aff>
<aff id="A17">Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Edwards</surname>
<given-names>Karen L.</given-names>
</name>
<aff id="A18">Department of Epidemiology, University of Washington, Seattle, WA, USA</aff>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Alvarez</surname>
<given-names>Victoria</given-names>
</name>
<aff id="A19">Genética Molecular-Instituto de Investigacion Nefrológica, Hospital Universitario Central de Asturias, Oviedo, Spain</aff>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Zabetian</surname>
<given-names>Cyrus P.</given-names>
</name>
<aff id="A20">Geriatric Research Education and Clinical Center S-182, Veterans Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108, USA
<email>zabetian@u.washington.edu</email>
</aff>
<aff id="A21">Department of Neurology, University of Washington, Seattle, WA, USA</aff>
</contrib>
</contrib-group>
<author-notes>
<fn fn-type="equal" id="FN1">
<p id="P1">Ignacio F. Mata and Carolyn M. Hutter contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted">
<day>5</day>
<month>2</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="epub">
<day>24</day>
<month>3</month>
<year>2009</year>
</pub-date>
<pub-date pub-type="ppub">
<month>10</month>
<year>2009</year>
</pub-date>
<pub-date pub-type="pmc-release">
<day>12</day>
<month>2</month>
<year>2010</year>
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<volume>10</volume>
<issue>4</issue>
<fpage>347</fpage>
<permissions>
<copyright-statement>£ Springer-Verlag 2009</copyright-statement>
<copyright-year>2009</copyright-year>
</permissions>
<abstract>
<p id="P2">Mutations in the leucine-rich repeat kinase 2 (
<italic>LRRK2</italic>
) gene together represent the most common genetic determinant of Parkinson's disease (PD) identified to date. The vast majority of patients with
<italic>LRRK2</italic>
-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the
<italic>LRRK2</italic>
region. Nine of the patients were of Basque origin and 20 were non-Basques. We inferred haplotypes using a Bayesian approach and utilized a maximum-likelihood method to estimate the age of the most recent common ancestor. Significant but incomplete allele sharing was observed over a distance of 6.0 Mb and a single, rare ten-marker haplotype 5.8 Mb in length was seen in all mutation carriers. We estimate that the most recent common ancestor lived 1,350 (95% CI, 1,020–1,740) years ago in approximately the seventh century. We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain.</p>
</abstract>
<kwd-group>
<kwd>Parkinson disease</kwd>
<kwd>
<italic>LRRK2</italic>
</kwd>
<kwd>R1441G</kwd>
<kwd>Founder effect</kwd>
<kwd>Basques</kwd>
</kwd-group>
<contract-num rid="NS1">K08 NS044138-05 ||NS</contract-num>
<contract-sponsor id="NS1">National Institute of Neurological Disorders and Stroke : NINDS</contract-sponsor>
</article-meta>
</front>
</pmc>
<affiliations>
<list>
<country>
<li>États-Unis</li>
</country>
<region>
<li>Texas</li>
</region>
<settlement>
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<orgName>
<li>Baylor College of Medicine</li>
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<name sortKey="Blazquez, Marta" sort="Blazquez, Marta" uniqKey="Blazquez M" first="Marta" last="Blazquez">Marta Blazquez</name>
<name sortKey="De Pancorbo, Marian M" sort="De Pancorbo, Marian M" uniqKey="De Pancorbo M" first="Marian" last="De">Marian De</name>
<name sortKey="Deng, Hao" sort="Deng, Hao" uniqKey="Deng H" first="Hao" last="Deng">Hao Deng</name>
<name sortKey="Edwards, Karen L" sort="Edwards, Karen L" uniqKey="Edwards K" first="Karen" last="Edwards">Karen Edwards</name>
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<name sortKey="Gonzalez Fernandez, Maria C" sort="Gonzalez Fernandez, Maria C" uniqKey="Gonzalez Fernandez M" first="María" last="González">María González</name>
<name sortKey="Guisasola, Luis M" sort="Guisasola, Luis M" uniqKey="Guisasola L" first="Luis" last="Guisasola">Luis Guisasola</name>
<name sortKey="Huerta, Cecilia" sort="Huerta, Cecilia" uniqKey="Huerta C" first="Cecilia" last="Huerta">Cecilia Huerta</name>
<name sortKey="Hutter, Carolyn M" sort="Hutter, Carolyn M" uniqKey="Hutter C" first="Carolyn" last="Hutter">Carolyn Hutter</name>
<name sortKey="Infante, Jon" sort="Infante, Jon" uniqKey="Infante J" first="Jon" last="Infante">Jon Infante</name>
<name sortKey="Lezcano, Elena" sort="Lezcano, Elena" uniqKey="Lezcano E" first="Elena" last="Lezcano">Elena Lezcano</name>
<name sortKey="Mata, Ignacio F" sort="Mata, Ignacio F" uniqKey="Mata I" first="Ignacio" last="Mata">Ignacio Mata</name>
<name sortKey="Ribacoba, Renee" sort="Ribacoba, Renee" uniqKey="Ribacoba R" first="Renee" last="Ribacoba">Renee Ribacoba</name>
<name sortKey="Salvador, Carlos" sort="Salvador, Carlos" uniqKey="Salvador C" first="Carlos" last="Salvador">Carlos Salvador</name>
<name sortKey="Zabetian, Cyrus P" sort="Zabetian, Cyrus P" uniqKey="Zabetian C" first="Cyrus" last="Zabetian">Cyrus Zabetian</name>
<name sortKey="Zarranz, Juan J" sort="Zarranz, Juan J" uniqKey="Zarranz J" first="Juan" last="Zarranz">Juan Zarranz</name>
</noCountry>
<country name="États-Unis">
<region name="Texas">
<name sortKey="Jankovic, Joseph" sort="Jankovic, Joseph" uniqKey="Jankovic J" first="Joseph" last="Jankovic">Joseph Jankovic</name>
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