Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset
Identifieur interne : 000489 ( Main/Corpus ); précédent : 000488; suivant : 000490Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset
Auteurs : Stefan-M. Pulst ; Nieves Santos ; Dai Wang ; Huiying Yang ; Duong Huynh ; Luis Velazquez ; K. Pattie FigueroaSource :
- Brain [ 0006-8950 ] ; 2005-10.
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- KwdEn :
Abstract
Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (P < 0.04) and genotypes (P < 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.
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DOI: 10.1093/brain/awh586
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Pulst</name><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Santos, Nieves" sort="Santos, Nieves" uniqKey="Santos N" first="Nieves" last="Santos">Nieves Santos</name><affiliation><mods:affiliation>Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias, Holguín, Cuba</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Wang, Dai" sort="Wang, Dai" uniqKey="Wang D" first="Dai" last="Wang">Dai Wang</name><affiliation><mods:affiliation>Department of Pediatrics and</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Yang, Huiying" sort="Yang, Huiying" uniqKey="Yang H" first="Huiying" last="Yang">Huiying Yang</name><affiliation><mods:affiliation>Department of Pediatrics and</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Huynh, Duong" sort="Huynh, Duong" uniqKey="Huynh D" first="Duong" last="Huynh">Duong Huynh</name><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Velazquez, Luis" sort="Velazquez, Luis" uniqKey="Velazquez L" first="Luis" last="Velazquez">Luis Velazquez</name><affiliation><mods:affiliation>Department of Neurobiology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Figueroa, K Pattie" sort="Figueroa, K Pattie" uniqKey="Figueroa K" first="K. 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Pulst</name><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Santos, Nieves" sort="Santos, Nieves" uniqKey="Santos N" first="Nieves" last="Santos">Nieves Santos</name><affiliation><mods:affiliation>Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias, Holguín, Cuba</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Wang, Dai" sort="Wang, Dai" uniqKey="Wang D" first="Dai" last="Wang">Dai Wang</name><affiliation><mods:affiliation>Department of Pediatrics and</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Yang, Huiying" sort="Yang, Huiying" uniqKey="Yang H" first="Huiying" last="Yang">Huiying Yang</name><affiliation><mods:affiliation>Department of Pediatrics and</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Huynh, Duong" sort="Huynh, Duong" uniqKey="Huynh D" first="Duong" last="Huynh">Duong Huynh</name><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Velazquez, Luis" sort="Velazquez, Luis" uniqKey="Velazquez L" first="Luis" last="Velazquez">Luis Velazquez</name><affiliation><mods:affiliation>Department of Neurobiology,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author><author><name sortKey="Figueroa, K Pattie" sort="Figueroa, K Pattie" uniqKey="Figueroa K" first="K. Pattie" last="Figueroa">K. Pattie Figueroa</name><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><title level="j" type="abbrev">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-10">2005-10</date><biblScope unit="volume">128</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="2297">2297</biblScope><biblScope unit="page" to="2303">2303</biblScope></imprint><idno type="ISSN">0006-8950</idno></series><idno type="istex">A50AE7B7BE835B027DABEFECA9772D2D11DA9E36</idno><idno type="DOI">10.1093/brain/awh586</idno><idno type="local">awh586</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AO = age of onset</term><term>CACNA1A</term><term>PC = Purkinje cell</term><term>age of disease onset, heritability</term><term>genetic modifier</term><term>polyQ = polyglutamine</term><term>spinocerebellar ataxia type 2 (SCA2)</term><term>spinocerebellar ataxia type 6 (SCA6)</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (P < 0.04) and genotypes (P < 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Stefan-M. Pulst</name><affiliations><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string></affiliations></json:item><json:item><name>Nieves Santos</name><affiliations><json:string>Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias, Holguín, Cuba</json:string><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string></affiliations></json:item><json:item><name>Dai Wang</name><affiliations><json:string>Department of Pediatrics and</json:string><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string></affiliations></json:item><json:item><name>Huiying Yang</name><affiliations><json:string>Department of Pediatrics and</json:string><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string></affiliations></json:item><json:item><name>Duong Huynh</name><affiliations><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string></affiliations></json:item><json:item><name>Luis Velazquez</name><affiliations><json:string>Department of Neurobiology,</json:string><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string></affiliations></json:item><json:item><name>K. Pattie Figueroa</name><affiliations><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string><json:string>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Original Articles</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>spinocerebellar ataxia type 2 (SCA2)</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>age of disease onset, heritability</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>genetic modifier</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CACNA1A</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>spinocerebellar ataxia type 6 (SCA6)</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>AO = age of onset</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PC = Purkinje cell</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>polyQ = polyglutamine</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (P > 0.04) and genotypes (P > 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.</abstract><qualityIndicators><score>8.107</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612.288 x 793.706 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>9</keywordCount><abstractCharCount>2097</abstractCharCount><pdfWordCount>4607</pdfWordCount><pdfCharCount>28008</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>327</abstractWordCount></qualityIndicators><title>Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset</title><genre><json:string>research-article</json:string></genre><host><volume>128</volume><pages><last>2303</last><first>2297</first></pages><issn><json:string>0006-8950</json:string></issn><issue>10</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2156</json:string></eissn><title>Brain</title></host><categories><wos><json:string>CLINICAL NEUROLOGY</json:string><json:string>NEUROSCIENCES</json:string></wos></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1093/brain/awh586</json:string></doi><id>A50AE7B7BE835B027DABEFECA9772D2D11DA9E36</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/A50AE7B7BE835B027DABEFECA9772D2D11DA9E36/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/A50AE7B7BE835B027DABEFECA9772D2D11DA9E36/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/A50AE7B7BE835B027DABEFECA9772D2D11DA9E36/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>OUP</p></availability><date>2005-07-06</date></publicationStmt><notesStmt><note>Corresponding author: Dr Stefan-M. Pulst, Division of Neurology, Cedars-Sinai Medical Center, Department of Medicine and Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA E-mail: Pulst@CSHS.org</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset</title><author><persName><forename type="first">Stefan-M.</forename><surname>Pulst</surname></persName><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation></author><author><persName><forename type="first">Nieves</forename><surname>Santos</surname></persName><affiliation>Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias, Holguín, Cuba</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation></author><author><persName><forename type="first">Dai</forename><surname>Wang</surname></persName><affiliation>Department of Pediatrics and</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation></author><author><persName><forename type="first">Huiying</forename><surname>Yang</surname></persName><affiliation>Department of Pediatrics and</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation></author><author><persName><forename type="first">Duong</forename><surname>Huynh</surname></persName><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation></author><author><persName><forename type="first">Luis</forename><surname>Velazquez</surname></persName><affiliation>Department of Neurobiology,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation></author><author><persName><forename type="first">K. Pattie</forename><surname>Figueroa</surname></persName><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation></author></analytic><monogr><title level="j">Brain</title><title level="j" type="abbrev">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-10"></date><biblScope unit="volume">128</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="2297">2297</biblScope><biblScope unit="page" to="2303">2303</biblScope></imprint></monogr><idno type="istex">A50AE7B7BE835B027DABEFECA9772D2D11DA9E36</idno><idno type="DOI">10.1093/brain/awh586</idno><idno type="local">awh586</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005-07-06</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (P < 0.04) and genotypes (P < 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>KWD</head><item><term>spinocerebellar ataxia type 2 (SCA2)</term></item><item><term>age of disease onset, heritability</term></item><item><term>genetic modifier</term></item><item><term>CACNA1A</term></item><item><term>spinocerebellar ataxia type 6 (SCA6)</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><head>ABR</head><item><term>AO = age of onset</term></item><item><term>PC = Purkinje cell</term></item><item><term>polyQ = polyglutamine</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2005-07-06">Created</change><change when="2005-10">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/A50AE7B7BE835B027DABEFECA9772D2D11DA9E36/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</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 xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">brain</journal-id><journal-id journal-id-type="nlm-ta">Brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-title>Brain</journal-title><abbrev-journal-title abbrev-type="publisher">Brain</abbrev-journal-title><issn pub-type="ppub">0006-8950</issn><issn pub-type="epub">1460-2156</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">awh586</article-id><article-id pub-id-type="doi">10.1093/brain/awh586</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Pulst</surname><given-names>Stefan-M.</given-names></name><xref rid="AFF1">1</xref><xref rid="AFF2">2</xref><xref rid="AFF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Santos</surname><given-names>Nieves</given-names></name><xref rid="AFF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Dai</given-names></name><xref rid="AFF4">4</xref><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Huiying</given-names></name><xref rid="AFF4">4</xref><xref rid="AFF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Huynh</surname><given-names>Duong</given-names></name><xref rid="AFF1">1</xref><xref rid="AFF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Velazquez</surname><given-names>Luis</given-names></name><xref rid="AFF3">6</xref></contrib><contrib contrib-type="author"><name><surname>Figueroa</surname><given-names>K. Pattie</given-names></name><xref rid="AFF1">1</xref></contrib><aff><target target-type="aff" id="AFF1"></target><label>1</label>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center, <target target-type="aff" id="AFF2"></target><label>2</label>Department of Medicine, <target target-type="aff" id="AFF3"></target><label>3</label>Department of Neurobiology, <target target-type="aff" id="AFF4"></target><label>4</label>Department of Pediatrics and <target target-type="aff" id="AFF5"></target><label>5</label>Department of Epidemiology, CSMC, Medical Genetics Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and <target target-type="aff" id="AFF6"></target><label>6</label>Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias, Holguín, Cuba</aff></contrib-group><author-notes><corresp>Corresponding author: Dr Stefan-M. Pulst, Division of Neurology, Cedars-Sinai Medical Center, Department of Medicine and Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA E-mail: <ext-link xlink:href="Pulst@CSHS.org" ext-link-type="email">Pulst@CSHS.org</ext-link></corresp></author-notes><pub-date pub-type="ppub"><month>October</month><year>2005</year></pub-date><pub-date pub-type="epub"><day>6</day><month>7</month><year>2005</year></pub-date><volume>128</volume><issue>10</issue><fpage>2297</fpage><lpage>2303</lpage><history><date date-type="accepted"><day>9</day><month>6</month><year>2005</year></date><date date-type="received"><day>28</day><month>3</month><year>2005</year></date><date date-type="rev-recd"><day>27</day><month>5</month><year>2005</year></date></history><copyright-statement>© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2005</copyright-year><abstract xml:lang="en"><p>Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (<italic>P</italic> < 0.04) and genotypes (<italic>P</italic> < 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.</p></abstract><kwd-group kwd-group-type="KWD" xml:lang="en"><kwd>spinocerebellar ataxia type 2 (SCA2)</kwd><kwd>age of disease onset, heritability</kwd><kwd>genetic modifier</kwd><kwd>CACNA1A</kwd><kwd>spinocerebellar ataxia type 6 (SCA6)</kwd></kwd-group><kwd-group kwd-group-type="ABR" xml:lang="en"><kwd>AO = age of onset</kwd><kwd>PC = Purkinje cell</kwd><kwd>polyQ = polyglutamine</kwd></kwd-group><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>2297</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>October 2005</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>Original Article</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset</title></titleInfo><name type="personal"><namePart type="given">Stefan-M.</namePart><namePart type="family">Pulst</namePart><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nieves</namePart><namePart type="family">Santos</namePart><affiliation>Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias, Holguín, Cuba</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dai</namePart><namePart type="family">Wang</namePart><affiliation>Department of Pediatrics and</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Huiying</namePart><namePart type="family">Yang</namePart><affiliation>Department of Pediatrics and</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Duong</namePart><namePart type="family">Huynh</namePart><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Luis</namePart><namePart type="family">Velazquez</namePart><affiliation>Department of Neurobiology,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">K. Pattie</namePart><namePart type="family">Figueroa</namePart><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><affiliation>Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2005-10</dateIssued><dateCreated encoding="w3cdtf">2005-07-06</dateCreated><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (P < 0.04) and genotypes (P < 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.</abstract><note type="author-notes">Corresponding author: Dr Stefan-M. Pulst, Division of Neurology, Cedars-Sinai Medical Center, Department of Medicine and Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA E-mail: Pulst@CSHS.org</note><subject lang="en"><genre>KWD</genre><topic>spinocerebellar ataxia type 2 (SCA2)</topic><topic>age of disease onset, heritability</topic><topic>genetic modifier</topic><topic>CACNA1A</topic><topic>spinocerebellar ataxia type 6 (SCA6)</topic></subject><subject lang="en"><genre>ABR</genre><topic>AO = age of onset</topic><topic>PC = Purkinje cell</topic><topic>polyQ = polyglutamine</topic></subject><relatedItem type="host"><titleInfo><title>Brain</title></titleInfo><titleInfo type="abbreviated"><title>Brain</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0006-8950</identifier><identifier type="eISSN">1460-2156</identifier><identifier type="PublisherID">brainj</identifier><identifier type="PublisherID-hwp">brain</identifier><identifier type="PublisherID-nlm-ta">Brain</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>128</number></detail><detail type="issue"><caption>no.</caption><number>10</number></detail><extent unit="pages"><start>2297</start><end>2303</end></extent></part></relatedItem><identifier type="istex">A50AE7B7BE835B027DABEFECA9772D2D11DA9E36</identifier><identifier type="DOI">10.1093/brain/awh586</identifier><identifier type="local">awh586</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 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