CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion
Identifieur interne : 005449 ( Main/Exploration ); précédent : 005448; suivant : 005450CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion
Auteurs : J.-M. Lee ; E. M. Ramos ; J.-H. Lee ; T. Gillis ; J. S. Mysore ; M. R. Hayden ; S. C. Warby ; P. Morrison ; M. Nance ; C. A. Ross ; R. L. Margolis ; F. Squitieri ; S. Orobello ; S. Di Donato ; E. Gomez-Tortosa ; C. Ayuso ; O. Suchowersky ; R. J. A. Trent ; E. Mccusker ; A. Novelletto ; M. Frontali ; R. Jones ; T. Ashizawa ; S. Frank ; M. H. Saint-Hilaire ; S. M. Hersch ; H. D. Rosas ; D. Lucente ; M. B. Harrison ; A. Zanko ; R. K. Abramson ; K. Marder ; J. Sequeiros ; J. S. Paulsen ; G. B. Landwehrmeyer ; R. H. Myers ; M. E. Macdonald ; J. F. GusellaSource :
- Neurology [ 0028-3878 ] ; 2012.
Abstract
Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.
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DOI: 10.1212/WNL.0b013e318249f683
PubMed: 22323755
PubMed Central: 3306163
Affiliations:
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Lee</name></author><author><name sortKey="Ramos, E M" sort="Ramos, E M" uniqKey="Ramos E" first="E. M." last="Ramos">E. M. Ramos</name></author><author><name sortKey="Lee, J H" sort="Lee, J H" uniqKey="Lee J" first="J.-H." last="Lee">J.-H. Lee</name></author><author><name sortKey="Gillis, T" sort="Gillis, T" uniqKey="Gillis T" first="T." last="Gillis">T. Gillis</name></author><author><name sortKey="Mysore, J S" sort="Mysore, J S" uniqKey="Mysore J" first="J. S." last="Mysore">J. S. Mysore</name></author><author><name sortKey="Hayden, M R" sort="Hayden, M R" uniqKey="Hayden M" first="M. R." last="Hayden">M. R. Hayden</name></author><author><name sortKey="Warby, S C" sort="Warby, S C" uniqKey="Warby S" first="S. C." last="Warby">S. C. Warby</name></author><author><name sortKey="Morrison, P" sort="Morrison, P" uniqKey="Morrison P" first="P." last="Morrison">P. Morrison</name></author><author><name sortKey="Nance, M" sort="Nance, M" uniqKey="Nance M" first="M." last="Nance">M. Nance</name></author><author><name sortKey="Ross, C A" sort="Ross, C A" uniqKey="Ross C" first="C. A." last="Ross">C. A. Ross</name></author><author><name sortKey="Margolis, R L" sort="Margolis, R L" uniqKey="Margolis R" first="R. L." last="Margolis">R. L. Margolis</name></author><author><name sortKey="Squitieri, F" sort="Squitieri, F" uniqKey="Squitieri F" first="F." last="Squitieri">F. Squitieri</name></author><author><name sortKey="Orobello, S" sort="Orobello, S" uniqKey="Orobello S" first="S." last="Orobello">S. Orobello</name></author><author><name sortKey="Di Donato, S" sort="Di Donato, S" uniqKey="Di Donato S" first="S." last="Di Donato">S. Di Donato</name></author><author><name sortKey="Gomez Tortosa, E" sort="Gomez Tortosa, E" uniqKey="Gomez Tortosa E" first="E." last="Gomez-Tortosa">E. Gomez-Tortosa</name></author><author><name sortKey="Ayuso, C" sort="Ayuso, C" uniqKey="Ayuso C" first="C." last="Ayuso">C. Ayuso</name></author><author><name sortKey="Suchowersky, O" sort="Suchowersky, O" uniqKey="Suchowersky O" first="O." last="Suchowersky">O. Suchowersky</name></author><author><name sortKey="Trent, R J A" sort="Trent, R J A" uniqKey="Trent R" first="R. J. A." last="Trent">R. J. A. Trent</name></author><author><name sortKey="Mccusker, E" sort="Mccusker, E" uniqKey="Mccusker E" first="E." last="Mccusker">E. Mccusker</name></author><author><name sortKey="Novelletto, A" sort="Novelletto, A" uniqKey="Novelletto A" first="A." last="Novelletto">A. Novelletto</name></author><author><name sortKey="Frontali, M" sort="Frontali, M" uniqKey="Frontali M" first="M." last="Frontali">M. Frontali</name></author><author><name sortKey="Jones, R" sort="Jones, R" uniqKey="Jones R" first="R." last="Jones">R. Jones</name></author><author><name sortKey="Ashizawa, T" sort="Ashizawa, T" uniqKey="Ashizawa T" first="T." last="Ashizawa">T. Ashizawa</name></author><author><name sortKey="Frank, S" sort="Frank, S" uniqKey="Frank S" first="S." last="Frank">S. Frank</name></author><author><name sortKey="Saint Hilaire, M H" sort="Saint Hilaire, M H" uniqKey="Saint Hilaire M" first="M. H." last="Saint-Hilaire">M. H. Saint-Hilaire</name></author><author><name sortKey="Hersch, S M" sort="Hersch, S M" uniqKey="Hersch S" first="S. M." last="Hersch">S. M. Hersch</name></author><author><name sortKey="Rosas, H D" sort="Rosas, H D" uniqKey="Rosas H" first="H. D." last="Rosas">H. D. Rosas</name></author><author><name sortKey="Lucente, D" sort="Lucente, D" uniqKey="Lucente D" first="D." last="Lucente">D. Lucente</name></author><author><name sortKey="Harrison, M B" sort="Harrison, M B" uniqKey="Harrison M" first="M. B." last="Harrison">M. B. Harrison</name></author><author><name sortKey="Zanko, A" sort="Zanko, A" uniqKey="Zanko A" first="A." last="Zanko">A. Zanko</name></author><author><name sortKey="Abramson, R K" sort="Abramson, R K" uniqKey="Abramson R" first="R. K." last="Abramson">R. K. Abramson</name></author><author><name sortKey="Marder, K" sort="Marder, K" uniqKey="Marder K" first="K." last="Marder">K. Marder</name></author><author><name sortKey="Sequeiros, J" sort="Sequeiros, J" uniqKey="Sequeiros J" first="J." last="Sequeiros">J. Sequeiros</name></author><author><name sortKey="Paulsen, J S" sort="Paulsen, J S" uniqKey="Paulsen J" first="J. S." last="Paulsen">J. S. Paulsen</name></author><author><name sortKey="Landwehrmeyer, G B" sort="Landwehrmeyer, G B" uniqKey="Landwehrmeyer G" first="G. B." last="Landwehrmeyer">G. B. Landwehrmeyer</name></author><author><name sortKey="Myers, R H" sort="Myers, R H" uniqKey="Myers R" first="R. H." last="Myers">R. H. Myers</name></author><author><name sortKey="Macdonald, M E" sort="Macdonald, M E" uniqKey="Macdonald M" first="M. E." last="Macdonald">M. E. Macdonald</name></author><author><name sortKey="Gusella, J F" sort="Gusella, J F" uniqKey="Gusella J" first="J. F." last="Gusella">J. F. Gusella</name></author></analytic><series><title level="j">Neurology</title><idno type="ISSN">0028-3878</idno><idno type="eISSN">1526-632X</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective:</title><p>Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.</p></sec><sec><title>Methods:</title><p>We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.</p></sec><sec><title>Results:</title><p>An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.</p></sec><sec><title>Conclusions:</title><p>Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. <italic>Neurology</italic>® 2012;78:690–695</p></sec></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Abramson, R K" sort="Abramson, R K" uniqKey="Abramson R" first="R. K." last="Abramson">R. K. Abramson</name><name sortKey="Ashizawa, T" sort="Ashizawa, T" uniqKey="Ashizawa T" first="T." last="Ashizawa">T. Ashizawa</name><name sortKey="Ayuso, C" sort="Ayuso, C" uniqKey="Ayuso C" first="C." last="Ayuso">C. Ayuso</name><name sortKey="Di Donato, S" sort="Di Donato, S" uniqKey="Di Donato S" first="S." last="Di Donato">S. Di Donato</name><name sortKey="Frank, S" sort="Frank, S" uniqKey="Frank S" first="S." last="Frank">S. Frank</name><name sortKey="Frontali, M" sort="Frontali, M" uniqKey="Frontali M" first="M." last="Frontali">M. Frontali</name><name sortKey="Gillis, T" sort="Gillis, T" uniqKey="Gillis T" first="T." last="Gillis">T. Gillis</name><name sortKey="Gomez Tortosa, E" sort="Gomez Tortosa, E" uniqKey="Gomez Tortosa E" first="E." last="Gomez-Tortosa">E. Gomez-Tortosa</name><name sortKey="Gusella, J F" sort="Gusella, J F" uniqKey="Gusella J" first="J. F." last="Gusella">J. F. Gusella</name><name sortKey="Harrison, M B" sort="Harrison, M B" uniqKey="Harrison M" first="M. B." last="Harrison">M. B. Harrison</name><name sortKey="Hayden, M R" sort="Hayden, M R" uniqKey="Hayden M" first="M. R." last="Hayden">M. R. Hayden</name><name sortKey="Hersch, S M" sort="Hersch, S M" uniqKey="Hersch S" first="S. M." last="Hersch">S. M. Hersch</name><name sortKey="Jones, R" sort="Jones, R" uniqKey="Jones R" first="R." last="Jones">R. Jones</name><name sortKey="Landwehrmeyer, G B" sort="Landwehrmeyer, G B" uniqKey="Landwehrmeyer G" first="G. B." last="Landwehrmeyer">G. B. Landwehrmeyer</name><name sortKey="Lee, J H" sort="Lee, J H" uniqKey="Lee J" first="J.-H." last="Lee">J.-H. Lee</name><name sortKey="Lee, J M" sort="Lee, J M" uniqKey="Lee J" first="J.-M." last="Lee">J.-M. Lee</name><name sortKey="Lucente, D" sort="Lucente, D" uniqKey="Lucente D" first="D." last="Lucente">D. Lucente</name><name sortKey="Macdonald, M E" sort="Macdonald, M E" uniqKey="Macdonald M" first="M. E." last="Macdonald">M. E. Macdonald</name><name sortKey="Marder, K" sort="Marder, K" uniqKey="Marder K" first="K." last="Marder">K. Marder</name><name sortKey="Margolis, R L" sort="Margolis, R L" uniqKey="Margolis R" first="R. L." last="Margolis">R. L. Margolis</name><name sortKey="Mccusker, E" sort="Mccusker, E" uniqKey="Mccusker E" first="E." last="Mccusker">E. Mccusker</name><name sortKey="Morrison, P" sort="Morrison, P" uniqKey="Morrison P" first="P." last="Morrison">P. Morrison</name><name sortKey="Myers, R H" sort="Myers, R H" uniqKey="Myers R" first="R. H." last="Myers">R. H. Myers</name><name sortKey="Mysore, J S" sort="Mysore, J S" uniqKey="Mysore J" first="J. S." last="Mysore">J. S. Mysore</name><name sortKey="Nance, M" sort="Nance, M" uniqKey="Nance M" first="M." last="Nance">M. Nance</name><name sortKey="Novelletto, A" sort="Novelletto, A" uniqKey="Novelletto A" first="A." last="Novelletto">A. Novelletto</name><name sortKey="Orobello, S" sort="Orobello, S" uniqKey="Orobello S" first="S." last="Orobello">S. Orobello</name><name sortKey="Paulsen, J S" sort="Paulsen, J S" uniqKey="Paulsen J" first="J. S." last="Paulsen">J. S. Paulsen</name><name sortKey="Ramos, E M" sort="Ramos, E M" uniqKey="Ramos E" first="E. M." last="Ramos">E. M. Ramos</name><name sortKey="Rosas, H D" sort="Rosas, H D" uniqKey="Rosas H" first="H. D." last="Rosas">H. D. Rosas</name><name sortKey="Ross, C A" sort="Ross, C A" uniqKey="Ross C" first="C. A." last="Ross">C. A. Ross</name><name sortKey="Saint Hilaire, M H" sort="Saint Hilaire, M H" uniqKey="Saint Hilaire M" first="M. H." last="Saint-Hilaire">M. H. Saint-Hilaire</name><name sortKey="Sequeiros, J" sort="Sequeiros, J" uniqKey="Sequeiros J" first="J." last="Sequeiros">J. Sequeiros</name><name sortKey="Squitieri, F" sort="Squitieri, F" uniqKey="Squitieri F" first="F." last="Squitieri">F. Squitieri</name><name sortKey="Suchowersky, O" sort="Suchowersky, O" uniqKey="Suchowersky O" first="O." last="Suchowersky">O. Suchowersky</name><name sortKey="Trent, R J A" sort="Trent, R J A" uniqKey="Trent R" first="R. J. A." last="Trent">R. J. A. Trent</name><name sortKey="Warby, S C" sort="Warby, S C" uniqKey="Warby S" first="S. C." last="Warby">S. C. Warby</name><name sortKey="Zanko, A" sort="Zanko, A" uniqKey="Zanko A" first="A." last="Zanko">A. Zanko</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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