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PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine tract within the ATXN1 gene. Normal alleles have been reported to range from 6 to 35 repeats, intermediate alleles from 36 to 38 repeats and fully penetrant pathogenic a...

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Autores principales: Nethisinghe, Suran, Pigazzini, Maria Lucia, Pemble, Sally, Sweeney, Mary G., Labrum, Robyn, Manso, Katarina, Moore, David, Warner, Jon, Davis, Mary B., Giunti, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080413/
https://www.ncbi.nlm.nih.gov/pubmed/30108484
http://dx.doi.org/10.3389/fncel.2018.00200
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author Nethisinghe, Suran
Pigazzini, Maria Lucia
Pemble, Sally
Sweeney, Mary G.
Labrum, Robyn
Manso, Katarina
Moore, David
Warner, Jon
Davis, Mary B.
Giunti, Paola
author_facet Nethisinghe, Suran
Pigazzini, Maria Lucia
Pemble, Sally
Sweeney, Mary G.
Labrum, Robyn
Manso, Katarina
Moore, David
Warner, Jon
Davis, Mary B.
Giunti, Paola
author_sort Nethisinghe, Suran
collection PubMed
description Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine tract within the ATXN1 gene. Normal alleles have been reported to range from 6 to 35 repeats, intermediate alleles from 36 to 38 repeats and fully penetrant pathogenic alleles have at least 39 repeats. This distribution was based on relatively few samples and the narrow intermediate range makes the accuracy of the repeat sizing crucial for interpreting and reporting diagnostic tests, which can vary between laboratories. Here, we examine the distribution of 6378 SCA1 chromosomes and identify a very late onset SCA1 family with a fully penetrant uninterrupted pathogenic allele containing 38 repeats. This finding supports the theory that polyQ toxicity is related to the increase of the length of the inherited tracts and not as previously hypothesized to the structural transition occurring above a specific threshold. In addition, the threshold of toxicity shifts to a shorter polyQ length with the increase of the lifespan in SCA1. Furthermore, we show that SCA1 intermediate alleles have a different behavior compared to the other polyglutamine disorders as they do not show reduced penetrance when uninterrupted. Therefore, the pathogenic mechanism in SCA1 is distinct from other cytosine-adenine-guanine (CAG) repeat disorders. Accurately sizing repeats is paramount in precision medicine and can be challenging particularly with borderline alleles. We examined plasmids containing cloned CAG repeat tracts alongside a triplet repeat primed polymerase chain reaction (TP PCR) CAG repeat ladder to improve accuracy in repeat sizing by fragment analysis. This method accurately sizes the repeats irrespective of repeat composition or length. We also improved the model for calculating repeat length from fragment analysis sizing by fragment analyzing 100 cloned repeats of known size. Therefore, we recommend these methods for accurately sizing repeat lengths and restriction enzyme digestion to identify interruptions for interpretation of a given allele’s pathogenicity.
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spelling pubmed-60804132018-08-14 PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption Nethisinghe, Suran Pigazzini, Maria Lucia Pemble, Sally Sweeney, Mary G. Labrum, Robyn Manso, Katarina Moore, David Warner, Jon Davis, Mary B. Giunti, Paola Front Cell Neurosci Neuroscience Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by an expansion of a polyglutamine tract within the ATXN1 gene. Normal alleles have been reported to range from 6 to 35 repeats, intermediate alleles from 36 to 38 repeats and fully penetrant pathogenic alleles have at least 39 repeats. This distribution was based on relatively few samples and the narrow intermediate range makes the accuracy of the repeat sizing crucial for interpreting and reporting diagnostic tests, which can vary between laboratories. Here, we examine the distribution of 6378 SCA1 chromosomes and identify a very late onset SCA1 family with a fully penetrant uninterrupted pathogenic allele containing 38 repeats. This finding supports the theory that polyQ toxicity is related to the increase of the length of the inherited tracts and not as previously hypothesized to the structural transition occurring above a specific threshold. In addition, the threshold of toxicity shifts to a shorter polyQ length with the increase of the lifespan in SCA1. Furthermore, we show that SCA1 intermediate alleles have a different behavior compared to the other polyglutamine disorders as they do not show reduced penetrance when uninterrupted. Therefore, the pathogenic mechanism in SCA1 is distinct from other cytosine-adenine-guanine (CAG) repeat disorders. Accurately sizing repeats is paramount in precision medicine and can be challenging particularly with borderline alleles. We examined plasmids containing cloned CAG repeat tracts alongside a triplet repeat primed polymerase chain reaction (TP PCR) CAG repeat ladder to improve accuracy in repeat sizing by fragment analysis. This method accurately sizes the repeats irrespective of repeat composition or length. We also improved the model for calculating repeat length from fragment analysis sizing by fragment analyzing 100 cloned repeats of known size. Therefore, we recommend these methods for accurately sizing repeat lengths and restriction enzyme digestion to identify interruptions for interpretation of a given allele’s pathogenicity. Frontiers Media S.A. 2018-07-31 /pmc/articles/PMC6080413/ /pubmed/30108484 http://dx.doi.org/10.3389/fncel.2018.00200 Text en Copyright © 2018 Nethisinghe, Pigazzini, Pemble, Sweeney, Labrum, Manso, Moore, Warner, Davis and Giunti. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Nethisinghe, Suran
Pigazzini, Maria Lucia
Pemble, Sally
Sweeney, Mary G.
Labrum, Robyn
Manso, Katarina
Moore, David
Warner, Jon
Davis, Mary B.
Giunti, Paola
PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption
title PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption
title_full PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption
title_fullStr PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption
title_full_unstemmed PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption
title_short PolyQ Tract Toxicity in SCA1 is Length Dependent in the Absence of CAG Repeat Interruption
title_sort polyq tract toxicity in sca1 is length dependent in the absence of cag repeat interruption
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080413/
https://www.ncbi.nlm.nih.gov/pubmed/30108484
http://dx.doi.org/10.3389/fncel.2018.00200
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