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Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort

BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) is a late onset autosomal dominant cerebellar ataxia, caused by CAG triplet repeat expansion in the ATXN1 gene. The frequency of SCA1 occurrence is more in Southern India than in other regions as observed from hospital-based studies. However there are...

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Autores principales: Kumaran, Dhanya, Balagopal, Krishnan, Tharmaraj, Reginald George Alex, Aaron, Sanjith, George, Kuryan, Muliyil, Jayaprakash, Sivadasan, Ajith, Danda, Sumita, Alexander, Mathew, Hasan, Gaiti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411758/
https://www.ncbi.nlm.nih.gov/pubmed/25344417
http://dx.doi.org/10.1186/s12881-014-0114-5
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author Kumaran, Dhanya
Balagopal, Krishnan
Tharmaraj, Reginald George Alex
Aaron, Sanjith
George, Kuryan
Muliyil, Jayaprakash
Sivadasan, Ajith
Danda, Sumita
Alexander, Mathew
Hasan, Gaiti
author_facet Kumaran, Dhanya
Balagopal, Krishnan
Tharmaraj, Reginald George Alex
Aaron, Sanjith
George, Kuryan
Muliyil, Jayaprakash
Sivadasan, Ajith
Danda, Sumita
Alexander, Mathew
Hasan, Gaiti
author_sort Kumaran, Dhanya
collection PubMed
description BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) is a late onset autosomal dominant cerebellar ataxia, caused by CAG triplet repeat expansion in the ATXN1 gene. The frequency of SCA1 occurrence is more in Southern India than in other regions as observed from hospital-based studies. However there are no reports on variability of CAG repeat expansion, phenotype-genotype association and founder mutations in a homogenous population from India. METHODS: Genomic DNA isolated from buccal mouthwash of the individuals in the cohort was used for PCR-based diagnosis of SCA1. Subsequently SNP’s found within the ATXN1 loci were identified by Taqman allelic discrimination assays. Significance testing of the genotype-phenotype associations was calculated by Kruskal-Wallis ANOVA test with post-hoc Dunnett’s test and Pearson’s correlation coefficient. RESULTS: By genetic analysis of an affected population in Southern India we identified 21 pre-symptomatic individuals including four that were well past the average age of disease onset of 44 years, 16 symptomatic and 63 normal individuals. All pre-symptomatic cases harbor “pure” expansions of greater than 40 CAGs. Genotyping to test for the presence of two previously identified SNPs showed a founder effect of the same repeat carrying allele as in the general Indian population. We show that SCA1 disease onset is significantly delayed when transmission of the disease is maternal. CONCLUSIONS: Our finding of early disease onset in individuals with a paternally inherited allele could serve as valuable information for clinicians towards early detection of SCA1 in patients with affected fathers. Identification of older pre-symptomatic individuals (n = 4) in our cohort among individuals with a shared genetic and environmental background, suggests that second site genetic or epigenetic modifiers might significantly affect SCA1 disease progression. Moreover, such undetected SCA1 cases could underscore the true prevalence of SCA1 in India.
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spelling pubmed-44117582015-04-29 Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort Kumaran, Dhanya Balagopal, Krishnan Tharmaraj, Reginald George Alex Aaron, Sanjith George, Kuryan Muliyil, Jayaprakash Sivadasan, Ajith Danda, Sumita Alexander, Mathew Hasan, Gaiti BMC Med Genet Research Article BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) is a late onset autosomal dominant cerebellar ataxia, caused by CAG triplet repeat expansion in the ATXN1 gene. The frequency of SCA1 occurrence is more in Southern India than in other regions as observed from hospital-based studies. However there are no reports on variability of CAG repeat expansion, phenotype-genotype association and founder mutations in a homogenous population from India. METHODS: Genomic DNA isolated from buccal mouthwash of the individuals in the cohort was used for PCR-based diagnosis of SCA1. Subsequently SNP’s found within the ATXN1 loci were identified by Taqman allelic discrimination assays. Significance testing of the genotype-phenotype associations was calculated by Kruskal-Wallis ANOVA test with post-hoc Dunnett’s test and Pearson’s correlation coefficient. RESULTS: By genetic analysis of an affected population in Southern India we identified 21 pre-symptomatic individuals including four that were well past the average age of disease onset of 44 years, 16 symptomatic and 63 normal individuals. All pre-symptomatic cases harbor “pure” expansions of greater than 40 CAGs. Genotyping to test for the presence of two previously identified SNPs showed a founder effect of the same repeat carrying allele as in the general Indian population. We show that SCA1 disease onset is significantly delayed when transmission of the disease is maternal. CONCLUSIONS: Our finding of early disease onset in individuals with a paternally inherited allele could serve as valuable information for clinicians towards early detection of SCA1 in patients with affected fathers. Identification of older pre-symptomatic individuals (n = 4) in our cohort among individuals with a shared genetic and environmental background, suggests that second site genetic or epigenetic modifiers might significantly affect SCA1 disease progression. Moreover, such undetected SCA1 cases could underscore the true prevalence of SCA1 in India. BioMed Central 2014-10-25 /pmc/articles/PMC4411758/ /pubmed/25344417 http://dx.doi.org/10.1186/s12881-014-0114-5 Text en © Kumaran et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Kumaran, Dhanya
Balagopal, Krishnan
Tharmaraj, Reginald George Alex
Aaron, Sanjith
George, Kuryan
Muliyil, Jayaprakash
Sivadasan, Ajith
Danda, Sumita
Alexander, Mathew
Hasan, Gaiti
Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort
title Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort
title_full Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort
title_fullStr Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort
title_full_unstemmed Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort
title_short Genetic characterization of Spinocerebellar ataxia 1 in a South Indian cohort
title_sort genetic characterization of spinocerebellar ataxia 1 in a south indian cohort
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411758/
https://www.ncbi.nlm.nih.gov/pubmed/25344417
http://dx.doi.org/10.1186/s12881-014-0114-5
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