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High-throughput mutational analysis of TOR1A in primary dystonia

BACKGROUND: Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some...

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Autores principales: Xiao, Jianfeng, Bastian, Robert W, Perlmutter, Joel S, Racette, Brad A, Tabbal, Samer D, Karimi, Morvarid, Paniello, Randal C, Blitzer, Andrew, Batish, Sat Dev, Wszolek, Zbigniew K, Uitti, Ryan J, Hedera, Peter, Simon, David K, Tarsy, Daniel, Truong, Daniel D, Frei, Karen P, Pfeiffer, Ronald F, Gong, Suzhen, Zhao, Yu, LeDoux, Mark S
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661056/
https://www.ncbi.nlm.nih.gov/pubmed/19284587
http://dx.doi.org/10.1186/1471-2350-10-24
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author Xiao, Jianfeng
Bastian, Robert W
Perlmutter, Joel S
Racette, Brad A
Tabbal, Samer D
Karimi, Morvarid
Paniello, Randal C
Blitzer, Andrew
Batish, Sat Dev
Wszolek, Zbigniew K
Uitti, Ryan J
Hedera, Peter
Simon, David K
Tarsy, Daniel
Truong, Daniel D
Frei, Karen P
Pfeiffer, Ronald F
Gong, Suzhen
Zhao, Yu
LeDoux, Mark S
author_facet Xiao, Jianfeng
Bastian, Robert W
Perlmutter, Joel S
Racette, Brad A
Tabbal, Samer D
Karimi, Morvarid
Paniello, Randal C
Blitzer, Andrew
Batish, Sat Dev
Wszolek, Zbigniew K
Uitti, Ryan J
Hedera, Peter
Simon, David K
Tarsy, Daniel
Truong, Daniel D
Frei, Karen P
Pfeiffer, Ronald F
Gong, Suzhen
Zhao, Yu
LeDoux, Mark S
author_sort Xiao, Jianfeng
collection PubMed
description BACKGROUND: Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some ΔGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify TOR1A Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia. METHODS: High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known ΔGAG DYT1 dystonia and 88 subjects with ΔGAG-negative dystonia. RESULTS: HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A ΔGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic ΔGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia. CONCLUSION: First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia.
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spelling pubmed-26610562009-03-26 High-throughput mutational analysis of TOR1A in primary dystonia Xiao, Jianfeng Bastian, Robert W Perlmutter, Joel S Racette, Brad A Tabbal, Samer D Karimi, Morvarid Paniello, Randal C Blitzer, Andrew Batish, Sat Dev Wszolek, Zbigniew K Uitti, Ryan J Hedera, Peter Simon, David K Tarsy, Daniel Truong, Daniel D Frei, Karen P Pfeiffer, Ronald F Gong, Suzhen Zhao, Yu LeDoux, Mark S BMC Med Genet Research Article BACKGROUND: Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some ΔGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify TOR1A Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia. METHODS: High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known ΔGAG DYT1 dystonia and 88 subjects with ΔGAG-negative dystonia. RESULTS: HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A ΔGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic ΔGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia. CONCLUSION: First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia. BioMed Central 2009-03-11 /pmc/articles/PMC2661056/ /pubmed/19284587 http://dx.doi.org/10.1186/1471-2350-10-24 Text en Copyright © 2009 Xiao et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Xiao, Jianfeng
Bastian, Robert W
Perlmutter, Joel S
Racette, Brad A
Tabbal, Samer D
Karimi, Morvarid
Paniello, Randal C
Blitzer, Andrew
Batish, Sat Dev
Wszolek, Zbigniew K
Uitti, Ryan J
Hedera, Peter
Simon, David K
Tarsy, Daniel
Truong, Daniel D
Frei, Karen P
Pfeiffer, Ronald F
Gong, Suzhen
Zhao, Yu
LeDoux, Mark S
High-throughput mutational analysis of TOR1A in primary dystonia
title High-throughput mutational analysis of TOR1A in primary dystonia
title_full High-throughput mutational analysis of TOR1A in primary dystonia
title_fullStr High-throughput mutational analysis of TOR1A in primary dystonia
title_full_unstemmed High-throughput mutational analysis of TOR1A in primary dystonia
title_short High-throughput mutational analysis of TOR1A in primary dystonia
title_sort high-throughput mutational analysis of tor1a in primary dystonia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661056/
https://www.ncbi.nlm.nih.gov/pubmed/19284587
http://dx.doi.org/10.1186/1471-2350-10-24
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