High-throughput mutational analysis of TOR1A in primary dystonia

Jianfeng Xiao, Robert W. Bastian, Joel S. Perlmutter, Brad A. Racette, Samer D. Tabbal, Morvarid Karimi, Randal C. Paniello, Andrew Blitzer, Sat Batish, Zbigniew K. Wszolek, Ryan J. Uitti, Peter Hedera, David K. Simon, Daniel Tarsy, Daniel D. Truong, Karen P. Frei, Ronald Pfeiffer, Suzhen Gong, Yu Zhao, Mark S. LeDoux

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number24
JournalBMC Medical Genetics
Volume10
DOIs
StatePublished - Mar 11 2009
Externally publishedYes

Fingerprint

Dystonic Disorders
Dystonia
Freezing
Exons
Mutation
Dysphonia
Blepharospasm
Torticollis
Sensitivity and Specificity
Movement Disorders

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Xiao, J., Bastian, R. W., Perlmutter, J. S., Racette, B. A., Tabbal, S. D., Karimi, M., ... LeDoux, M. S. (2009). High-throughput mutational analysis of TOR1A in primary dystonia. BMC Medical Genetics, 10, [24]. https://doi.org/10.1186/1471-2350-10-24

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; Wszolek, Zbigniew K.; Uitti, Ryan J.; Hedera, Peter; Simon, David K.; Tarsy, Daniel; Truong, Daniel D.; Frei, Karen P.; Pfeiffer, Ronald; Gong, Suzhen; Zhao, Yu; LeDoux, Mark S.

In: BMC Medical Genetics, Vol. 10, 24, 11.03.2009.

Research output: Contribution to journalArticle

Xiao, J, Bastian, RW, Perlmutter, JS, Racette, BA, Tabbal, SD, Karimi, M, Paniello, RC, Blitzer, A, Batish, S, Wszolek, ZK, Uitti, RJ, Hedera, P, Simon, DK, Tarsy, D, Truong, DD, Frei, KP, Pfeiffer, R, Gong, S, Zhao, Y & LeDoux, MS 2009, 'High-throughput mutational analysis of TOR1A in primary dystonia', BMC Medical Genetics, vol. 10, 24. https://doi.org/10.1186/1471-2350-10-24
Xiao J, Bastian RW, Perlmutter JS, Racette BA, Tabbal SD, Karimi M et al. High-throughput mutational analysis of TOR1A in primary dystonia. BMC Medical Genetics. 2009 Mar 11;10. 24. https://doi.org/10.1186/1471-2350-10-24
Xiao, Jianfeng ; Bastian, Robert W. ; Perlmutter, Joel S. ; Racette, Brad A. ; Tabbal, Samer D. ; Karimi, Morvarid ; Paniello, Randal C. ; Blitzer, Andrew ; Batish, Sat ; Wszolek, Zbigniew K. ; Uitti, Ryan J. ; Hedera, Peter ; Simon, David K. ; Tarsy, Daniel ; Truong, Daniel D. ; Frei, Karen P. ; Pfeiffer, Ronald ; Gong, Suzhen ; Zhao, Yu ; LeDoux, Mark S. / High-throughput mutational analysis of TOR1A in primary dystonia. In: BMC Medical Genetics. 2009 ; Vol. 10.
@article{499c60f245c74c1b851a72ab82b6afdc,
title = "High-throughput mutational analysis of TOR1A in primary dystonia",
abstract = "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.",
author = "Jianfeng Xiao and Bastian, {Robert W.} and Perlmutter, {Joel S.} and Racette, {Brad A.} and Tabbal, {Samer D.} and Morvarid Karimi and Paniello, {Randal C.} and Andrew Blitzer and Sat Batish and Wszolek, {Zbigniew K.} and Uitti, {Ryan J.} and Peter Hedera and Simon, {David K.} and Daniel Tarsy and Truong, {Daniel D.} and Frei, {Karen P.} and Ronald Pfeiffer and Suzhen Gong and Yu Zhao and LeDoux, {Mark S.}",
year = "2009",
month = "3",
day = "11",
doi = "10.1186/1471-2350-10-24",
language = "English (US)",
volume = "10",
journal = "BMC Medical Genetics",
issn = "1471-2350",
publisher = "BioMed Central",

}

TY - JOUR

T1 - High-throughput mutational analysis of TOR1A in primary dystonia

AU - Xiao, Jianfeng

AU - Bastian, Robert W.

AU - Perlmutter, Joel S.

AU - Racette, Brad A.

AU - Tabbal, Samer D.

AU - Karimi, Morvarid

AU - Paniello, Randal C.

AU - Blitzer, Andrew

AU - Batish, Sat

AU - Wszolek, Zbigniew K.

AU - Uitti, Ryan J.

AU - Hedera, Peter

AU - Simon, David K.

AU - Tarsy, Daniel

AU - Truong, Daniel D.

AU - Frei, Karen P.

AU - Pfeiffer, Ronald

AU - Gong, Suzhen

AU - Zhao, Yu

AU - LeDoux, Mark S.

PY - 2009/3/11

Y1 - 2009/3/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=63149199473&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=63149199473&partnerID=8YFLogxK

U2 - 10.1186/1471-2350-10-24

DO - 10.1186/1471-2350-10-24

M3 - Article

VL - 10

JO - BMC Medical Genetics

JF - BMC Medical Genetics

SN - 1471-2350

M1 - 24

ER -