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Genotype–phenotype correlations in THAP1 dystonia: Molecular foundations and description of new cases

LeDoux, MS; Xiao, J; Rudzińska, M; Bastian, RW; Wszolek, ZK; Van Gerpen, JA; Puschmann, Andreas LU ; Momčilović, D; Vemula, S and Zhao, Y (2012) In Parkinsonism & Related Disorders 18(5). p.414-425
Abstract
An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense... (More)
An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Dystonia, THAP1, DYT6, Spasmodic dysphonia, Tremor
in
Parkinsonism & Related Disorders
volume
18
issue
5
pages
414 - 425
publisher
Elsevier
external identifiers
  • wos:000306039200002
  • scopus:84862807301
ISSN
1873-5126
DOI
10.1016/j.parkreldis.2012.02.001
language
English
LU publication?
yes
id
88ee6101-866a-4912-98af-9f44c773301c (old id 2430516)
date added to LUP
2012-03-30 09:24:33
date last changed
2017-09-03 03:02:29
@article{88ee6101-866a-4912-98af-9f44c773301c,
  abstract     = {An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1114 subjects with mainly adult-onset primary dystonia (Neurology 2010; 74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1.},
  author       = {LeDoux, MS and Xiao, J and Rudzińska, M and Bastian, RW and Wszolek, ZK and Van Gerpen, JA and Puschmann, Andreas and Momčilović, D and Vemula, S and Zhao, Y},
  issn         = {1873-5126},
  keyword      = {Dystonia,THAP1,DYT6,Spasmodic dysphonia,Tremor},
  language     = {eng},
  number       = {5},
  pages        = {414--425},
  publisher    = {Elsevier},
  series       = {Parkinsonism & Related Disorders},
  title        = {Genotype–phenotype correlations in THAP1 dystonia: Molecular foundations and description of new cases},
  url          = {http://dx.doi.org/10.1016/j.parkreldis.2012.02.001},
  volume       = {18},
  year         = {2012},
}