Genotype-phenotype correlations in THAP1 dystonia

Molecular foundations and description of new cases

Mark Ledoux, Jianfeng Xiao, Monika Rudzińska, Robert W. Bastian, Zbigniew K. Wszolek, Jay A. Van Gerpen, Andreas Puschmann, Dragana Momčilović, Satya R. Vemula, Yu Zhao

Research output: Contribution to journalReview article

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)414-425
Number of pages12
JournalParkinsonism and Related Disorders
Volume18
Issue number5
DOIs
StatePublished - Jun 1 2012

Fingerprint

Dystonia
Genetic Association Studies
Missense Mutation
Age of Onset
Dystonic Disorders
Mutation
Neck
Blepharospasm
Tremor
Neurology
Arm
Phenotype
Proteins

All Science Journal Classification (ASJC) codes

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

Cite this

Genotype-phenotype correlations in THAP1 dystonia : Molecular foundations and description of new cases. / Ledoux, Mark; Xiao, Jianfeng; Rudzińska, Monika; Bastian, Robert W.; Wszolek, Zbigniew K.; Van Gerpen, Jay A.; Puschmann, Andreas; Momčilović, Dragana; Vemula, Satya R.; Zhao, Yu.

In: Parkinsonism and Related Disorders, Vol. 18, No. 5, 01.06.2012, p. 414-425.

Research output: Contribution to journalReview article

Ledoux, M, Xiao, J, Rudzińska, M, Bastian, RW, Wszolek, ZK, Van Gerpen, JA, Puschmann, A, Momčilović, D, Vemula, SR & Zhao, Y 2012, 'Genotype-phenotype correlations in THAP1 dystonia: Molecular foundations and description of new cases', Parkinsonism and Related Disorders, vol. 18, no. 5, pp. 414-425. https://doi.org/10.1016/j.parkreldis.2012.02.001
Ledoux, Mark ; Xiao, Jianfeng ; Rudzińska, Monika ; Bastian, Robert W. ; Wszolek, Zbigniew K. ; Van Gerpen, Jay A. ; Puschmann, Andreas ; Momčilović, Dragana ; Vemula, Satya R. ; Zhao, Yu. / Genotype-phenotype correlations in THAP1 dystonia : Molecular foundations and description of new cases. In: Parkinsonism and Related Disorders. 2012 ; Vol. 18, No. 5. pp. 414-425.
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