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Zech, M. ; Jochim, A.* ; Boesch, S.* ; Weber, S. ; Meindl, T.* ; Peters, A. ; Gieger, C. ; Mueller, J.C.* ; Messner, M.* ; Ceballos-Baumann, A.* ; Poewe, W.* ; Haslinger, B.* ; Winkelmann, J.

Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls.

Parkinsonism Relat. Disord. 31, 119-123 (2016)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
BACKGROUND: An increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts. METHODS: We screened the entire coding sequence and the 5'-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-ΔGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset. RESULTS: In the case cohort, we identified a rare 5'-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-ΔGAG variants was 0.4%. CONCLUSIONS: Our study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Dyt1 ; Dystonia ; Gene ; Rare Variant Analysis ; Tor1a; Mutation; Phenotypes; Genetics
ISSN (print) / ISBN 1353-8020
e-ISSN 1873-5126
Journal Parkinsonism & Related Disorders
Quellenangaben Volume: 31, Issue: , Pages: 119-123 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)