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Kafantari, E.* ; Hernandez, V.J.* ; Necpál, J.* ; Leonidou, M.* ; Baureder, R.* ; Hedberg-Oldfors, C.* ; Jech, R.* ; Zech, M. ; Schwartz, T.U.* ; Puschmann, A.*

TOR1AIP2 as a candidate gene for dystonia-hemichorea/hemiballism.

Parkinsonism Relat. Disord. 134:107781 (2025)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Dystonia is a movement disorder characterized by genetic and clinical heterogeneity. A recurring p.(Glu303del)-deletion in TOR1A is a well-established cause for DYT-TOR1A (DYT1), an autosomal dominant early-onset isolated dystonia. TOR1A encodes TorsinA, an AAA + ATPase located in the nuclear envelope. By whole exome analyses of a family with a novel dystonia-hemichorea-/hemiballism phenotype, we identified a TOR1AIP2 NM_001199260.2 c.1234A > G p.(Arg412Gly) variant. The variant is very rare in databases and was absent from whole exome data from >1000 dystonia patients. TOR1AIP2 encodes LULL1, a transmembrane protein that activates TorsinA, and correct interaction between TorsinA and LULL1 is essential for proper nuclear envelope architecture. The p.(Arg412Gly) variant disrupts the binding interface between TorsinA and LULL1 around p.Arg412; this same interface is also impaired in DYT1. Functional analyses via a co-purification assay revealed that interaction between TorsinA-LULL1Arg412Gly is weaker than the wild-type interaction, and that it resembles the situation in DYT1 (TorsinAΔE303-LULL1). A second family with milder dystonia, hemichorea, and stereotypic leg flexion during gait and a TOR1AIP2 p.(Gln338His) variant was identified. The clinical phenotype of both families shared proximal arm movements, and flutter in facial musculature. Expressivity of the movement disorder symptoms was variable. Several proteins in the nuclear envelope have been implicated in various forms of neurodevelopmental disorders with dystonia. Taken together, our findings suggest TOR1AIP2 as a new candidate gene implicated in a complex hereditary movement disorder with dystonia and hemichorea/hemiballism.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dyt1 ; Dystonia ; Hemiballism ; Hemichorea ; Nuclear Envelope ; Stereotypy ; Tor1aip2 ; Torsina; Classification; Guidelines; Lap1
ISSN (print) / ISBN 1353-8020
e-ISSN 1873-5126
Zeitschrift Parkinsonism & Related Disorders
Quellenangaben Band: 134, Heft: , Seiten: , Artikelnummer: 107781 Supplement: ,
Verlag Elsevier
Verlagsort 125 London Wall, London, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen NIH
Skane University Hospital
Swedish government (ALF, avtal for lakarutbildning och forskning)
German Research Foundation
EJP RD (EJP RD Joint Transnational Call 2022)
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)
Federal Ministry of Education and Research (BMBF)
Free State of Bavaria under the Excellence Strategy of the Federal Government and the Lander in Germany
Technical University of Munich - Institute for Advanced Study in Germany
Else Kroner-Fresenius-Stiftung
U.S. Department of Defense
Czech Ministry of Health
NIH Pre-Doctoral Training Grant
National Institute for Neurological Research, Czech Republic (Programme EXCELES)
European Union - Next Generation EU
Region Skane