Mutations in GNAL cause primary torsion dystonia

• Type of Material: Article
• Authors: Tania Fuchs, Mount Sinai School of Medicine; Rachel Saunders-Pullman, Beth Israel Medical Center; Ikuo Masuho, Scripps Research Institute; Marta San Luciano, University of California San Francisco; Deborah Raymond, Beth Israel Medical Center; Stewart Factor, Emory University; Anthony E. Lang, Toronto Western Hospital; Tsao-Wei Liang, Jefferson Hospital for Neuroscience; Richard M. Trosch, Parkinson's and Movement Disorders Center; Sierra White, Mount Sinai School of Medicine; Edmond Ainehsazan, Mount Sinai School of Medicine; Denis Herve, INSERM; Nutan Sharma, Massachusetts General Hospital; Michelle E. Ehrlich, Mount Sinai School of Medicine; Kirill A. Martemyanov, Scripps Research Institute; Susan B. Bressman, Beth Israel Medical Center; Laurie J. Ozelius, Mount Sinai School of Medicine
• Language: English
• Date: 2013-01-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Nature America, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ng.2496
• Title of Journal or Parent Work: Nature Genetics
• ISSN: 1061-4036
• Volume: 45
• Issue: 1
• Start Page: 88
• End Page: U128
• Grant/Funding Information: This work was supported by research grants from the Dystonia Medical Research Foundation (T.F.), the Bachmann-Strauss Dystonia and Parkinson Foundation (L.J.O.), the Lockwood Family Foundation (N.S. and L.J.O.), the National Institute of Neurological Disorders and Stroke (NS26656, S.B.B., R.S.-P. and L.J.O.; NS037409, N.S. and L.J.O.; K02-NS073836, R.S.-P.) the National Institute on Drug Abuse (DA021743 and DA026405, K.A.M.) and Agence Nationale de la Recherche (ANR09-MNPS-014, D.H.).
• Keywords: ASHKENAZI JEWS; Science & Technology; Genetics & Heredity; MYOCLONUS-DYSTONIA; AUTOSOMAL-DOMINANT INHERITANCE; ADULT-ONSET; Life Sciences & Biomedicine; DYT1 DYSTONIA; BASAL GANGLIA; MOUSE MODEL; GENETIC-ANALYSIS; ADENYLYL-CYCLASE; CERVICAL DYSTONIA
• Research Categories: Biology, Neuroscience; Biology, Genetics

Abstract

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.