Mutations in GNAL cause primary torsion dystonia

Abstract

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. 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)3, THAP1 (DYT6)4 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.

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Figure 1: Mutations identified in GNAL in individuals with PTD.
Figure 2: Effect of mutations on Gαolf coupling to D1R.

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Acknowledgements

We wish to thank all individuals with dystonia and their family members who participated in this study. We are indebted to the following physicians for referring families with dystonia included in this manuscript: S. Reich, J. Hammerstadt, D. Hobson, D. Truong, F. Danisi, M. Hutchinson, S. O'Riordan, T. Lynch and J. Rogers. We would also like to thank the following physicians who examined study subjects during their movement disorder fellowships: R. Tabamo, E. Chai, K. Blatt, P. Kavanagh, P. Kapoor and G. Petzinger. We thank R. Sachidanandam for the bioinformatics analysis related to the splice-site mutation; H. Lederman for technical help; N.A. Lambert (Georgia Health Sciences University) for sharing Venus155-239-Gβ1 and Venus1-155-Gγ2; and B. Malnic (Universidade de São Paulo) for the gift of the Ric-8B construct. 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.). The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison, including the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

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Contributions

T.F. developed the computational analysis pipeline, analyzed the next-generation and Sanger sequencing data and wrote the manuscript. S.W. and E.A. performed molecular experiments. N.S. provided funding for the linkage studies. D.H. provided the antibody to GNAL. D.R. collected samples and provided clinical information for the subjects. M.S.L. and R.S.-P. performed the statistical analysis related to phenotype. S.F., A.E.L., T.-W.L., R.M.T., R.S.-P. and S.B.B. examined subjects. S.B.B. and R.S.-P. supervised the acquisition of clinical data and blood samples and assigned final clinical status. K.A.M. and M.E.E. formulated the functional assay. I.M. performed the assays of Gαolf function. K.A.M. and I.M. analyzed and interpreted the functional data. L.J.O. designed and supervised the genetic studies. T.F., I.M., A.E.L., D.H., D.R., R.S.-P., M.S.L., N.S., K.A.M., M.E.E., S.B.B. and L.J.O. edited the manuscript.

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Correspondence to Laurie J Ozelius.

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The authors declare no competing financial interests.

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Fuchs, T., Saunders-Pullman, R., Masuho, I. et al. Mutations in GNAL cause primary torsion dystonia. Nat Genet 45, 88–92 (2013). https://doi.org/10.1038/ng.2496

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