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Case Report/Case Series
April 2014

Mutations in GNAL: A Novel Cause of Craniocervical Dystonia

Author Affiliations
  • 1Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
  • 2Department of Neurogenetics, Kolling Medical Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia
  • 3Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida
  • 4Department of Clinical Neuroscience, Institute of Health Bioscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan
  • 5Department of Neurology, Klinikum Kassel, Kassel, Germany
  • 6Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 7Department of Pediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
  • 8Institute of Neurology CSS, School of Medicine, Belgrade, Serbia
  • 9Department of Neurosciences, Philippine General Hospital, Manila, Philippines
  • 10Department of Neurology and Psychiatry, University of Santo Tomas Hospital, Manila, Philippines
  • 11Child Neurology Section, Philippine Children’s Medical Center, Quezon City, Philippines
JAMA Neurol. 2014;71(4):490-494. doi:10.1001/jamaneurol.2013.4677

Importance  Mutations in the GNAL gene have recently been shown to cause primary torsion dystonia. The GNAL-encoded protein (Gαolf) is important for dopamine D1 receptor function and odorant signal transduction. We sequenced all 12 exons of GNAL in 461 patients from Germany, Serbia, and Japan, including 318 patients with dystonia (190 with cervical dystonia), 51 with hyposmia and Parkinson disease, and 92 with tardive dyskinesia or acute dystonic reactions.

Observations  We identified the following two novel heterozygous putative mutations in GNAL: p.Gly213Ser in a German patient and p.Ala353Thr in a Japanese patient. These variants were predicted to be pathogenic in silico, were absent in ethnically matched control individuals, and impaired Gαolf coupling to D1 receptors in a bioluminescence energy transfer (BRET) assay. Two additional variants appeared to be benign because they behaved like wild-type samples in the BRET assay (p.Ala311Thr) or were detected in ethnically matched controls (p.Thr92Ala). Both patients with likely pathogenic mutations had craniocervical dystonia with onset in the fifth decade of life. No pathogenic mutations were detected in the patients with hyposmia and Parkinson disease, tardive dyskinesias, or acute dystonic reactions.

Conclusions and Relevance  Mutations in GNAL can cause craniocervical dystonia in different ethnicities. The BRET assay may be a useful tool to support the pathogenicity of identified variants in the GNAL gene.