title: Mutations in GNAL: a novel cause of craniocervical dystonia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany2Department of Neurogenetics, Kolling Medical Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia.
authors.forename: Kishore R
authors.initials: KR
authors.lastname: Kumar
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Masuho
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Bioscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Miyamoto
authors.affiliation: Department of Neurology, Klinikum Kassel, Kassel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Kasten
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Hagenah
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Brüggemann
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Graf
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany7Department of Pediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.affiliation: Institute of Neurology CSS, School of Medicine, Belgrade, Serbia.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Kostic
authors.affiliation: Department of Neurogenetics, Kolling Medical Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany9Department of Neurosciences, Philippine General Hospital, Manila, Philippines.
authors.forename: Aloysius R
authors.initials: AR
authors.lastname: Domingo
authors.affiliation: Department of Neurology and Psychiatry, University of Santo Tomas Hospital, Manila, Philippines.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Rosales
authors.affiliation: Child Neurology Section, Philippine Children's Medical Center, Quezon City, Philippines.
authors.forename: Lilian V
authors.initials: LV
authors.lastname: Lee
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Freimann
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Westenberger
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Bioscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Mukai
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Bioscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.affiliation: Department of Clinical Neuroscience, Institute of Health Bioscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
authors.affiliation: Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmidt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D005858:Germany / Q000208:ethnology; D006801:Humans; D007564:Japan / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D055771:Serbia / Q000208:ethnology; D014103:Torticollis / Q000208:ethnology / Q000209:etiology* / Q000235:genetics*; D055815:Young Adult
chemical_list: D044385:GTP-Binding Protein alpha Subunits; C084618:olfactory G protein subunit alpha olf