Format

Send to

Choose Destination
See comment in PubMed Commons below
JAMA Neurol. 2014 Apr;71(4):490-4. doi: 10.1001/jamaneurol.2013.4677.

Mutations in GNAL: a novel cause of craniocervical dystonia.

Author information

1
Institute of Neurogenetics, University of Luebeck, Luebeck, Germany2Department of Neurogenetics, Kolling Medical Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia.
2
Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.
3
Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida.
4
Department of Clinical Neuroscience, Institute of Health Bioscience, Graduate School of Medicine, University of Tokushima, Tokushima, Japan.
5
Department of Neurology, Klinikum Kassel, Kassel, Germany.
6
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.
7
Institute of Neurology CSS, School of Medicine, Belgrade, Serbia.
8
Department of Neurogenetics, Kolling Medical Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia.
9
Institute of Neurogenetics, University of Luebeck, Luebeck, Germany9Department of Neurosciences, Philippine General Hospital, Manila, Philippines.
10
Department of Neurology and Psychiatry, University of Santo Tomas Hospital, Manila, Philippines.
11
Child Neurology Section, Philippine Children's Medical Center, Quezon City, Philippines.

Abstract

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.

Comment in

PMID:
24535567
PMCID:
PMC4237020
DOI:
10.1001/jamaneurol.2013.4677
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems Icon for PubMed Central
    Loading ...
    Support Center