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Mutations in GNAL: a Novel Cause of Craniocervical Dystonia

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Mutations in GNAL: a Novel Cause of Craniocervical Dystonia Research Case Report/Case Series Mutations in GNAL A Novel Cause of Craniocervical Dystonia Kishore R. Kumar, MBBS, FRACP; Katja Lohmann, PhD; Ikuo Masuho, PhD; Ryosuke Miyamoto, MD; Andreas Ferbert, MD; Thora Lohnau, BS; Meike Kasten, MD; Johann Hagenah, MD; Norbert Brüggemann, MD; Julia Graf, MD; Alexander Münchau, MD; Vladimir S. Kostic, MD, PhD; Carolyn M. Sue, MBBS, FRACP, PhD; Aloysius R. Domingo, MD; Raymond L. Rosales, MD, PhD; Lilian V. Lee, MD; Karen Freimann, MS; Ana Westenberger, PhD; Youhei Mukai, MD; Toshitaka Kawarai, MD; Ryuji Kaji, MD; Christine Klein, MD; Kirill A. Martemyanov, PhD; Alexander Schmidt, MD Video at jamaneurology.com IMPORTANCE Mutations in the GNAL gene have recently been shown to cause primary torsion Supplemental content at dystonia. The GNAL-encoded protein (Gαolf) is important for dopamine D1 receptor function and jamaneurology.com 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. Author Affiliations: Author CONCLUSIONS AND RELEVANCE Mutations in GNAL can cause craniocervical dystonia in affiliations are listed at the end of this different ethnicities. The BRET assay may be a useful tool to support the pathogenicity of article. identified variants in the GNAL gene. Corresponding Author: Christine Klein, MD, Institute of Neurogenetics, University of Luebeck, Ratzeburger JAMA Neurol. 2014;71(4):490-494. doi:10.1001/jamaneurol.2013.4677 Allee 160, 23538 Luebeck, Germany Published online February 17, 2014. (christine.klein@neuro .uni-luebeck.de). n two independent studies,1,2 exome sequencing of the GNAL unit is also involved in odorant signal transduction.5 Notably, gene (RefSeq NM_001142339) was used recently to study Gnal-null mice are anosmic,6 raising the possibility that mu- I GNAL mutations as a cause of autosomal dominant pri- tations in GNAL may also cause hyposmia in humans.2 Be- mary torsion dystonia in patients of European and African Ameri- cause Gαolf plays a role in dopamine signal transduction, mu- can ancestry. The GNAL gene is located on the short arm of chro- tations in GNAL potentially increase susceptibility to mosome 18p11, and the absence of GNAL may contribute to movement disorders induced by dopamine antagonists. Dif- dystonia in patients with the 18p deletion syndrome.3 Onset ferential methylation of CpG islands in the vicinity of exon 1 among mutation carriers occurred mainly in the neck (82%) at also exists, suggestive of genomic imprinting of the GNAL a mean age at onset of 31.3 (range, 7-54) years. On examination, gene.7 We screened for GNAL mutations in a multiethnic almost all patients had cervical dystonia (93%), but cranial (57%) sample with different dystonia phenotypes and other clinical and speech involvement (44%) were also quite common.1 phenotypes linked to the putative function of the gene. The GNAL gene encodes the stimulatory α subunit, Gαolf, that links G protein–coupled receptors to downstream effec- tor molecules and functions as a heterotrimer composed of α, Methods β, and γ subunits. The Gαolf subunit is expressed prominently in the brain, especially in the striatum, where it may couple The study was approved by the respective institutional re- dopamine D1 receptors and adenosine A2A receptors to the ac- view boards, and all patients gave written informed consent. tivation of adenylyl cyclase type 5.1,4 In fact, efficiency of het- Patients were recruited from movement disorder clinics in Ger- erotrimer formation or coupling to D1 receptors was previ- many, Serbia, and Japan. The sample populations (Table) con- ously shown to be impaired in GNAL mutation carriers using sisted of patients with different dystonia phenotypes, includ- 1 a bioluminescence energy transfer (BRET) assay. The Gαolf sub- ing cervical, segmental, and generalized dystonia; patients with 490 JAMA Neurology April 2014 Volume 71, Number 4 jamaneurology.com Copyright 2014 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Mutations in GNAL and Craniocervical Dystonia Case Report/Case Series Research Table. Sample Population Characteristics for Patients and Controls Sex, No. of Family History, Patients Time, Mean (SD) [Range], y No. (%) Positive/ Sample Population No. Negative/ Phenotype No. of Patientsa Male Female Age at Examination Age at Onset Disease Duration No. Unknown Cervical dystonia 190 (84/26/80) 91 99 52.2 (14.0) [23-86] 36.7 (12.2) [10-71] 15.1 (11.2) [1-55] 34 (17.9)/111/45 Musician’s dystonia 54 (54/0/0) 37 17 41.5 (11.9) [22-77] 24.6 (7.2) [15-64] 16.9 (11.5) [3-51] 22 (40.7)/31/1 Writer’s cramp 6 (6/0/0) 3 3 38.2 (3.6) [35-45] 23.4 (7.9) [12-34] 15.2 (5.7) [11-25] 2 (33.3)/3/1 Segmental dystonia 36 (24/0/12) 21 15 55.0 (10.9) [33-74] 34.1 (18.2) [6-62] 21.3 (12.5) [3-46] 1 (2.8)/30/5 Generalized dystonia 32 (19/2/11) 14 18 36.5 (17.6) [10-72] 10.6 (6.2) [1-24] 25.9 (16.6) [1-62] 14 (43.8)/13/5 PD and hyposmia 51 (51/0/0) 30 21 65.4 (10.0) [44-82] NL NL NL Acute dystonic 44 (44/0/0) 22 22 48.2 (12.9) [25-86] NL NL NL reactions Tardive dyskinesias 48 (48/0/0) 26 22 53.0 (16.3) [25-90] NL NL NL German controls 269 146 123 70.3 (5.9) [53-81] NA NA NA Filipino controls 285 137 148 36.1 (14.4) [19-88] NA NA NA Japanese controls 96 50 46 40.4 (4.5) [30-56] NA NA NA Abbreviations: NA, not applicable; NL, not listed; PD, Parkinson disease. a Numbers in parentheses indicate patients recruited in Germany/Serbia/Japan. idiopathic PD with low scores (<15th percentile) on the Uni- with NanoLuc luciferase, thereby producing the BRET signal versity of Pennsylvania Smell Identification Test; and pa- (described in detail in the Supplement [eMethods] and tients with tardive dyskinesias or acute dystonic reactions to elsewhere1). dopamine receptor–blocking agents. The diagnoses were based on accepted clinical criteria. A detailed neurological assess- ment was performed on mutation carriers, including a video- Results taped neurological examination and assessment of dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale8) and cog- Four hundred sixty-one patients underwent screening, includ- nition (Montreal Cognitive Assessment9). Olfaction was as- ing 318 with dystonia, 51 with PD and hyposmia, and 92 with sessed using either the Brief Smell Identification Test (BSIT; tardive dyskinesia or acute dystonic reactions. Approxi- Sensonics, Inc) or by intravenous administration of thiamine mately 18% of patients with cervical dystonia had a known propyldisulfide (Alinamin) as previously described.10 The GAG positive family history. We identified the following two puta- deletion in TOR1A (RefSeq NM_000113) and mutations in THAP1 tively pathogenic heterozygous missense variants in the GNAL (RefSeq NM_018105) had previously been excluded in the Ger- gene (Figure 1): p.Gly213Ser in a German patient and man and Serbian patients with dystonia.11 p.Ala353Thr in a Japanese patient. Mutations were predicted We extracted DNA from blood samples using standard to be damaging using three different software tools (Muta- methods. Sanger sequencing was performed for all 12 exons tion Taster [http://www.mutationtaster.org], PolyPhen-2 [http: of GNAL and exon-intron junctions (Supplement [eTable 1]). //genetics.bwh.harvard.edu/pph2], and SIFT [http://sift.jcvi When a potentially pathogenic variant was identified, we .org]) (Supplement [eTable 2]) and were absent in the exome screened for this variant in an ethnically matched control variant server database (http://evs.gs.washington.edu/EVS) and sample. Quantitative polymerase chain reaction of exon 9 was in ethnically matched (538 German or 192 Japanese) control performed on a commercially available system (LightCycler chromosomes. Furthermore, the BRET assay found that both 480; Roche Diagnostics) using an asymmetrical cyanine dye variants disturbed Gαolf function markedly, with increased (SYBR Green; Life Technologies) to test for whole gene dele- basal BRET ratios (R0) and a severely attenuated signal after tions/duplications (Supplement [eMethods]). To screen for application of dopamine (Rmax −R0) reflecting impairments in GNAL expression in mutation carriers, RNA was extracted from Gαolf-Gβγ heterotrimer formation and functional coupling to peripheral blood leukocytes using a commercially available kit D1 receptors, respectively (Figure 2). A p.Ala311Thr variant was (PAXgene blood kit; Qiagen). After reverse transcription– found in a German patient with sporadic dystonia con- polymerase chain reaction, sequencing was performed using founded by the diagnosis of relapsing-remitting multiple scle- primers located within exons 4 and 12 (Supplement [eTable 1]). rosis. The variant was absent in the German controls and pre- Functional consequences of mutations were investigated using dicted to be pathogenic on Mutation Taster and SIFT but was a BRET cell-based assay, whereby stimulation of D1 receptors benign on PolyPhen-2 and indistinguishable from the wild type by dopamine results in the dissociation of Gαolf from the het- on the BRET assay.
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