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Achint Kaur - One of the best experts on this subject based on the ideXlab platform.
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Rare autosomal dominant mutations in GNAL are associated with primary torsion dystonia.
Clinical genetics, 2013Co-Authors: Achint KaurAbstract:Mutations in GNAL cause primary torsion dystonia Fuchs et al. (2013) Nature Genetics 45: 88–92.
Tania Fuchs - One of the best experts on this subject based on the ideXlab platform.
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Mutations in GNAL cause primary torsion dystonia
2016Co-Authors: Tania Fuchs, Rachel Saunders-pullman, Ikuo Masuho, Anthony E. Lang, Tsao-wei Liang, Richard Trosch, Marta San Luciano, Stewart Factor, Kirill A. Martemyanov, Susan B. BressmanAbstract:Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due 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 CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutatio
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GNAL mutation in isolated laryngeal dystonia.
Movement disorders : official journal of the Movement Disorder Society, 2016Co-Authors: Gregory Garbès Putzel, Tania Fuchs, Giovanni Battistella, Estee Rubien-thomas, Steven J. Frucht, Andrew Blitzer, Laurie J. Ozelius, Kristina SimonyanAbstract:Background Up to 12% of patients with laryngeal dystonia report a familial history of dystonia, pointing to involvement of genetic factors. However, its genetic causes remain unknown. Method Using Sanger sequencing, we screened 57 patients with isolated laryngeal dystonia for mutations in known dystonia genes TOR1A (DYT1), THAP1 (DYT6), TUBB4A (DYT4), and GNAL (DYT25). Using functional MRI, we explored the influence of the identified mutation on brain activation during symptomatic task production. Results We identified 1 patient with laryngeal dystonia who was a GNAL mutation carrier. When compared with 26 patients without known mutations, the GNAL carrier had increased activity in the fronto-parietal cortex and decreased activity in the cerebellum. Conclusions Our data show that GNAL mutation may represent one of the rare causative genetic factors of isolated laryngeal dystonia. Exploratory evidence of distinct neural abnormalities in the GNAL carrier may suggest the presence of divergent pathophysiological cascades underlying this disorder. © 2016 International Parkinson and Movement Disorder Society
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Neural Correlates of GNAL Mutation in Laryngeal Dystonia
2016Co-Authors: Kristina Simonyan, Gregory Garbès Putzel, Tania Fuchs, Giovanni Battistella, Estee Rubien-thomas, Steven J. Frucht, Andrew Blitzer, Laurie J. OzeliusAbstract:Isolated laryngeal dystonia (LD), or spasmodic dysphonia, is a focal adult-onset dystonia primarily affecting speech production. LD is characterized by involuntary spasm-inducing voice breaks with strained and strangled voice quality in the adductor form (ADLD) and excessive breathiness in the abductor form (ABLD). While the underlying causes of LD remain unknown, familial history of dystonia in about 12 % of patients1 points to the contribution of genetic risk factors. We investigated the contribution of DYT1, DYT4, DYT6 and DYT25 mutations as possible genetic causes of isolated sporadic and/or familial LD using Sanger sequencing of the corresponding coding regions. Because genes have direct influence on brain organization, we conducted an exploratory study to examine brain activation in an identified mutation carrier compared to healthy controls as well as to sporadic and familial LD cases using functional MRI during symptomatic speech and syllable production. Figure 1. Mutation identified in GNAL in a sporadic ADLD patient. (top) Schematic of the exon-intron structure of the short isoform o
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Mutations in GNAL cause primary torsion dystonia.
Nature genetics, 2012Co-Authors: Tania Fuchs, Rachel Saunders-pullman, Ikuo Masuho, Marta San Luciano, Deborah Raymond, Stewart A. Factor, Anthony E. Lang, Tsao-wei Liang, Richard Trosch, Sierra WhiteAbstract:Laurie Ozelius and colleagues identify mutations in GNAL in families with primary torsion dystonia, a movement disorder characterized by repetitive twisting muscle contractions and postures. GNAL encodes Gαolf, a stimulatory G protein α subunit.
Mark S. Ledoux - One of the best experts on this subject based on the ideXlab platform.
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GNAL haploinsufficiency causes genomic instability and increased sensitivity to haloperidol.
Experimental neurology, 2019Co-Authors: Mohammad Moshahid Khan, Jianfeng Xiao, Tj Hollingsworth, Damini Patel, Dana E. Selley, Trevor L. Ring, Mark S. LedouxAbstract:GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine siGNALing. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent siGNALing in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in GNAL+/- mice and their isogenic GNAL+/+ littermates. In comparison to GNAL+/+ littermates, GNAL+/- mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged GNAL+/- mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf) deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf) dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.
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GNAL mutations cause adult-onset primary dystonia
Neurology, 2013Co-Authors: Satya R. Vemula, Andreas Puschmann, Jianfeng Xiao, Yu-xia Zhao, Monika Rudzińska, Zbigniew K. Wszolek, Mark S. LedouxAbstract:OBJECTIVE: Identification of the causal mutation in an African-American family with adult-onset primary dystonia. BACKGROUND: The vast majority of patients with dystonia are adults with primary focal or segmental anatomical distributions. Familial and sporadic dystonia appear to share the same genetic etiological background. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large pedigrees suited for linkage analysis are uncommon. In previous work, we excluded THAP1 and TOR1A mutations in an African-American family with clinical phenotypes that included cervical, laryngeal and hand-forearm dystonia. DESIGN/METHODS: Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in order to identify the causal mutation (GNAL, c.913G>T) in our African-American family with dystonia. High resolution melting and Sanger sequencing were used to screen 768 additional subjects with primary cervical or segmental dystonia for sequence variants in GNAL. RESULTS: The missense mutation in GNAL (c.913G>T, p.V305F) was found to co-segregate with dystonia in our African-American pedigree. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) is highly expressed in the olfactory bulb, striatum and cerebellar Purkinje cells. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. Screening identified two additional pedigrees with GNAL mutations (c.822-823insA [p.R275T∗13] and c.964C>T [p.R322∗]). None of these sequence variants were found in 760 controls. CONCLUSIONS: Mutations in GNAL are causally-associated with adult-onset primary cervical and segmental dystonia. The prominent expression of Gα(olf) in striatum and cerebellar Purkinje cells points to potential sites of functional pathology in primary dystonia. (Less)
Ikuo Masuho - One of the best experts on this subject based on the ideXlab platform.
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Mutations in GNAL cause primary torsion dystonia
2016Co-Authors: Tania Fuchs, Rachel Saunders-pullman, Ikuo Masuho, Anthony E. Lang, Tsao-wei Liang, Richard Trosch, Marta San Luciano, Stewart Factor, Kirill A. Martemyanov, Susan B. BressmanAbstract:Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due 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 CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutatio
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Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia
Neurology. Genetics, 2016Co-Authors: Ikuo Masuho, Mingyan Fang, Chunyu Geng, Jianguo Zhang, Hui Jiang, Rıza Köksal Özgül, Didem Yucel Yilmaz, Dilek Yalnizoglu, Deniz Yüksel, Anna YarrowAbstract:Heterozygous loss-of-function mutations in the GNAL gene encoding the α subunit of the heterotrimeric G protein Golf (Gαolf) are known to cause isolated dystonia.1,2 Gαolf is enriched in the striatum where it couples D1 dopamine (D1R) and A2A adenosine (A2AR) receptors to the activation of adenylyl cyclase type 5 (AC5). Mutations in ADCY5 , the gene encoding AC5, are also known to lead to chorea and dystonia.3,4 Previous functional studies of mutated Gαolf variants have revealed deficiencies in activation after D1R stimulation.1,5 Acknowledgment: The authors thank the patients and their family for their participation; without their support, this work would not have been possible.
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Mutations in GNAL: A Novel Cause of Craniocervical Dystonia
JAMA neurology, 2014Co-Authors: Kishore R. Kumar, Ikuo Masuho, Katja Lohmann, Ryosuke Miyamoto, Andreas Ferbert, Thora Lohnau, Meike Kasten, Johann Hagenah, Norbert Brüggemann, Julia GrafAbstract:Importance Mutations in the GNAL gene have recently been shown to cause primary torsion dystonia. The GNAL -encoded protein (Gα olf ) is important for dopamine D 1 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 Gα olf coupling to D 1 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.
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Mutations in GNAL cause primary torsion dystonia.
Nature genetics, 2012Co-Authors: Tania Fuchs, Rachel Saunders-pullman, Ikuo Masuho, Marta San Luciano, Deborah Raymond, Stewart A. Factor, Anthony E. Lang, Tsao-wei Liang, Richard Trosch, Sierra WhiteAbstract:Laurie Ozelius and colleagues identify mutations in GNAL in families with primary torsion dystonia, a movement disorder characterized by repetitive twisting muscle contractions and postures. GNAL encodes Gαolf, a stimulatory G protein α subunit.
Sierra White - One of the best experts on this subject based on the ideXlab platform.
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Mutations in GNAL cause primary torsion dystonia.
Nature genetics, 2012Co-Authors: Tania Fuchs, Rachel Saunders-pullman, Ikuo Masuho, Marta San Luciano, Deborah Raymond, Stewart A. Factor, Anthony E. Lang, Tsao-wei Liang, Richard Trosch, Sierra WhiteAbstract:Laurie Ozelius and colleagues identify mutations in GNAL in families with primary torsion dystonia, a movement disorder characterized by repetitive twisting muscle contractions and postures. GNAL encodes Gαolf, a stimulatory G protein α subunit.