Primary torsion dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, with dystonia as the only clinical sign (except for tremor) and in the absence of neuronal degeneration or an acquired cause. There are multiple genetic causes, with overlapping phenotypes. We have now identified a series of mutations in GNAL, encoding G?olf, in patients with early onset torsion dystonia (EOTD) who do not harbor mutations in TOR1A or THAP1. G?olf is a G protein that couples striatal dopamine D1 (D1R) and adenosine A2a (A2AR) receptors to adenylyl cyclase V. Therefore, it is expressed in striatal output medium size spiny neurons and cholinergic interneurons. Abundant evidence supports dysfunction of the basal ganglia in dystonia, although other regions, e.g. cerebellum and cortex, are also involved. Within the basal ganglia, the focus has been on the dopamine D2 receptor (D2R) and striatal cholinergic interneurons. Other than mutations in the tyrosine hydroxylase biosynthetic pathway, GNAL is the first EOTD gene that directly points to the DA signal transduction system as the origin of pathophysiology, particularly to D1R. TorsinA is a AAA-ATPase protein and Thap1 is a transcription factor. Their specific functions, however, remain enigmatic, particularly as to how their mutations result in dystonia. Therefore, the connection between G?olf and the nigrostriatal dopamine system allows for directed, comparative assays of this system in mouse models of the three forms of EOTD. The rationale behind these studies is that dissecting the direct effects and compensatory maladaptations in neurotransmission, particularly dopaminergic and adenosinergic, Gnal heterozygote-null mice will offer clues to pathophysiology in DYT1 (TOR1A) and DYT6 (THAP1) EOTD as well.
In Specific Aim 1, it will be determined whether mutations in EOTD genes TOR1A, THAP1 and GNAL result in similar altered DA neurotransmission in the striatum as evidenced by DA level and release, G protein activity, and cAMP production.
In Specific Aim 2, baseline and pharmacologically induced behavior will be analyzed in the same genotypes. The molecular counterparts of the behaviors will be assayed via measures of induction of phosphorylation of ERK and DARPP-32, following D1R, D2R, and A2AR receptor agonists and antagonists.
In Specific Aim 3, RNA-seq will be performed in the Gnal+/- mouse and THAP1-C54Y knockin mouse, and compared to those in the Tor1a GAG+/-mouse (via collaboration) to identify downstream targets, particularly in neurotransmitter pathways. Identification of a final common pathway in different forms of EOTD will aid in directing discovery of therapeutic targets for this currently incurable disorder.

Public Health Relevance

We have identified mutations in a new gene, GNAL, which directly points to the dopamine (DA) signal transduction system as the cause of early onset torsion dystonia (EOTD) in these cases. We will compare the DA system in mouse 'models' of the three genetic forms of EOTD (TOR1A, THAP1, GNAL). Identification of a final common pathway in different forms of EOTD will aid in directing discovery of therapeutic targets for this currently incurable disorder.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Aguilo, Francesca; Zakirova, Zuchra; Nolan, Katie et al. (2017) THAP1: Role in Mouse Embryonic Stem Cell Survival and Differentiation. Stem Cell Reports 9:92-107
Vaine, Christine A; Shin, David; Liu, Christina et al. (2017) X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B. Neurobiol Dis 100:108-118
Shamseldin, Hanan E; Masuho, Ikuo; Alenizi, Ahmed et al. (2016) GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition. Genome Biol 17:195
Beauvais, Genevieve; Bode, Nicole M; Watson, Jaime L et al. (2016) Disruption of Protein Processing in the Endoplasmic Reticulum of DYT1 Knock-in Mice Implicates Novel Pathways in Dystonia Pathogenesis. J Neurosci 36:10245-10256
Dos Santos, Camila Oliveira; Masuho, Ikuo; da Silva-Júnior, Francisco Pereira et al. (2016) Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function. J Neurol 263:665-8
Sundermann, Erin Elizabeth; Wang, Cuiling; Katz, Mindy et al. (2016) Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein ?4 on memory decline in older adults. Neurobiol Aging 41:200.e7-200.e12
de Gusmão, Claudio M; Fuchs, Tania; Moses, Andrew et al. (2016) Dystonia-Causing Mutations as a Contribution to the Etiology of Spasmodic Dysphonia. Otolaryngol Head Neck Surg 155:624-8
Masuho, Ikuo; Fang, Mingyan; Geng, Chunyu et al. (2016) Homozygous GNAL mutation associated with familial childhood-onset generalized dystonia. Neurol Genet 2:e78
Xie, Keqiang; Masuho, Ikuo; Shih, Chien-Cheng et al. (2015) Stable G protein-effector complexes in striatal neurons: mechanism of assembly and role in neurotransmitter signaling. Elife 4:
Masuho, Ikuo; Martemyanov, Kirill A; Lambert, Nevin A (2015) Monitoring G Protein Activation in Cells with BRET. Methods Mol Biol 1335:107-13

Showing the most recent 10 out of 13 publications