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)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Sieber, Beth-Anne
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Kumar, Kishore R; Lohmann, Katja; Masuho, Ikuo et al. (2014) Mutations in GNAL: a novel cause of craniocervical dystonia. JAMA Neurol 71:490-4