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General Information
Name
dystonia 1
FlyBase ID
FBhh0000043
Disease Ontology Term
Parent Disease
Overview

This report describes dystonia 1 (DYT1), which is a subtype of dystonia; DYT1 exhibits autosomal dominant inheritance. The human gene implicated in this disease is TOR1A, which is a member of the AAA family of adenosine triphosphatases (ATPases). There is a single high-scoring fly ortholog, Torsin, for which targeted amorphic alleles and RNAi-targeting constructs have been generated. Disease models have also been established in mouse and C. elegans. There are additional paralogous genes in human, TOR1B, TOR2A, TOR3A and TOR4A, none of which is implicated in human disease.

Multiple UAS constructs of the human Hsap\TOR1A gene have been introduced into flies, including wild-type TOR1A and TOR1A genes carrying mutational lesions. Significant heterologous rescue (functional complementation) of larval mobility defects is observed. When pathogenic variants of the human gene are expressed in the nervous system or muscles, heat-sensitive locomotor defects are observed in adult flies.

Variant(s) implicated in human disease tested (as transgenic human gene, TOR1A): two variant forms, E302/E303del (designated as Hsap\TOR1AΔE.UAS) and aa323-328del (designated as Hsap\TOR1AΔFY.UAS) have been introduced into flies.

Animals homozygous for amorphic alleles of Dmel\Torsin usually die prior to adulthood; larvae exhibit locomotion defects. Characterization of homozygous larvae implicate Torsin in cellular lipid metabolism. Torsin protein has also been identified as playing a role in the process by which large ribonucleoprotein granules exit the nucleus by budding through the nuclear envelope; this may offer an explanation for the "nuclear blebbing" cellular phenotype found in dystonia. Genetic and physical interactions of Dmel\Torsin have been described; see below and in the gene report for Torsin.

[updated Sep. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: dystonia
Symptoms and phenotype

Dystonia describes a neurologic condition characterized by involuntary, sustained muscle contractions affecting one or more sites of the body; 'torsion' refers to the twisting nature of body movements observed in some types of dystonia. Dystonia has been classified as primary (dystonia as the sole or major symptom) or secondary (a symptom of another disorder), and by age of onset, muscle groups affected, and mode of inheritance (Muller and Kupke, 1990, pubmed:2404852; Nemeth, 2002, pubmed:11912106). [from OMIM:128100; 15.07.07]

Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonias are classified by several clinical characteristics including age of onset (infancy (birth to 2 years), childhood (3-12 years), adolescence (13-20 years), early adulthood (21-40 years), and late adulthood (over 40 years)), temporal pattern (static or progressive disease course and the variability of symptoms, which may persist, fluctuate diurnally or occur only with specific actions or in paroxysms), by body distribution, which is divided into focal (affecting a single body part), segmental (affecting two or more contiguous muscle groups, multifocal (affecting two or more non-contiguous muscle groups), hemidystonia (affecting an arm and a leg on one side of the body), or generalized (affecting the trunk and two or more other sites), and by coexistence of other movement disorders. (Balint and Bhatia, 2014, PMID:24978640, Gene_reviews, Dystonia Overview, 2015.07.09)

Specific Disease Summary: dystonia 1
OMIM report

[DYSTONIA 1, TORSION, AUTOSOMAL DOMINANT; DYT1](https://omim.org/entry/128100)

Human gene(s) implicated

[TORSIN 1A; TOR1A](https://omim.org/entry/605204)

Symptoms and phenotype

DYT1 (early-onset primary dystonia) is a condition characterized by progressive problems with movement involving involuntary tensing of the muscles, twisting of specific body parts, rythmic shaking, and other uncontrolled movements. DYT1 dystonia usually starts with action dystonia in one limb and progresses to a segmental or generalized distribution; the cranial and cervical muscles are rarely involved. The first signs are usually spasms in a leg (average age 9 years) or an arm (average age 15 years) that occur during a specific action, such as writing or walking. Contractions frequently become less action-specific and may occur at rest; symptoms may progress over a period of months to years. The abnormal movements persist throughout life but do not usually cause pain. DYT1 does not affect a person's intelligence. Signs and symptoms vary from individual to individual, even in the same affected family. Severity ranges from mild cases affecting only one body part, e.g. writer's cramp, to severe cases in which abnormal movement occurs in many regions of the body. [From Genetics Home Reference, GHR condition: early-onset-primary-dystonia, 2015.07.09, Gene Reviews:NBK1492 DYT1 Early-Onset Primary Dystonia, 2015.07.09, Albanese and Lalli, 2012, PMID:22610459]

Genetics

DYT1 is inherited as an autosomal dominant. Penetrance is estimated at ~30% but varies considerably between families; DYT1 is caused by a 3-bp deletion in the gene TOR1A (delE302/303). [from OMIM:605204, OMIM:128100; 15.07.09]

DYT1 is inherited as an autosomal dominant with reduced penetrance (30%). It is estimated to account for approximately 16% to 53% of early-onset dystonia in non-Jews and approximately 80% to 90% in Ashkenazi Jews. It's prevalence is estimated at 1 in 3,000-9,000 in those of Ashkenazi Jewish heritage and 1 in 10,000-30,000 in the non-Jewish population. Although the phenotype is highly variable, most affected individuals have a 3 base-pair deletion c.907_909delGAG in TOR1A. [From Genetics Home Reference, GHR condition:early-onset-primary-dystonia , 2015.07.09, Gene Reviews:NBK1492 DYT1 Early-Onset Primary Dystonia, 2015.07.09]

Cellular phenotype and pathology

Mutant TOR1A aggregates in perinuclear inclusions in contrast to the wild type distribution in endoplasmic reticulum. The deletion mutant acts as a dominant-negative through a mechanism presumably involving association of wildtype and mutant protein, which may contribute to the autosomal dominant nature of DYT1. DYT1 is thought to be associated with defects in neuronal nuclear membrane structure and function. [from OMIM:605204; 15.07.09]

TOR1A protein is found in the nuclear envelope and in the endoplasmic reticulum where it interacts with various proteins. It also associates with kinesin light chain 1 (KLC1) and is present at the synapse, where it binds snapin. TOR1A protein appears to be involved in the degradation of e-sarcoglycan (SGCE), in the traffic of AP-3, the localisation of dopamine transporter (DAT), the recycling of synaptotagmin I (SytI) and the correct function of vesicular monoamine transporter 2 (VMAT2). In the deletion mutants, TOR1A and other factors controlling synaptic vesicle dynamics and composition are sequestered in perinuclear inclusions and the translocation of TOR1A to the endoplasmic reticulum is prevented; the structure of the nuclear envelope is abnormal; KLC1 function and Syt1 recycling may be affected. ATPase activity is also reduced. (Albanese and Lalli, 2012, PMID:22610459).

Molecular information

TOR1A encodes a protein which is a member of the AAA family of adenosine triphosphatases (ATPases). It contains an ATP-binding domain and a putative N-terminal leader sequence. It is 1 of 4 mammalian torsin ATPases and it is thought that one or more of the functionally homologous torsins may compensate for loss of TOR1A in non-neuronal tissues. [from OMIM:605204; 15.07.09]

The protein encoded by Tor1A (TorsinA) is a member of the AAA family of adenosine triphosphatases (ATPases) (RefSeq Jul 2008). TorsinA is located in several subcellular compartments of neurons, such as the endoplasmic reticulum, the nuclear envelope, the cytoskeleton, the cytoplasm and the synaptic vesicles (Fig. 2), wherein it is thought to contribute to multiple functions, including vesicle fusion, membrane trafficking, protein folding, and cytoskeletal dynamics (Albanese and Lalli, 2012, PMID:22610459).

External links
Disease synonyms
DYT1
dystonia musculorum deformans 1
early-onset torsion dystonia
EOTD
ideopathic torsion dystonia
ITD
early-onset primary dystonia
early-onset generalized dystonia
Oppenheim's dystonia
torsion dystonia 1
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Two to one; 2 human to 1 Drosophila; orthologous human genes are TOR1A and TOR1B. Additional more distantly related genes exist in human (see DIOPT, link below).

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Torsin (Torsin) encodes an AAA-ATPase that is implicated in the export of large ribonuclear protein particles through the nuclear membrane. It regulates dopamine levels. [Date last reviewed: 2018-10-18]
    Molecular function (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human genes TOR1A, TOR1B (1 Drosophila to 2 human; additional more distantly related genes in human). Dmel\Torsin shares 35% identity and 57% similarity with human TOR1A; 36% identity and 55% similarity with human TOR1B.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (4 groups)
    protein-protein
    Interacting group
    Assay
    References
    experimental knowledge based
    anti bait coimmunoprecipitation, western blot
    experimental knowledge based
    experimental knowledge based
    Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)
    Models Based on Experimental Evidence ( 4 )
    Modifiers Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Interaction
    References
    Models Based on Experimental Evidence ( 2 )
    Modifiers Based on Experimental Evidence ( 2 )
    Allele
    Disease
    Interaction
    References
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    amorphic allele - molecular evidence
    ends-out gene targeting
    amorphic allele - molecular evidence
    ends-out gene targeting
    References (17)