REVIEW

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

William Dauer

# The American Society for Experimental NeuroTherapeutics, Inc. 2014

Abstract Isolated inherited dystonia—formerly referred to asprimary dystonia—is characterized by abnormal motor func-tioning of a grossly normal appearing brain. The diseasemanifests as abnormal involuntary twisting movements. Theabsence of overt neuropathological lesions, while intriguing,has made it particularly difficult to unravel the pathogenesis ofisolated inherited dystonia. The explosion of genetictechology enabling the identification of the causative genemutations is transforming our understanding of dystonia path-ogenesis, as the molecular, cellular and circuit level conse-quences of these mutations are identified in experimentalsystems. Here, I review the clinical genetics and cell biologyof three forms of inherited dystonia for which the causativemutation is known: DYT1 (TOR1A), DYT6 (THAP1),DYT25 (GNAL).

Keywords Isolated Inherited Dystonia . DYT1 (TOR1A) .

DYT6 (THAP1) . DYT25 (GNAL) . Dystonia Pathogenesis

Introduction

Dystonic movements were defined in 1984 as a syndromeconsisting “of sustained muscle contractions, frequently caus-ing twisting and repetitive movements, or abnormal postures[1].”While this definition proved extremely useful, the explo-sion of interest in, and study of, movement disorders since thattime has highlighted a variety of ways that dystonia can

manifest clinically that are not captured by this definition.For example, dystonic movements are not always prolongedenough to cause twisting and turning, and may be intermittent,leading to tremulous-type movements. The original definitionalso failed to capture some characteristic features of dystonicmovements, including their striking directionality, repetitivestereotyped nature, and their relation to action. These limita-tions led to the creation of an international panel of investiga-tors that proposed an updated definition of dystonic move-ments to incorporate this new understanding: “Dystonia is amovement disorder characterized by sustained or intermittentmuscle contractions causing abnormal, often repetitive, move-ments, postures, or both. Dystonic movements are typicallypatterned, twisting, and may be tremulous. Dystonia is ofteninitiated or worsened by voluntary action and associated withoverflow muscle activation [1].”

Among the terms used to describe different types of abnormalmovements, “dystonia” is perhaps the most confusing, since itrefers to both a type of abnormal movement (described above)and a disease entity [2]. As a type of abnormal movement,dystonia can occur in a wide range of neurological disorders thatdamage the motor system, ranging from Parkinson disease in theaged to metabolic diseases that manifest in the first years of life.When it occurs in the context of underlying disease, dystonia istypically accompanied by signs and symptoms characteristic ofthe associated illness. In contrast, when used to describe a diseaseentity, “dystonia” refers to an illness inwhich dystonia is the onlyneurological sign, with the exception of tremor, and is notaccompanied by obvious central nervous system (CNS) injury.These two clinical contexts in which dystonia appears have beentermed “primary” (isolated dystonia, no overt CNS lesion) and“secondary” (dystonia in the context of other CNS-damaginginsult). However, these terms lack clarity and precision becausethey incorporate both clinical-phenomenological and etiologicfeatures into single terms (e.g., primary dystonia denotes bothisolated dystonia and the absence of any CNS lesion or

Electronic supplementary material The online version of this article(doi:10.1007/s13311-014-0297-7) contains supplementary material,which is available to authorized users.

W. Dauer (*)Department of Neurology, Department of Cell and DevelopmentalBiology, University of Michigan Medical School, Ann Arbor,MI 48109-220, USAe-mail: dauer@med.umich.edu

NeurotherapeuticsDOI 10.1007/s13311-014-0297-7

exogenous cause). To overcome this limitation, a new nomen-clature has been proposed with separate axes to describe theclinical (“Axis I”) and etiological (“Axis II”) features. In this newnomenclature, the Axis I clinical terms are “isolated” and “com-bined,” and imply nothing about etiology. The Axis II etiologicalcategories include inherited, acquired (e.g., brain injury) andidiopathic. This review focuses exclusively on the genetics andcellular mechanisms of the three forms of inherited isolateddystonia for which the causative gene has been identified andvalidated extensively: DYT1 (caused by mutations in TOR1Aencoding the AAA + protein torsinA), DYT6 (caused by muta-tions in THAP1 encoding transcription factor THAP1) andDYT25 (caused by mutations in GNAL encoding the G-proteinGαolf). Variations in CIZ1 [3] and ANO3 [4] have been reportedmore recently in subjects with isolated dystonia. However, theevidence in favor of a pathogenic role for these genes is not yetsufficiently conclusive, so they will not be considered further inthis review (see [5] for further discussion of these genes).

Clinical Genetics

The clinical characteristics of isolated dystonia of genetic oridiopathic etiology were most comprehensively described byBressman and colleagues in Ashkenazi Jewish subjects [6, 7],but their findings are broadly applicable. These studies dem-onstrated that age-at-onset of dystonia is a critical factorpredicting likelihood of genetic etiology and degree of spreadfrom the initially affected body region. In general, this workdemonstrates that compared to adult-onset disease (typicallyin 40s–50s), younger age-at-onset (particularly during child-hood) is more likely to be of genetic etiology and spread toinvolve a greater number of body parts.

DYT1

DYT1 dystonia is a dominantly inherited disease that typicallybegins in school-aged children, with a mean age at onset of~12 years. Characteristically, it initially affects an arm or leg,and subsequently spreads to involve additional limbs and/orthe trunk. Up to 50% of affected subjects may ultimatelydevelop generalized involvement. The tendency to generalizedistinguishes DYT1 dystonia (and other childhood-onset ge-netic etiologies) from adult onset idiopathic isolated dystonia,which typically remains focal or segmental. DYT1 dystoniatypically spares facial and laryngeal structures (presentin ~11–14% of cases), and involves the neck in a minorityof cases (present in ~25% of cases) [8–10]. This clinicalpicture of DYT1 dystonia is highly stereotyped, but excep-tional cases and families have been reported, including withmuch earlier or later onset, onset in the larynx, or a phenotypeof isolated writer’s cramp [11, 12].

In 1997, an in-frame 3 base-pair deletion (Δgag; ΔE) in theTOR1A gene encoding the AAA + protein torsinA was discov-ered as the cause of DYT1 dystonia [13].While best described inAshkenazi Jews, the DYT1 mutation has arisen de novo severaltimes in diverse popoulations [14–16]. Clinical studies subse-quent to mutation identification confirmed earlier findings basedon haplotype analysis, showing that the mutation is roughly 30%penetrant, and exhibits considerable variation in symptom ex-pressivity. Mutation-carrying subjects exhibit abnormalities ofbrain metabolism as assessed by fluorodeoxyglucose positronemission tomography analysis, regardless of clinical status [17].Mutation carriers who do not develop dystonia by their early 20salmost always remain symptom-free for life, suggesting thepresence of a developmental window of susceptibility duringwhich torsinA function is critical for brain function. Based onthese findings, diagnostic testing for the DYT1 mutation isrecommended for subjects developing dystonia before age26 years, unless other factors (e.g., a relative with early-onsetdystonia) are present [10].

Several investigators have sought genetic modifiers of diseasepenetrance and expressivity, and examined the potential role oftorsinA in other forms of dystonia. A torsinA coding polymor-phism acting in trans reduces the risk of disease penetrance [18],and may alter the risk of non-DYT1 adult-onset idiopathicdystonia [19]. These effects may relate to the propensity of thispolymorphism to cause torsinA to misfold [20]. Genetic back-ground appears to confer only a modest influence on the clinicalphenotype of theDYT1mutation [21]. No studies have identifiedgenetic or environmental factors that contribute to the strikingvariability in disease severity among manifesting subjects. Stud-ies examining a possible association of torsinA sequence varia-tion with adult-onset idiopathic isolated dystonia are mixed[22–26]. No evidence has been found linking TOR1A to suscep-tibility to causes of dystonia such as neuroleptic drugs or perina-tal asphyxia [27]. Similarly, studies exploring a role for theDYT1 mutation in musician’s dystonia, one form of use-associated “occupational” dystonia, found either no association[28] or identified the mutation in a single individual [29]. Defin-itive identification of environmental factors that impact mutationpenetrance or expressivity would require a prospective study ofasymptomatic mutation carriers, but such a study has not yetbeen reported. In contrast to other inherited CNS diseases (e.g.,spinocerebellar ataxias), the variable expressivity in DYT1 dys-tonia relates almost exclusively to the distribution and severity ofdystonia; additional neurological findings, with the possible ex-ception of tremor, do not complicate the clinical phenotype.

DYT6

DYT6 dystonia is also inherited dominantly. This form ofdystonia was characterized and mapped initially in theAmish-Mennonite population [30, 31]. Similar to DYT1

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dystonia, the disease in this population typically begins inchildhood, with a mean age at onset of ~16 years. In contrastto DYT1 dystonia, however, roughly 50% of DYT6 subjectsinitially develop dystonia of cranial muscles (larynx, tongue,face) or the neck, with only ~5% initially manifesting in theleg (a common site of onset in DYT1 dystonia) [31]. Whilesymptoms commonly spread and ultimately involve the leg(s)in many patients, leg involvement is typically mild, and dis-ability in DYT6 dytstonia arises most commonly fromcraniocervical involvement. Penetrance in the Amish-Mennonite population is ~60%, and women appeared morefrequently affected.

In 2008, two mutations in the THAP1 gene encoding thetranscription factor thanatos-associated protein 1 (THAP1) wereidentified as the cause of DYT6 dystonia [32]. In this report, theAmish-Mennonite population were found to have an insertion-deletion (“indel”) mutation and a German family was found tohave a missense mutation (F81L) that appeared to impair DNAbinding. Subsequently, a large number of different mutations inTHAP1 have been identified in a wide range of ethnicities[33–37], linking this gene to a far larger number of inheritedcases of dystonia than had been suspected previously. The num-ber of reported mutations led to the creation of a locus-specificdatabase (http://www.umd.be/THAP1/{Blanchard), which by2011 already included 56 different families, most of whichhave unique mutations. THAP1 mutations span the gamut fromthose that lead to very early truncations (e.g., at amino acid 3) tomissense, but no genotype-phenotype correlation is apparent. Inaddition to the typical dominantly inherited mutations, two fam-ilies with apparently recessively inherited mutations have beendescribed [38, 39], furthering the evidence for a loss-of-functionmechanism in DYT6 dystonia. The clinical characteristics of themany non-Amish-Mennonite subjects described subsequent tothe initial discovery of THAP1 conforms to the initially describedclinical phenotype, with either initial involvement in or frequentspread to craniocervical regions, though it has become apparentthat the age at onset may extend into the late 40s [35]. Cases offocal dystonia (torticollis and blepharospasm) have been found toharbor mutations in THAP1 [36, 40], but this an uncommonmanifestation of DYT6 dystonia [41], and genotype-phenotypecorrelations demonstrates that the THAP1 variations in thesecases are predicted to be benign [42]. It is also possible that thesepatients will ultimately develop segmental disease. Despite thedifferences in pattern of involvement between DYT1 and DYT6dystonia, intraoperativemicroelectrode recordings exhibit a com-mon electrophysiological signature [43], indicating sharedmech-anism at the level of neural circuits.

DYT25

The identification of TOR1A and THAP1 mutations weremajor advances that spawned a range of exciting research

effort focused on identifying molecular and cellular underpin-nings of dystonia. Yet these genes cause isolated dystonia thatis primarily of childhood-onset; isolated dystonia much morecommonly begins in adulthood. Against this backdrop, theidentification of GNAL mutations (DYT25) is particularlyexciting [44], being the first gene linked to adult-onset focal/segmental dystonia—a condition commonly seen by move-ment disorders neurologists. Indeed, the discovery of this genewill allow studies exploring potential links betweenchildhood- and adult-onset dystonia—an important questionin dystonia research.

Just since 2012, 5 independent groups have identifiedGNAL mutations in patients with adult-onset dystonia, typi-cally beginning in or involving the neck. Fuchs and colleaguesinitially reportedGNALmutations in 8 families, each of whichhad a unique variant. These mutations included nonsense,frameshift, missense and deletion mutations [44]. The averageage at onset was ~31 years in the 28 patients, most of whom(82%) had neck onset or eventual neck involvement (93%).Dystonia remained focal in about half of these patients, withthe rest showing spread to contiguous regions (e.g., develop-ing segmental dystonia). Subsequent reports [45–49] demon-strated yet additional GNAL mutations in patients with asimilar clinical phenotype (i.e., adult-onset, cervical predom-inant). While the age at onset is typically in the fifth to sixthdecade,GNALmutations lead to a rather broad range of age atonset, spanning from age 7 to 54 years. These reports broad-ened the ethnic diversity in which mutations are found, whichnow includes Caucasian, Asian and African American sub-jects. Interestingly, mutations in TOR1A, THAP1 and GNALcan all be found within one ethnic group—as demonstrated inAmish-Mennonites—emphasizing the genetic heterogenetityof dystonia even in narrowly defined populations, and theimportance of not assuming genetic etiology based uponethnicity [48].

Gene Function

The brains of subjects with isolated dystonia do not exhibitovert histopathological change, and subtle abnormalities (e.g.,those recently reported in cerebellum [50], or others recentlyreviewed [51]) are of uncertain significance or yet to beindependently validated. This situation creates conceptualchallenges distinct from those encountered in neurodegenera-tive disease, where the cellular effect to be studied—celldeath—is defined clearly. Consequently, much of the researchon the genes linked to isolated dystonia has focused on defin-ing the cellular pathways in which they participate, and theconsequences for these pathways provoked by pathogenicmutations. There has also been considerable effort at manip-ulating isolated dystonia genes in vivo to create a mousemodel of the disease. Here, I focus almost exclusively on the

Inherited Isolated Dystonia: Clinical Genetics

cell biological aspects of isolated dystonia genes, referring toresults from animal models only where they bear directly onthe cell biological aspects of gene function, including whetherpathogenic mutations act via a gain- or loss-of-function. Com-prehensive reviews of human pathophysiological studies ofprimary dystonia [2] or the behavioral and electrophysiolog-ical features of mouse models of isolated dystonia, includingsynaptic alterations in torsinA mutant mice [52], are availableelsewhere. The first discovered cause of isolated inheriteddystonia, mutations in TOR1A encoding torsinA (DYT1),were identified more than a decade before the next identifiedgene, THAP1 (DYT6). Consequently, most work has beendone on torsinA, the review of which will comprise themajority of the following discussion.

TorsinA (DYT1)

TorsinA Function

TorsinA is expressed widely in neuronal and non-neuronaltissues and is a member of the AAA+ (ATPase associated witha variety of cellular activities) protein family. AAA+ proteinstypically function as oligomers and use the energy of ATPhydrolysis to disassemble protein complexes [53]. Within thisfamily it is related closely to the ClpB/Hsp104 proteins, whichprotect cells from denaturant stress by unfolding damagedproteins [54], and can regulate prion protein conformation[55]. AAA+ proteins contain a conserved ATPase domainspanning ~250 residues, which allows them to derive energyfrom ATP hydrolysis. These proteins typically assembleinto ring-shaped oligomers (often hexamers) and functionvia a cycle of substrate binding➙non-covalent substratemodification➙substrate release, thus acting as a type ofchaperone. This cycle is typically linked to ATP binding andhydrolysis: the binding of ATP leads to a high affinity sub-strate interaction, and modified substrate is released followingATP hydrolysis. In fact, experimental mutations in the AAA+domain that prevent ATP hydrolysis often cause AAA+ pro-teins to lock onto substrates (so-called “substrate trap” E/Qmutations [53]). AAA+ proteins modify substrates in a widevariety of cellular contexts. For example, the AAA proteinNSF (N-ethylmaleimide sensitive factor) dissociates theSNARE complex after the completion of membrane fusion[56]. AAA+ proteins utilize this chaperone-like activity in adiverse range of biological functions, including but not limitedto membrane trafficking, powering cellular motors, and pro-tein chaperoning [53]. Thus, the inclusion of torsinA in theAAA+ protein family indicates how torsinA likely acts onsubstrates, but provides little insight into the cellular role oftorsinA.

Clues to the role of torsinA come from its localization inthe endoplasmic reticular/nuclear envelope (ER/NE)

endomembrane space. TorsinA resides in the lumen of theER/NE endomembrane system as a peripheral membraneprotein glycoprotein [57, 58]. The ER is an intracellular mem-brane compartment through which all membrane localized orsecreted proteins must traffic. The ER has several well definedsubdomains, which include the smooth and rough ER, and theNE, with which it is continuous. The subcellular localizationof torsinA and identification of its interacting proteins withinthe ER/NE space indicates that it functions in both majorsubcompartments. Exogenously expressed wild type torsinAresides predominantly in the ER but concentrates in the NE toa somewhat greater extent than typical ER proteins [59].Multiple laboratories have observed that artificially engineer-ing a “substrate trap” mutant of torsinA that prevents it fromdissociating from protein partners causes it to accumulateabnormally in the NE [59–61]. Moreover, torsinA interactswith inner nuclear membrane-localized protein lamina-associated polyprotein 1 (LAP1, also known as torsin-1A-interacting protein 1) and the main ER-localized protein lu-menal domain like LAP1 (LULL1, also known as torsin-1A-interacting protein 2) [62]. Both LAP1 and LULL1 have beenshown to function with torsinA. Loss of torsinA functioncauses characteristic abnormalities of nuclear membranestructure (reviewed below) and similar abnormalities occurin LAP1 knockout mice [63, 64]. Moreover, binding of eitherLAP1 or LULL1 greatly stimulate the ATPase activity oftorsinA [65]. These data indicate a novel situation in whichtorsinA function can be independently regulated in differentdomains of the ER/NE space by LAP1 (at the NE) and LULL1(in the main ER).

The precise biological role that torsinA plays within theER/NE space is not well understood, but several themes haveemerged (Fig. 1). Within the ER, several reports have pointedto a role for torsinA in protein trafficking or protein qualitycontrol. TorsinA is reported to participate in ER-associatedprotein degradation (“ERAD”)—a process wherebymisfolded ER proteins are exported from the ER space anddegraded [66]. Studies in Caenorhabditis elegans [67] alsopoint to a role in protein quality control pathways. Otherstudies indicate that torsinA regulates the trafficking ofpolytopic membrane proteins, including the dopamine trans-porter [68], or ER-based mechanisms controlling proteinsecrection [69, 70]. These pathways are tightly interrelated,so these different findings may well reflect a core function oftorsinA that manifests in a variety of ways depending upon theexperimental approach. A recent study exploring torsinAfunction in mammalian neurons in vivo using a novel set oftorsinA mouse mutants is consistent with these findings inin vitro systems and lower organisms. This work demonstratesthat loss of torsinA function causes activation of ER stresspathways and neurodegeneration in a set of discrete set ofsensorimotor brain regions linked previously to the patho-physiology of DYT1 dystonia [71].

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A growing body of work also highlights potential roles fortorsinA within the NE. The potential importance of NE-localized torsinA function to DYT1 dystonia is underscoredby the finding thatΔE-torsinA abnormally concentrates at thenuclear membrane [59–61]. While the specific function ofNE-localized torsinA is unclear, one possibility is regulationof the connections between proteins that tether the nucleus tothe cytoskeletal network [72, 73]. Nucleo-cytoskeletal (N-C)connections are critical for the control of nuclear movements,and such movements are essential for several CNS develop-mental events, including neurogenesis, neural tube closure,and neural migration [74]. Neurons are highly polarized cells,so nuclear positioning is likely to be a critical, if poorlyunderstood, aspect of normal function. N-C connections de-pend upon nesprin and SUN proteins. Nesprins are outernuclear membrane proteins that participate in the N-C linkby binding to the cytosolic cytoskeletal network. Nesprins areanchored to NE through binding to SUN protein family mem-bers, which themselves are localized to the inner nuclearmembrane. TorsinA has been reported to interact with SUN1[75] and Nesprin-3, which itself is mislocalized in murinetorsinA null fibroblasts and DYT1 patient fibroblasts. Over-expression of torsinA in a neuronal cell line inhibits neuriteoutgrowth [76], an effect that may relate to its interactionswith nesprin-3 [77].

TorsinA has also been linked to striking changes in nuclearmembrane morphology, which may relate to the N-C couplingmachinery. Loss of torsinA function in vivo causes the forma-tion of membranous “blebs” that emerge from the inner nu-clear membrane, and similar structures are seen followingoverexpression of a “substrate-trap” E/Q version of torsinA(see above) [61], in vivo deletion of LAP1 [64], and disruptionof N-C connections [78]. These membranous blebs appearsimilar to those formed during the egress of herpesvirus— aprocess in which torsinA has been implicated [79]. Virusestypically act by usurping normal cellular processes, suggest-ing a function for trans-membrane nuclear transport indepen-dent of the normal nuclear pore-based route. In drosophila,torsinA has been linked to the formation of such structuresimplicated in the transport of ribonucleoprotein granules [80,81], whereas in mouse these torsinA-related structures havebeen linked to the transport of nuclear ubiquitinated nuclearproteins [71].

The ER and NE effects of torsinA are not mutually exclu-sive, and multiple abnormalities of the ER/NE system likelycontribute to the cellular dysfunction underlying DYT1 dys-tonia, especially considering the presence of functionally val-idated torsinA-activating proteins in both compartments.

Effect of the DYT1 Mutation

A seminal question of disease pathogenesis is determiningwhether the DYT1 mutation acts via a gain- or loss-of-

function mechanism. Early studies showed that the ΔE-mutation does not appear to grossly alter torsinA proteinstability or solubility [57]. Further, wild type and ΔE-torsinA show no difference in distribution on a sucrose gradi-ent; both forms are found in a range of fractions, suggestingthat the ΔE mutation does not grossly disturb the ability oftorsinA tomultimerize [57]. Potentially consistent with a gain-of-function mechanism, multiple investigators [20, 57, 60, 82,83] find that overexpressed DYT1-torsinA or another poten-tially disease-related variant [84] concentrate in ER-associatedclumps that are largely or completely segregated from ERmarkers. These immunoreactive clumps of mutant torsinAimmunostaining are not insoluble aggregates [57] and theyappear to include whorled double-membrane structures [60,82]. It is important to note that these structures only form athigh levels of overexpression [20, 59 85] and have not beenobserved in patient or mouse tissues [71, 86, 87]. Thesepoints, and the fact that similar membranous structures formfrom the overexpression of ER membrane proteins [88], sug-gest that the formation of these structures may not reflectproperties of torsinA in vivo at endogenous levels.

In contrast, accumulating evidence—including mouse ge-netic, biochemical and cell biological studies—indicates thatthe DYT1 mutation impairs torsinA function. TorsinA knock-out and homozygous DYT1 knock in mice phenocopy eachother [63], both displaying perinatal lethality and characteris-tic deformities of the neuronal nuclear membrane; these datagenetically define ΔE as a loss-of-function mutation. Bio-chemical studies show that the DYT1 mutation impairs theATPase activity of torsinA [65]. This effect appears related toan intrinsic effect on torsinA protein, as well as by impairingits interaction with LAP1 and LULL1 [65, 89]—proteinsrequired for its enzymatic activity [65]. The DYT1 mutationalso decreases the levels of torsinA protein—an effect ob-served in skin fibroblasts from DYT1 subjects and tissue fromDYT1 knock-in mice [63, 90]. AAA+ proteins function asmultimers, and additional evidence suggests that disease mu-tant torsinA may also act via a dominant-negative mechanism[59, 61, 68]. There are also numerous examples of cell bio-logical effects (including several of those described above)observed when overexpressing wild type torsinA that arereduced or abolished by the DYT1 mutation e.g., [67–69,91]. The recent creation of mouse mutants recapitulating theovert twisting movements that characterize dystonia providefurther evidence for a loss-of-function mechanism [71]. Thisstudy demonstrated that conditional CNS deletion of torsinAor isolated CNS expression of DYT1 mutant torsinA (withoutwild type protein, e.g., Tor1aΔE/– in the CNS) both cause suchovert movement abnormalities and a characteristic histopa-thology involving regions implicated in human DYT1 sub-jects. These findings show that the DYT1 mutation impairstorsinA function in an in vivo context, and link thishypofunction to dystonic-like twisting movements.

Inherited Isolated Dystonia: Clinical Genetics

THAP1 (DYT6)

THAP1 is an atypical zinc finger protein with a highly con-served N-terminal domain, termed THAP, which defines afamily of over 100 proteins in diverse species, including 12proteins in humans. This metal-coordinating domain encodesa DNA-binding domain that recognizes an 11-nucleotide se-quence within the promoters of target genes [92, 93]. Crystal-lization of a drosophila THAP protein indicates that the pro-tein binds DNA through a bipartite interaction, implying thatTHAP1 dimerizes, as is typical of zinc finger transcriptionfactors. Indeed, THAP1 has been demonstrated to dimerize,an interaction that requires a 13-amino acid region of itscoiled-coil domain [94]. As noted above, there are a largenumber of mutations reported to occur across the wholeprotein [95], including some that are recessively inherited.These mutations include early truncations (e.g., at amino acid3) and deletions that disrupt dimerization [94]. The conse-quence of many of the missense mutations is less clear, withsome investigators finding that they disrupt DNA binding [32]whereas others do not observe this effect [96]. Some datasuggest that missense mutations may disrupt the stability ofthe DNA binding domain, or potentially change the specificityof DNA binding [96]. Considered together, it seems over-whelmingly likely that DYT6 mutations act by impairingTHAP1 function.

THAP1 is expressed widely throughout the brain. Similarto torsinA, THAP1 mRNA levels show marked changes dur-ing early postnatal development, attaining stable expression in

mouse brain at about 2 weeks of age [97]. Very little isknown about THAP1 target genes. Only 1 report [98],published prior to the discovery of the connection be-tween THAP1 and DYT6, has explored this question,implicating cell cycle genes of the pRB/E2F pathway. Inthat report, either overexpression or knockdown ofTHAP1 inhibited the proliferation of endothelial cells.Other work suggested an interaction with Par-4 proteinin nuclear PML bodies and found THAP1 overexpres-sion to promote apoptosis in HeLa cells [99]. There areno reports of THAP1 function (or loss-of-function) inneurons, however, which will be essential to determinethe relevance of these studies the pathophysiology ofDYT6 dystonia.

Several reports have explored a connection betweenTHAP1 and other dystonia proteins. Two reports demonstratethat THAP1 can bind the TOR1A promoter [100, 101]; bothfind that DYT6 mutations impair this association. One ofthese studies [100] demonstrated that THAP1 could enhancethe expression of a luciferase reporter linked to the TOR1Apromoter, but no differences in torsinAmRNAor protein wereobserved in fibroblasts derived from DYT6 dystonia subjects.Given its nuclear localization, it is plausible that THAP1 couldinteract with torsinA-related pathways, including via pRB orLAP1, which localize to the inner nuclear membrane bybinding A-type lamins. DYT3 is a form of dystonia knownas X-linked dystonia Parkinsonism, or “Lubag,” and is pre-dominantly seen in Filipino men. THAP1 is also reported tobind O-GlcNAc transferase, a gene present in the DYT3

Fig. 1 Summary of TorsinAFunction and Effects of Loss-of-Function. TorsinA is a AAA +ATPase that likely exists as ahexamer. The DYT1 mutationimpairs torsinA ATPase activity,and may also exert a dominantnegative effect on wild typetorsinA. TorsinA resides in theendoplasmic reticulum/nuclearenvelope (ER/NE) luminal space.The major known functions,interacting proteins, andconsequences of loss-of-functionin the ER (blue box) and NE(yellow box) are listed

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locus, but whether this is indeed the DYT3 gene remains to bedetermined [102].

DYT25 (GNAL)

There are several links between the dysregulation of dopaminesignaling and dystonia, including dopa-responsive dystonia(DYT5) caused by mutations in the genes encoding GTPcyclohydrolase or tyrosine hydroxylase, tardive dystoniacaused by drugs that block dopamine receptors, and the fre-quent occurrence of dystonic movements that complicatelevodopa therapy in Parkinson disease. The relationship ofthese observations (and dopaminergic dysfunction) to primarydystonia has been uncertain, as subjects with primary dystoniado not typically respond to medications that modulate dopa-minergic signaling. The discovery of GNAL mutations inDYT25 are the most direct link between dopamine signalingand primary dystonia (a concept reviewed in detail inGoodchild et al. [103]). GNAL encodes Gαolf—a protein thatplays a critical role in striatal dopamine function, particularlyin transducing signals downstream of D1 dopamine receptorsin the “direct” striatonigral projecting GABAergic

The dopamine receptors (and other G protein-coupled re-ceptors) utilize heterotrimeric G protein complexes to trans-duce signals to downstream effector molecules subsequent todopamine binding. Stimulation of D1-type receptors (D1 andD5) activates a stimulatory G protein complex, leading toupregulation of adenylate cyclase and cAMP generation,whereas stimulation of D2-type receptors (D2, D3, D4) acti-vates an inhibitory G protein complex with opposite effects.GNAL encodes Gαolf (so named because it was identified inolfactory neurons), a G protein that is ~80% identical in aminoacid sequence with GαS—the predominant CNS stimulatoryG protein [104]. While GαS mediates stimulatory responsesthroughout the brain, this protein is essentially replaced in thestriatum by the homologous Gαolf, which is expressed in bothdirect (dopamine receptor D1 expressing) and indirect (dopa-mine receptor D2 expressing) neurons, as well as in choliner-gic interneurons [105, 106].

Most work has focused on the role of Gαolf in D1 signaling(in “direct” pathway striatonigral neurons), but it also trans-duces signals downstream of adenosine 2A receptors (A2A) in“indirect” pathway striatopallidal neurons [105]; its functionin cholinergic neurons is poorly defined, but potentially crit-ical considering role of these cells in primary dystonia [107].Characterization of Gαolf null mice has established key rolesfor this protein in D1-mediated molecular and behavioralresponses. Gαolf null mice are hyperactive at baseline, impli-cating loss of Gαolf with a hyperkinetic state [108]. Thesemice show marked deficiencies in locomotor and molecularresponses linked to D1 activation, including a blunted increasein movement to D1 agonists or acute cocaine, and reducedactivation of cAMP, PKA, ERK or c-fos [109–111] following

D1 treatment. This link to D1 signaling is particularly intrigu-ing considering that D1 hypersensitivity is strongly implicatedin L-dopa induced dyskinesias in Parkinson disease in con-nection with abnormal plasticity [112]—a pathogenic mecha-nism thought to be important in the pathogenesis of primarydystonia [113–114]. The connection to D1 signaling is com-plex, however, as comparisons between heterozygous Gαolf

(representing the likelymolecular situation in DYT25) and D1dopamine receptor mice show several interesting differencesat the molecular and behavioral level. For example, Gαolf

heterozygous mice show a decreased behavioral responseand cAMP increase to cocaine or D-amphetamine, whereassimilar behavioral changes are not observed in D1 receptorheterozygous mice [106, 111]. These and related differences(reviewed in detail in Herve [104]), and the role of Gαolf inA2A signaling and in cholinergic neurons, highlight the needfor further studies identifying which of these roles (or combi-nation of effects) is key for dystonia pathogenesis.

Conclusion

There are several reasons for optimism that the next severalyears will witness accelerated progress in our understandingof the pathophysiology of inherited isolated dystonia, in-cluding the identification of cellular mechanisms or specificmolecules that are rational therapeutic targets. The identifi-cation of GNAL provides a specific target of investigationfor the large group of investigators actively studying striatalneurotransmission. The identification of THAP1 is likely toyield clear molecular pathways involved in DYT6, asstraightforward and practical strategies exist for the identi-fication of transcription factor target genes, and such stud-ies are benefiting tremendously from rapid advances ingenetic technologies (e.g., Chip-Seq). Moreover, the devel-opment of the first mouse model based on one of thesegenes (torsinA) with overt abnormal movements will enablea range of studies not previously possible. As these lines ofwork gain momentum, it will be particularly important andinteresting to explore whether these genes function in acommon molecular pathway. Presently, there is no convinc-ing data to suggest this is the case, though future studiesmay reveal that distinct molecular effects may neverthelessyield a common cellular or circuit defect around whichinvestigators could focus therapeutic efforts.

Acknowledgments I thank Ric Liang for his assistance with figurepreparation. I also thank Drs. Stanley Fahn and Susan Bressman for theirmentorship and initially introducing me to dystonia research. This work wassupported by a grant to W.D. from the National Institute of NeurologicalDisorders and Stroke (1R01NS077730).

Inherited Isolated Dystonia: Clinical Genetics

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