Alternative titles; symbols
HGNC Approved Gene Symbol: TOR1A
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:129,812,942-129,824,136 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | {Dystonia-1, modifier of} | 3 | ||
| Arthrogryposis multiplex congenita 5 | 618947 | Autosomal recessive | 3 | |
| Dystonia-1, torsion | 128100 | Autosomal dominant | 3 |
Torsin-1A is a member of the AAA family of adenosine triphosphatases (ATPases), associated with diverse cellular activities (Konakova et al., 2001).
Ozelius et al. (1997) constructed a cosmid contig spanning the region of chromosome 9 to which early-onset torsion dystonia (128100) had been mapped. Using exon trapping and identification of cDNAs encoded in this region, and mutational screening by SSCP and sequence analysis of cDNA and genomic DNA from affected individuals and controls, they identified the TOR1A gene. The deduced protein, termed 'torsinA' by them, comprises 332 amino acids and has a calculated molecular mass of 37,813 Da. It contains an ATP-binding domain and a putative N-terminal leader sequence. TOR1A has high homology to 3 additional mammalian genes and a nematode gene and distal similarity to the family of heat-shock proteins and the Clp protease family. Northern blot analysis detected 2 ubiquitously expressed transcripts of 1.8 kb and 2.2 kb and an additional low-abundance transcript of 5 kb in fetal brain, lung, and kidney, as well as in adult brain, heart, and pancreas.
Using an mRNA probe for DYT1 in normal human postmortem brains, Augood et al. (1998) found high expression in melanized neurons of the pars compacta of the substantia nigra, as well as in the cerebellum and the dentate gyrus and stratum pyramidal of CA3.
Using polyclonal antibodies directed against human torsin-A and torsin-B (608050), Konakova et al. (2001) analyzed the expression of the proteins in normal human brain regions and found widespread neuronal distribution. Areas of intense labeling included the dentate nucleus and Purkinje cells of the cerebellum, all layers of the cerebral cortex, all subfields of the hippocampus, particularly CA3, the thalamus, the spinal cord, and the midbrain, and there was weak labeling in the substantia nigra. Staining was predominantly cytoplasmic, but also extended into the axons, dendrites, and neuropil. Glial cells showed no expression of the proteins. Torsin-B showed a similar pattern of expression, but was found to have some polarization toward the cell edge, and was detected in the pigmented cells of the substantia nigra. Both proteins were present at high levels in regions not affected by disease (cortex, cerebellum, spinal cord). Konakova et al. (2001) noted that the staining pattern was granular and present in the neuronal processes, suggesting a role in regulating neurotransmitter release.
Goodchild and Dauer (2004) found that delE302/303 (605204.0001) torsin-A protein predominantly localized to the nuclear envelope in neurons of transgenic mice carrying the mutation, in transfected cultured hamster fibroblasts, and in fibroblasts from dystonia patients with the mutation. Electron microscopy further localized mutant torsin-A protein to the perinuclear space. In contrast, most wildtype torsin-A localized to the endoplasmic reticulum, with lesser amounts of protein localized to the nuclear envelope. Transfection of mutant protein into cells with wildtype protein resulted in relocalization of wildtype protein to the nuclear envelope. Goodchild and Dauer (2004) concluded that wildtype torsin-A has a role at the nuclear envelope and suggested that the mutant protein exerts a dominant effect by recruiting wildtype torsin-A to the nuclear envelope.
To probe torsin-A's normal cellular function, Naismith et al. (2004) used torsin-A mutants with defects in ATP hydrolysis (ATP bound) and ATP binding (ATP free). Surprisingly, ATP-bound torsin-A was recruited to the nuclear envelope of transfected cells, where it altered connections between inner and outer nuclear membranes. In contrast, ATP-free torsin-A was diffusely distributed throughout the endoplasmic reticulum and had no effect on the nuclear envelope. Among the AAA (ATPases associated with various cellular activities) family of ATPases, affinity for substrates is high in the ATP-bound and low in the ATP-free state, which led Naismith et al. (2004) to propose that one or more components of the nuclear envelope may be substrates for torsin-A. They also found that the disease-promoting delE302/303 mutant (605204.0001) is in the nuclear envelope, and that this relocalization, as well as the mutant's previously described ability to induce membranous inclusions (Hewett et al., 2000), is eliminated by the ATP-binding mutation. These results suggested that changes in interactions involving torsin-A in the nuclear envelope could be important for the pathogenesis of dystonia and pointed to torsin-A and related proteins as a class of ATPases that may operate in the nuclear envelope. Thus, torsion dystonia-1 may be one of a group of diseases associated with defects in nuclear membrane structure and function.
Goodchild and Dauer (2005) found that mouse torsin-1A interacted with both Lap1 (TOR1AIP1; 614512) and Lull1 (TOR1AIP2; 614513) in transfected baby hamster kidney (BHK) cells. Torsin-1A with an ATPase-inactivating mutation or the delta-E mutation (605204.0001) showed enhanced interaction with Lap1 and Lull1. Mutation analysis revealed that the C-terminal luminal domain of Lap1 or Lull1 was required for interaction with torsin-1A. Interaction of torsin-1A with Lap1 resulted in recruitment of torsin-1A to the nuclear envelope in BHK cells. Recruitment by Lap1 was enhanced with ATPase-dead or delta-E torsin-1A.
Hewett et al. (2007) found that fibroblasts from DYT1 patients secreted markedly less Gaussia luciferase, a naturally secreted luciferase, than control fibroblasts. Mouse embryonic fibroblasts lacking torsin-A also displayed reduced secretion, suggesting that loss of torsin-A may explain the reduced secretory activity and that torsin-A acts as an endoplasmic reticulum chaperone protein.
By yeast 2-hybrid analysis of a rat brain cDNA library, Giles et al. (2009) showed that N-terminally truncated torsin-A interacted with rat printor (KLHL14; 613772). Immunohistochemical analysis confirmed interaction of endogenous torsin-A with printor in mouse cerebellum homogenates. Using mutant torsin-A proteins, Giles et al. (2009) found that printor interacted predominantly with the ATP-free form of torsin-A. ATP binding by torsin-A induced its dissociation from printor and its translocation from the endoplasmic reticulum to the nuclear envelope. Torsin-A with the delta-E mutation (605204.0001) associated with early-onset generalized dystonia failed to interact with printor.
Using mild detergent extraction of human osteosarcoma cells, followed by BN-PAGE, Vander Heyden et al. (2009) found that TOR1A migrated as a hexameric species. Overexpression of LULL1 in human osteosarcoma cells did not alter the oligomeric structure of TOR1A, but it caused redistribution of TOR1A and a smaller portion of LULL1 from the ER to the nuclear envelope. Accumulation of TOR1A caused distortion of the nuclear envelope and displacement of SUN2 (613569), nesprin-2 (SYNE2; 608442), and nesprin-3 (610861), but not SUN1 (607723), from the nuclear envelope. LULL1 also caused redistribution of TOR1A with the delta-E mutation toward the nuclear envelope, but mutant TOR1A did not cause distortion of the nuclear envelope and was less efficient in displacing SUN2. Mutation analysis revealed that the N terminus of TOR1A was required for interaction of TOR1A with LULL1.
In HeLa cells and human neuroblastoma (SH-SY5Y) cells, Kaiser et al. (2010) demonstrated that the THAP1 (609520) protein binds to the promoter of TOR1A and suppresses promoter activity in a concentration-dependent manner. A THAP-binding site was found in the TOR1A promoter. DYT6 (602629)-associated THAP1 mutations abolished THAP1-mediated repression of TOR1A in these cells, but knockdown of THAP1 in fibroblasts from individuals both with and without a THAP1 mutation showed no change in TOR1A expression. The lack of effect on TOR1A protein levels in fibroblasts and lymphocytes was confirmed by Western blot analysis. The authors suggested that interaction between THAP1 and TOR1A observed in in vitro studies may be specific to nerve cells or brain tissue, or be subject to developmental regulation. Kaiser et al. (2010) suggested that TOR1A is a target for the transcription factor activity of THAP1, suggesting a molecular link between DYT1 and DYT6.
Torsin-A is 1 of 4 predicted mammalian torsin ATPases associated with assorted cellular activities (AAA+) proteins, raising the possibility that expression of a functionally homologous torsin compensates for torsin-A loss in nonneuronal tissues. Jungwirth et al. (2010) reported that all 4 mammalian torsins were endoplasmic reticulum resident glycoproteins. Torsin-A, torsin-B (TOR1B; 608050), and torsin-2 (TOR2A; 608052) were all present in large relative molecular mass complexes, suggesting that each may assemble into an oligomeric AAA+ enzyme. Introducing a mutation that typically stabilizes AAA+ proteins in a substrate-bound state caused torsin-A and torsin-B to associate with a shared nuclear envelope (NE) binding partner, and this NE localization required the torsin-A interacting protein lamina-associated polypeptide-1 (LAP1, also known as TOR1AIP1). Although torsin proteins are widely expressed in the adult mouse, embryonic neuronal tissues contain relatively low torsin-B levels. The authors concluded that torsin-B expression inversely correlated with the cell and developmental requirement for torsin-A, and that multiple cell types appear to utilize torsin AAA+ proteins. They proposed that differential expression of torsin-B may contribute to both the neuronal specific importance of torsin-A and the symptom specificity of DYT1 dystonia.
Using transgenic C. elegans expressing wildtype or mutant human TOR1A, Chen et al. (2010) showed that wildtype TOR1A protected worms against ER stress caused by exposure to tunicamycin or dithiothreitol. TOR1A-mediated protection involved reduced generation of the activated alternative isoform of the unfolded protein response protein Xbp1 (194355). Mutation analysis revealed that both ER localization and ATPase activity of TOR1A were required for the protective effect. In contrast with wildtype TOR1A, expression of TOR1A with the delta-E mutation in worms induced an ER stress response, even in the absence of additional stressors. Furthermore, expression of delta-E TOR1A with wildtype TOR1A in worms abrogated the protective effect of wildtype TOR1A against tunicamycin- or dithiothreitol-induced ER stress. Tor1a -/- mouse embryonic fibroblasts (MEFs) were more sensitive than wildtype MEFs to ER stress induced by either dithiothreitol or tunicamycin. In addition, Tor1a -/- MEFs showed an elevated basal stress response, including elevated Bip (HSPA5; 138120) expression. Chen et al. (2010) concluded that TOR1A is a homeostatic regulator of the ER stress response.
Torsion Dystonia 1, Autosomal Dominant
Ozelius et al. (1997) found a heterozygous 3-bp deletion in the DYT1 gene (E302/303del; 605204.0001) in all affected and obligate carrier individuals with chromosome 9-linked primary torsion dystonia (DYT1; 128100), regardless of ethnic background and surrounding haplotype. The deletion resulted in loss of 1 of a pair of glutamic acid residues; GAG was deleted from a GAGGAG sequence that is conserved in all human, rat, and mouse torsin-A and torsin-B transcripts, suggesting that it is part of a functional domain. From analysis of 3 new single-basepair polymorphisms in a 5-kb region surrounding the GAG deletion, Ozelius et al. (1997) concluded that the same mutation must have arisen more than once. The finding of the same 3-bp mutation in heterozygous state in most cases of typical early-onset dystonia is comparable to the few examples of the same recurrent mutation causing other dominantly inherited conditions. These include the FGFR3 mutation responsible for almost all cases of achondroplasia (134934.0001) and the loss of a positively charged arginine in the fourth transmembrane helix of the alpha-1 subunit of the L-type voltage-sensitive calcium channel (CACNA1S; 114208.0001), which Ozelius et al. (1997) noted was the only type of mutation found thus far to cause hypokalemic periodic paralysis (170400). In these cases, as well as in the case of the CAG expansions in the coding regions of a number of genes causing neurodegenerative diseases (e.g., Huntington disease, 143100), the same mutations occurred repeatedly as independent events, whereas other mutations in the same gene cause a different syndrome, have no phenotype, or are incompatible with life.
Friedman et al. (2000) excluded the GAG deletion in the DYT1 gene as the cause of focal dystonia among 18 musicians with the disorder, including 2 affected sisters. A total of 5 (29%) patients reported a family history of tremor or dystonia.
Heiman et al. (2004) administered a standard psychiatric interview to 96 manifesting carriers of the DYT1 GAG deletion mutation (605204.0001), 60 nonmanifesting carriers of the mutation, and 65 noncarriers. The risk for early-onset (before 30 years) recurrent major depression (see 608516) was increased in both manifesting mutation carriers (relative risk of 3.62) and nonmanifesting mutation carriers (relative risk of 4.95) compared to noncarriers. The severity of dystonia in manifesting carriers was not associated with the likelihood of major depression, and mutation carriers did not have an increased risk for other affective disorders. Heiman et al. (2004) concluded that early-onset recurrent major depression is a clinical expression of the DYT1 gene mutation that is independent of dystonia. In an accompanying commentary, Richard and McDonald (2004) noted that the DYT1 gene is likely involved in dopamine release or turnover and that the findings of Heiman et al. (2004) suggested a link between basal ganglia disease and depression. The authors noted that other basal ganglia diseases, including Parkinson disease (168600), Huntington disease (143100), and caudate stroke are associated with high rates of depression.
Clarimon et al. (2005) presented evidence suggesting an association between a torsin-A haplotype and the development of sporadic idiopathic dystonia in Iceland. The haplotype associated with dystonia included single-nucleotide polymorphisms (SNPs) 246G/A (rs2296793), 191G/T (rs1182) and a 1-bp deletion (G) in a muscle-specific Mt binding site (SNP MtDEL). Among 223 German patients with sporadic dystonia, Hague et al. (2006) found no disease association with the haplotype reported by Clarimon et al. (2005) in Icelandic patients.
Among 243 individuals with sporadic dystonia from southern Germany and Austria, Kamm et al. (2006) reported a significant association between the disorder and a C/T SNP (rs13283584; p = 0.000008) located centromeric to the TOR1A gene between the 3-prime untranslated regions of TOR1A and TOR1B (608050), and a C/A SNP (rs1182; p = 0.00001) within the TOR1A 3-prime untranslated region.
Kock et al. (2006) used the structure of the related bacterial heat-shock protein ClpB (616254) to provide a model of the AAA+ domain of torsin-A. Motifs important for ATP hydrolysis (sensor 1 and sensor 2) were identified, mutagenized, and used to validate predictions of this model. The delGAG mutation (605204.0001) associated with dystonia removes 1 residue from an alpha-helix in the C-terminal portion of the AAA+ domain, possibly resulting in misfolding, endoplasmic reticulum (ER)-derived inclusions, and loss of function. The D216H polymorphism (605204.0003), which has an allele frequency of 0.12, falls in the N-terminal portion of the AAA+ domain near the sensor 1 motif. Cells expressing torsinA with H216 developed inclusions similar to those associated with delGAG-torsinA. However, introducing H216 into delGAG-torsinA reduced its tendency to form inclusions, suggesting that the 2 changes offset each other. The authors suggested a possible connection between D216H and the penetrance of DYT1 dystonia.
Although a GAG deletion in the DYT1 gene (605204.0001) is the major cause of early-onset dystonia, expression as clinical disease occurs in only 30% of mutation carriers. To gain insight into genetic factors that may influence penetrance, Risch et al. (2007) evaluated 3 DYT1 SNPs including D216H (605204.0003), a coding-sequence variation that moderates the effects of the DYT1 GAG deletion in cellular models. The D216H polymorphism encodes aspartic acid (D) in 88% and histidine (H) in 12% of control-population alleles (Ozelius et al., 1997: Leung et al., 2001). Risch et al. (2007) tested 119 DYT1 GAG-deletion carriers with clinical signs of dystonia and 113 mutation carriers without signs of dystonia as well as 197 control individuals; they found a frequency of the 216H allele to be increased in GAG-deletion carriers without dystonia and to be decreased in carriers with dystonia, compared with the control individuals. Analysis of haplotypes demonstrated a highly protective effect of the H allele in trans with the GAG deletion; there was also suggestive evidence that the D216 allele in cis is required for the disease to be penetrant. The findings established, for the first time, a clinically relevant gene modifier of DYT1.
Giles et al. (2008) found that wildtype torsin-A showed enhanced and preferential localization to the nuclear envelope in cultured human neuronal cells compared to nonneuronal HeLa cells, in which torsin-A showed preferential localization to the endoplasmic reticulum. Similar experiments with mutant torsin-A (605204.0001 and 605204.0002) showed increased translocation from the ER to the nuclear envelope in neuronal cells, but not in nonneuronal cells. The ability of mutant proteins to oligomerize with wildtype torsin-A was not affected in neuronal cells. However, both mutant proteins were less stable than wildtype torsin-A, suggesting accelerated degradation. Inhibition studies indicated that wildtype torsin-A was degraded through the autophagy-lysosome pathway only, whereas the mutant proteins were degraded by both the proteasome and autophagy-lysosome pathways. Giles et al. (2008) suggested that the nuclear envelope in neuronal cells may be particularly susceptible to torsin-A dysfunction and that mutations in the DYT1 gene confer a loss of function.
Arthrogryposis Multiplex Congenita 5
In 4 patients from 3 unrelated consanguineous Iranian families with arthrogryposis multiplex congenita-5 (AMC5; 618947), Kariminejad et al. (2017) identified homozygous mutations in the TOR1A gene (E303del, 605204.0001 and G318S, 605204.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all 3 families. None of the carrier parents had evidence of torsion dystonia, consistent with incomplete penetrance of the dominant phenotype.
In a 7-month-old boy, born of Mexican parents, with AMC5, Reichert et al. (2017) identified compound heterozygous mutations in the TOR1A gene (605204.0001 and 605204.0007). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
In a 4.5-month-old boy, born of reportedly unrelated Bulgarian parents, with AMC5, Isik et al. (2019) identified a homozygous nonsense mutation in the TOR1A gene (R288X; 605204.0008). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The infant died of cardiorespiratory failure.
Caldwell et al. (2003) established a model system for torsin activity in C. elegans. Using an in vivo assay for polyglutamine repeat-induced protein aggregation, the authors determined that ectopic overexpression of both human and C. elegans torsin proteins results in a dramatic reduction of polyglutamine-dependent protein aggregation, in a manner similar to that reported for molecular chaperones. The suppressive effects of torsin overexpression persisted as animals aged, whereas a mutant nematode torsin protein was incapable of ameliorating aggregate formation. Antibody staining of transgenic animals indicated that both the C. elegans torsin-related protein TOR2 and ubiquitin (UBB; 191339) were localized to sites of protein aggregation. The authors proposed a role for torsins in managing protein folding, and suggested that breakdown in a neuroprotective mechanism that is, in part, mediated by torsins may be responsible for the neuronal dysfunction associated with dystonia.
Koh et al. (2004) established a Drosophila model of early-onset torsion dystonia. Expression of human delE302/303 mutant but not normal torsin-A elicited locomotor defects in Drosophila. As in mammalian systems, delE302/303-mutant flies formed protein accumulations that localized to synaptic membranes, nuclei, and endosomes. Electron microscopy detected various morphologic defects at the neuromuscular junction in larvae, some of which resemble those reported for mutants with defects in TGF-beta (190180) signaling, suggesting that Dyt1 mutations may interfere with some aspect of TGF-beta signaling from synapses to endosomes or nuclei. Consistent with this possibility, neuronal overexpression of Drosophila or human SMAD2 (601366), a downstream effector of the TGF-beta pathway, suppressed the behavioral and ultrastructural defects of delE-mutant flies. Koh et al. (2004) hypothesized that a defect in TGF-beta signaling might also underlie early-onset torsion dystonia in humans.
Shashidharan et al. (2005) generated 4 independent lines of transgenic mice by overexpressing human delE-torsin-A using a neuron-specific enolase promoter. Approximately 40% of the transgenic mice developed abnormal involuntary movements with dystonic-appearing self-clasping of limbs, hyperkinesia, and rapid bidirectional circling. Neurochemical analyses revealed decreased striatal dopamine in affected transgenic mice, and immunohistochemical studies demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin (UBB; 191339), torsin-A, and lamin (LMNA; 150330). Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to that described in DYT1 patients.
Gonzalez et al. (2018) found that about 30% of Tor1a -/- mouse embryos had macroscopic brain defects, including exencephaly. Morphologic defects first appeared in Tor1a -/- mice around embryonic day-11.5 (E11.5), with earlier development appearing normal. At E11.5, Tor1a -/- mice produced more radial glia neural progenitor cells, and proliferative zones were abnormally large and contained cytoarchitectural defects, including mislocalized and elevated numbers of mitotic nuclei, compared with controls. At E14.5, Tor1a -/- embryos had excess neuronal production in brain. Radial glial cells failed to perform normal behaviors that depended on apicobasal polarity and caused breakdown of proliferative zone cytoarchitecture, leading to development of morphologically abnormal brain. Proliferative zones of Tor1a -/- embryos were enriched with nuclear envelope linker of nucleoskeleton and cytoskeleton (LINC) complex proteins normally rare in these cells, resulting in multiple defects in radial glial cell organization and behavior. Reduction in LINC complex levels via Sun2 (613569) deletion prevented morphologic and radial glial defects in Tor1a -/- mouse embryos, suggesting that excess LINC complexes caused morphologically abnormal brain development in Tor1a -/- mice.
Cascalho et al. (2020) found that lipin (LPIN1; 605518) phosphatidic acid phosphatase (PAP) activity was increased in brains of 4 different mouse models of recessive Tor1a disease, as well as in human DYT-TOR1A patient cells. Genetic reduction of Lpin1 improved survival and suppressed neurodegeneration, motor dysfunction, and nuclear membrane pathology in mouse models of recessive Tor1a disease. The authors concluded that TOR1A disease mutations cause abnormal PAP metabolism, suggesting that suppression of lipin PAP activity may be therapeutically useful for TOR1A disease.
Torsion Dystonia 1, Autosomal Dominant
In cases of early-onset torsion dystonia (DYT1; 128100), Ozelius et al. (1997) identified a heterozygous 3-bp deletion, GAG (delE302/303), resulting in the loss of 1 of a pair of conserved glutamic acid residues in a novel ATP-binding protein termed torsin-A. The GAG deletion was the only mutation detected in a large number of patients from different ethnic backgrounds. Most (90%) patients with an atypical presentation had no identifiable mutation in the DYT1 gene. At least 4 different background haplotypes were observed with the GAG deletion, indicating that the mutation had arisen more than once to cause ITD. Given the highly variable phenotype and reduced penetrance observed in ITD, the identification of the DYT1 mutation was a major advance for accurate diagnosis of the disorder.
Because this mutation deletes one of 2 contiguous glutamic acid codons of the DYT1 gene, Goodchild and Dauer (2004) and Naismith et al. (2004) referred to it as delE302/303.
Ikeuchi et al. (1999) described the apparently sporadic occurrence of primary torsion dystonia in a 25-year-old Japanese man who first noted at age 13 years that his left shoulder occasionally turned involuntarily to the left. By age 16 years his neck also became involved, twisting involuntarily to the left like his shoulder. He showed moderate improvement with diazepam (20 mg) and trihexyphenidyl (18 mg). Neither parent and none of the 4 grandparents showed any movement disorder or complained of writer's cramp. Nucleotide sequence analysis detected the GAG deletion in the patient's DYT1 gene. Restriction fragment length polymorphism (RFLP) analysis using BseRI showed that the GAG deletion was present not only in the patient but also in his mother, but not in his father.
Kamm et al. (1999) examined 57 patients with idiopathic torsion dystonia for the 3-bp GAG deletion in the DYT1 gene. Three of 5 patients with early limb-onset torsion dystonia, one of them with a positive family history, tested positive for the mutation, as did 1 young patient with multifocal dystonia and a short course of the disease. Two patients with early-onset generalized dystonia beginning in the cervical muscles, as well as 5 other patients with multifocal, 14 patients with segmental, and 30 patients with focal cervical dystonia did not carry the mutation. This suggested that the GAG deletion is responsible for most cases of typical early limb-onset dystonia, but not for other types of dystonia, in the German population studied.
Hjermind et al. (2002) performed mutation analysis for the GAG deletion in the DYT1 gene in 107 unrelated Danish probands with primary torsion dystonia (37 were known familial cases). Clinical examinations showed that 22 probands had generalized dystonia (20 of whom had early limb-onset), 2 had hemidystonia, 5 had multifocal dystonia, 15 had segmental dystonia, and 63 had focal dystonia. Among the 107 probands investigated, the GAG deletion was only detected in 3 (2.8%) in whom the phenotype was typical. This corresponded to 15% of the 20 probands with early limb-onset generalized dystonia. Of the 3 probands with the GAG deletion, only 1 had familial dystonia, with the mutation detected in the affected father and in 6 asymptomatic adult relatives. In the second proband the DYT1 mutation was also encountered in the asymptomatic mother, while in the third case none of the parents had the GAG deletion and therefore represented a de novo mutation.
Ikeuchi et al. (2002) studied 6 unrelated Japanese pedigrees with dystonia due to the GAG deletion in the DYT1 gene. None of the haplotypes in these families shared strong similarity to the Ashkenazi Jewish haplotype, suggesting that the GAG deletion occurred independently in the Japanese population. Some sharing was observed among haplotypes of the Japanese families, but there was nonetheless an indication of multiple independent events resulting in the deletion in these pedigrees.
Among 256 patients with various subtypes of dystonia, Grundmann et al. (2003) identified 6 patients (2%) with the GAG deletion in the DYT1 gene. Two patients had classic features of early-onset primary generalized dystonia, 2 had multifocal dystonia (1 with involvement of cranial and cervical muscles), and 2 had only writer's cramp with slight progression. Apart from 1 patient with onset at 41 years, the mean age at onset was 9 years. Grundmann et al. (2003) emphasized the wide range of phenotypic variability caused by this DYT1 mutation.
Wong et al. (2005) described a 10-year-old boy with the DYT1 deletion who had an unusual clinical presentation. At age 4 years, he presented with stiffness of the left ankle that progressed to the other leg. A year later he developed severe, painful myoclonic muscle spasms that were either spontaneous or precipitated by changes in posture, loud noises, or emotional upset, and were associated with profuse sweating. During these episodes, there was extreme truncal and limb stiffness and rigidity. EMG showed continuous motor unit activity during muscle spasms, suggestive of stiff-person syndrome (SPS; 184850), but no anti-GAD65 (138275) antibodies were found. He soon developed progressive dystonia and was wheelchair-bound by age 7 years. The patient experienced clinical improvement following plasmapheresis, which was unexplainable to the authors. His asymptomatic mother had the same DYT1 deletion, and a 13-year-old sister had type 1 diabetes mellitus (T1D; 222100) and was positive for anti-GAD65 antibodies. Wong et al. (2005) suggested a diagnosis of 'stiff-child syndrome,' but also considered that the patient may have had a phenotypic variation of primary torsion dystonia. Greene and Dauer (2006) suggested that the patient reported by Wong et al. (2005) had a severe form of DYT1 dystonia with painful limb dystonia.
Arthrogryposis Multiplex Congenita 5
In 2 unrelated girls, each born of consanguineous Iranian parents (families 2 and 3), with arthrogryposis multiplex congenita-5 (AMC5; 618947), Kariminejad et al. (2017) identified a homozygous 3-bp deletion (c.907_909del) in the TOR1A gene, resulting in the deletion of glu303 (E303del). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant is present in heterozygous state only in 30 of 282,658 alleles in the gnomAD database. None of the carrier parents had evidence of torsion dystonia, consistent with incomplete penetrance of the dominant phenotype. Functional studies of the variant and studies of patient cells were not performed.
For discussion of the E303del mutation in the TOR1A gene, that was found in compound heterozygous state in a patient with AMC5 by Reichert et al. (2017), see 605204.0007.
Variant Function
Hewett et al. (2000) overexpressed wildtype and mutant (GAG-deleted) torsin-A in mouse neural CAD cells and observed the distribution pattern of the proteins by immunocytochemistry. The wildtype protein was found throughout the cytoplasm and neurites with a high degree of colocalization with the endoplasmic reticulum (ER) marker, protein disulfide isomerase. In contrast, the mutant protein accumulated in multiple, large inclusions in the cytoplasm around the nucleus. These inclusions were composed of membrane whorls, apparently derived from the ER. The authors hypothesized that if disrupted processing of the mutant protein leads to its accumulation in multilayer membranous structures in vivo, these may interfere with membrane trafficking in neurons.
Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of 1 glutamic acid in the carboxyl terminus of the torsin-A protein. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wildtype protein. There is evidence that dysfunction of the dopamine system is implicated in the development of EOTD. Torres et al. (2004) studied the biologic function of torsin-A and its relation to dopaminergic neurotransmission. They showed that torsin-A can regulate the cellular trafficking of the dopamine transporter (126455), as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsin-A. The delta-Glu mutant causing dystonia did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in delta-Glu-torsin-A reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of the wildtype torsin-A through a mechanism presumably involving association of wildtype and mutant protein. Taken together, these results provided evidence for a functional role of torsin-A and for a loss of function and a dominant-negative phenotype of the delta-Glu-torsin-A mutation. These properties may contribute to the autosomal dominant nature of EOTD.
Chen et al. (2010) showed that expression of human TOR1A with the delta-E mutation in C. elegans induced an ER stress response, even in the absence of additional stressors. Furthermore, expression of delta-E TOR1A with wildtype TOR1A in worms abrogated the protective effect of wildtype TOR1A expression against tunicamycin- or dithiothreitol-induced ER stress.
In vitro cellular expression studies by Hettich et al. (2014) indicated that the delE303 mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, decreased neurite extension, and caused vacuolization and morphologic changes in the endoplasmic reticulum and nuclear envelope compared to wildtype.
This variant, formerly titled DYSTONIA, EARLY-ONSET ATYPICAL, WITH MYOCLONIC FEATURES, has been reclassified based on the findings of Klein et al. (2002) and Doheny et al. (2002).
In a patient with early-onset dystonia (128100) and myoclonic features, Leung et al. (2001) found an 18-bp deletion in heterozygous state in the DYT1 gene. The deletion in exon 5, which was detected by SSCP and confirmed by sequencing, resulted in loss of amino acids phe323 through tyr328 in the C terminus of torsin-A. In addition to the proband, her brother, mother, and maternal grandfather also carried this 18-bp deletion in heterozygous state. These other carriers showed possible neurologic features related to dystonia and myoclonus, but the father of the patient, who lacked the deletion, was also said to have possible myoclonus. The findings were interpreted as consistent with autosomal dominant transmission of early-onset atypical dystonia in this family with reduced penetrance.
In the 2 affected sibs of the family reported by Leung et al. (2001), Klein et al. (2002) identified a 587T-G missense mutation in exon 5 of the SGCE gene, resulting in a leu196-to-arg substitution (L196R; 604149.0006). The SGCE missense change was not detected in 500 control chromosomes and the DYT1 deletion was absent in 3,000 controls. The sibs had inherited the DYT1 deletion from their mother, who showed dystonic features, and the SGCE mutation from their father, who showed myoclonic features. Due to the SGCE mutation and the phenotypic dystonic and myoclonic features of both sibs, Klein et al. (2002) suggested that the family may in fact have myoclonus-dystonia syndrome (159900). Doheny et al. (2002) described the clinical features of this family in greater detail. The proband had onset at age 5 years of myoclonic jerky movements of the legs and arms, which later progressed to the head, and dystonic features. Psychiatric evaluation revealed depression and anxiety. Her brother had onset of motor jerks at age 6 years, which later developed into multifocal myoclonus at rest, and dystonic posturing. Psychiatric evaluation revealed depression, anxiety and panic disorders, attention deficit disorder, and alcoholism. The mother, who carried the DYT1 mutation, had intermittent lip puckering, neck stiffness, tremulous voice, clumsiness, involuntary toe movements, and posttraumatic stress disorder after the death of her mother. No myoclonus was noted. The father, who carried the SGCE mutation, had occasional jerking of the upper limbs and action tremor. Psychiatric history was negative. The maternal grandfather, who carried the DYT1 mutation, reportedly had lip puckering and tremulous voice, as well as depression, anxiety and panic disorders, and post-traumatic stress disorder. Doheny et al. (2002) noted that the clinical picture in this family is unique and that the contributions of each mutation to the clinical phenotype could not definitively be determined. See also Furukawa and Rajput (2002).
Risch et al. (2007) found the frequency of a SNP in the DYT1 coding region, a C-to-G transversion in exon 4 (rs1801968) resulting in an asp216-to-his substitution (D216H), to be increased in GAG deletion (605204.0001) carriers without dystonia (128100) and decreased in carriers with dystonia, compared with control individuals. The allele frequency difference of the 216H allele between nonmanifesting carriers and manifesting carriers was highly significant (chi square = 22.55; P less than 0.000002). Analysis of haplotypes demonstrated a highly protective effect of the H allele in trans with the GAG deletion; there was also suggestive evidence that the D216 allele in cis is required for the disease to be penetrant. The D216H polymorphism encodes aspartic acid (D) in 88% and histidine (H) in 12% of control-population alleles (Ozelius et al., 1997: Leung et al., 2001).
Kamm et al. (2008) found that none of 42 symptomatic patients from 35 European families with dystonia carried the D216H variant, whereas 6 (12.5%) of 48 chromosomes from 24 asymptomatic mutation carriers had the D216H SNP. The findings indicated that deletion carriers with the his216 allele have a greatly reduced risk of developing symptoms of dystonia: the disease penetrance of those with the his216 allele is about 3% compared to about 35% in deletion carriers with the asp216 allele. The authors noted that although the his216 allele is generally rare, with a maximum frequency of 19% in Europeans, it should be included in molecular genetic testing for the disorder.
Chen et al. (2010) showed that expression of human TOR1A containing his216 in C. elegans elevated the ER stress response to tunicamycin. However, expression of TOR1A containing his216 in trans with either wildtype TOR1A or TOR1A with the delta-E mutation (605204.0001) greatly reduced the stress response and returned protection to the level exhibited by wildtype TOR1A alone.
In a man with late-onset focal torsion dystonia (DYT1; 128100) of the oromandibular region, Calakos et al. (2010) identified a heterozygous 613T-A transversion in exon 3 of the TOR1A gene, resulting in a phe205-to-ile (F205I) substitution in a highly conserved residue in the beta-strand motif in the AAA domain. The mutation was not found in 1,600 control chromosomes. The patient had onset of involuntary jaw movements and grimacing in his fifth decade. Neurologic examination showed cogwheel tone without rigidity and mild action tremor in the upper limbs, as well as absent ankle reflexes. He had a history of bipolar disorder, treatment with lithium, and remote history of treatment with a dopamine receptor blocking agent. There was a family history of tremor and depression, but no family history of dystonia. In vitro functional expression studies in cultured cells showed that the F205I-mutant protein produced TOR1A inclusion bodies that colocalized with the endoplasmic reticulum in about 44% of cells. Transfection of the common GAGdel mutation (605204.0001) produced inclusions in 79% of cells, and wildtype TOR1A produced inclusions in about 10% of cells. The findings suggested that the F205I mutation had impaired function that differed from the GAGdel mutation, and that F205I may contribute to the milder phenotype in this patient.
In vitro cellular expression studies by Hettich et al. (2014) indicated that the F205I mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, decreased neurite extension, and caused vacuolization and morphologic changes in the endoplasmic reticulum and nuclear envelope compared to wildtype.
In an 18-year-old girl with severe early-onset torsion dystonia (DYT1; 128100), Zirn et al. (2008) identified a heterozygous c.863G-A transition in exon 5 of the TOR1A gene, resulting in an arg288-to-gln (R288Q) substitution at a conserved residue in vertebrates within subdomain alpha-5. The mutation was inherited from the patient's unaffected mother, but was not found in 500 German control individuals. Transfection of the mutation into HEK293 cells resulted in a focally enlarged perinuclear space filled with membrane remnants; these abnormal findings were also observed in cells transfected with the common delE302/303 mutation (605204.0001), but were not observed in cells transfected with wildtype DYT1. The presence of the mutation in the unaffected mother was consistent with incomplete penetrance, which has been observed in DYT1.
In vitro cellular expression studies by Hettich et al. (2014) indicated that the R288Q mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, and caused vacuolization and morphologic changes in the nuclear envelope compared to wildtype. The R288Q mutation appeared to have a less adverse effect on DYT1 function compared to the delE302/303 and F205I (605204.0004) proteins.
In 2 brothers, born of consanguineous Iranian parents (family 1) with arthrogryposis multiplex congenita-5 (AMC5; 618947), Kariminejad et al. (2017) identified a homozygous c.952G-A transition in exon 5 of the TOR1A gene, resulting in a gly318-to-ser (G318S) substitution. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous carrier parents did not have torsion dystonia, consistent with incomplete penetrance of the dominant phenotype. In vitro expression studies in cells transfected with the mutation showed abnormal localization of the mutant protein from the endoplasmic reticulum to the nuclear envelope, as well as the formation of spheroid bodies.
In a 7-month-old boy, born of Mexican parents, with arthrogryposis multiplex congenita-5 (AMC5; 618947), Reichert et al. (2017) identified compound heterozygous mutations in the TOR1A gene: a 1-bp deletion (c.961delA), resulting in a frameshift and premature termination (Thr321ArgfsTer6), and the common 3-bp deletion (E303del; 605204.0001). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.
In a 4.5-month-old boy, born of reportedly unrelated Bulgarian parents, with arthrogryposis multiplex congenita-5 (AMC5; 618947), Isik et al. (2019) identified a homozygous c.862C-T transition in exon 5 of the TOR1A gene, resulting in an arg288-to-ter (R288X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant was found at a low frequency in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. The infant died of cardiorespiratory failure.
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