A three base-pair deletion in the widely expressed TOR1A gene causes the childhood onset, neurological disease of DYT1 dystonia. Mouse Tor1a gene knockout also specifically affects the developing nervous system. However, in both cases, the basis of neuronal tissue specificity is unknown. TorsinA is one of four predicted mammalian torsin ATPases associated with assorted cellular activities (AAA+) proteins, raising the possibility that expression of a functionally homologous torsin compensates for torsinA loss in non-neuronal tissues. We find that all four mammalian torsins are endoplasmic reticulum resident glycoproteins. TorsinA, torsinB and torsin2 are all present in large M(r) complexes, which suggests that each assembles into an oligomeric AAA+ enzyme. Introducing a mutation (WB(EQ)) that typically stabilizes AAA+ proteins in a substrate-bound state causes torsinA and torsinB to associate with a shared nuclear envelope (NE) binding partner and this NE localization requires the torsinA interacting protein, lamina associated polypeptide 1. Although torsin proteins are widely expressed in the adult mouse, we identified that embryonic neuronal tissues contain relatively low torsinB levels. Therefore, our results reveal that torsinB expression inversely correlates with the cell and developmental requirement for torsinA. In conclusion, multiple cell types appear to utilize torsin AAA+ proteins and differential expression of torsinB may contribute to both the neuronal specific importance of torsinA and the symptom specificity of DYT1 dystonia.

BackgroundDYT1 dystonia is an autosomal dominant neurological condition caused by a mutation that removes a single glutamic acid residue (ΔE) from the torsinA (torA) AAA+ protein. TorA appears to possess a nuclear envelope (NE) localized activity that requires Lamina-Associated-Polypeptide 1 (LAP1), which is an inner nuclear membrane localized torA-binding partner. Although hypoactive, the DYT1 dystonia torA-ΔE isoform often concentrates in the NE, suggesting that torA-ΔE also interacts with an NE-localized binding partner.ResultsWe confirm that NE-localized torA-ΔE does not co-immunoprecipitate with LAP1, and find that torA-ΔE continues to concentrate in the NE of cells that lack LAP1. Instead, we find that variability in torA-ΔE localization correlates with the presence of the SUN-domain and Nesprin proteins that assemble into the LINC complex. We also find that siRNA depletion of SUN1, but not other LINC complex components, removes torA-ΔE from the NE. In contrast, the LAP1-dependent NE-accumulation of an ATP-locked torA mutant is unaffected by loss of LINC complex proteins. This SUN1 dependent torA-ΔE localization requires the torA membrane association domain, as well as a putative substrate-interaction residue, Y147, neither of which are required for torA interaction with LAP1. We also find that mutation of these motifs, or depletion of SUN1, decreases the amount of torA-WT that colocalizes with NE markers, indicating that each also underlies a normal NE-localized torA binding interaction.ConclusionsThese data suggest that the disease causing ΔE mutation promotes an association between torA and SUN1 that is distinct to the interaction between LAP1 and ATP-bound torA. This evidence for two NE-localized binding partners suggests that torA may act on multiple substrates and/or possesses regulatory co-factor partners. In addition, finding that the DYT1 mutation causes abnormal association with SUN1 implicates LINC complex dysfunction in DYT1 dystonia pathogenesis, and suggests a gain-of-function activity contributes to this dominantly inherited disease.

A three base-pair deletion in the widely expressed TOR1A gene causes the childhood onset, neurological disease of DYT1 dystonia. Mouse Tor1a gene knockout also specifically affects the developing nervous system. However, in both cases, the basis of neuronal tissue specificity is unknown. TorsinA is one of four predicted mammalian torsin ATPases associated with assorted cellular activities (AAA1) proteins, raising the possibility that expression of a functionally homologous torsin compensates for torsinA loss in non-neuronal tissues. We find that all four mammalian torsins are endoplasmic reticulum resident glycoproteins. TorsinA, torsinB and torsin2 are all present in large M r complexes, which suggests that each assembles into an oligomeric AAA1 enzyme. Introducing a mutation (WB EQ ) that typically stabilizes AAA1 proteins in a substratebound state causes torsinA and torsinB to associate with a shared nuclear envelope (NE) binding partner and this NE localization requires the torsinA interacting protein, lamina associated polypeptide 1. Although torsin proteins are widely expressed in the adult mouse, we identified that embryonic neuronal tissues contain relatively low torsinB levels. Therefore, our results reveal that torsinB expression inversely correlates with the cell and developmental requirement for torsinA. In conclusion, multiple cell types appear to utilize torsin AAA1 proteins and differential expression of torsinB may contribute to both the neuronal specific importance of torsinA and the symptom specificity of DYT1 dystonia.

The odontogenic keratocyst (OKC) is a benign but locally aggressive cyst that has a potentially high recurrence rate and morbidity associated with different treatment approaches. Decompression of odontogenic cysts is a well-established technique that has been shown to decrease the size of the cyst and need for sacrificing local structures during ensuing definitive treatment. Multiple devices have been previously described for decompression of OKCs utilizing varying drain material and modes of fixation, but have been complicated by device malposition, soft tissue overgrowth, poor hygiene, and suture dehiscence. This paper describes the application of a custom titanium drain (Biomet ® Jacksonville, FL) secured using bone screws for decompression of an OKC in a 77-year-old male.