Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1)

Zirn, Birgit; Grundmann, Kathrin; Huppke, Peter; Puthenparampil, J; Wolburg, Hartwig; Rieß, Olaf; Müller, Ulrich

doi:10.1136/jnnp.2008.148270

Cited by 72 publications

(54 citation statements)

References 19 publications

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“…The 18-bp mutation reduces ATPase activity in vitro (5) and induces locomotor disability and anatomical changes in fruit flies (14). A third mutation that causes an Arg288Gln exchange was also reported (15). Genetic studies using Dyt1 ÁGAG knock-in (KI), Dyt1 knockout (KO), Dyt1 knock-down and the cerebral cortex-specific Dyt1 conditional KO mice suggested that a loss of torsinA function contributes to the pathology of the disease (1618).…”

mentioning

confidence: 99%

Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

Yokoi

Yang

et al. 2010

The Journal of Biochemistry

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mentioning

confidence: 99%

Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

Yokoi

Yang

et al. 2010

The Journal of Biochemistry

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“…At the time when we identified this variant, it was novel but is now reported in 3 individuals (3/13006=0.0002) from the NHLBI Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS/). The third detected rare, protein-changing variant (c.863G>A, p.R288Q) was identified in one patient that has previously been reported (Zirn, et al, 2008). This only became obvious after having corresponded with the authors of the first description of this mutation.…”

Section: Patients and Mutation Screeningmentioning

confidence: 67%

“…The vast majority of DYT1 cases are caused by the same in-frame three-base-pair deletion in Exon 5 of the TOR1A gene (c.904_906delGAG/c.907_909delGAG; p.302/p.303delE (ΔE)) (Klein, et al, 1999;Ozelius, et al, 1997). At present, three additional mutations in TOR1A have been described in single patients (c.613T>A, p.F205I; c.863G>A, p.R288Q; c.966_983del, p.F323_Y328del) (Calakos, et al, 2010;Leung, et al, 2001;Zirn, et al, 2008). Moreover, an out-of-frame four-base-pair deletion was detected in a putatively healthy control (c.934_937del, p.R312Ffs*14) (Kabakci, et al, 2004).…”

Section: Introductionmentioning

confidence: 96%

Unraveling Cellular Phenotypes of NovelTorsinA/TOR1AMutations

et al. 2014

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A three-nucleotide (GAG) deletion (ΔE) in TorsinA (TOR1A) has been identified as the most common cause of dominantly inherited early-onset torsion dystonia (DYT1). TOR1A encodes a chaperone-like AAA+-protein localized in the endoplasmic reticulum. Currently, only three additional, likely mutations have been reported in single dystonia patients. Here, we report two new, putative TOR1A mutations (p.A14_P15del and p.E121K) that we examined functionally in comparison with wild-type (WT) protein and two known mutations (ΔE and p.R288Q). While inclusion formation is a characteristic feature for ΔE TOR1A, elevated levels of aggregates for other mutations were not observed when compared with WT TOR1A. WT and mutant TOR1A showed preferred degradation through the autophagy-lysosome pathway, which is most pronounced for p.A14_P15del, p.R288Q, and ΔE TOR1A. Notably, blocking of the autophagy pathway with bafilomycin resulted in a significant increase in inclusion formation in p.E121K TOR1A. In addition, all variants had an influence on protein stability. Although the p.A14_P15del mutation affects the proposed oligomerization domain of TOR1A, this mutation did not disturb the ability to dimerize. Our findings demonstrate functional changes for all four mutations on different levels. Thus, both diagnostic and research genetic screening of dystonia patients should not be limited to testing for the ∆E mutation.

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“…Another individual was found to have a 4 base-pair deletion in DYT1, starting at position 312 of torsinA, although they appeared healthy and were not neurologically examined [48][49][50]. Yet another novel mutation in the conserved ATPase domain of torsinA (F205I) was identified in an individual with late-onset, focal dystonia; this is suggestive of a possible genetic link between inherited generalized and more common focal forms of dystonia [51].…”

Section: A Dyt1: Early-onset Torsion Dystoniamentioning

confidence: 98%

Invertebrate Models of Dystonia

Caldwell¹,

Shu²,

Roberts³

et al. 2013

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Abstract:The neurological movement disorder dystonia is an umbrella term for a heterogeneous group of related conditions where at least 20 monogenic forms have been identified. Despite the substantial advances resulting from the identification of these loci, the function of many DYT gene products remains unclear. Comparative genomics using simple animal models to examine the evolutionarily conserved functional relationships with monogenic dystonias represents a rapid route toward a comprehensive understanding of these movement disorders. Current studies using the invertebrate animal models Caenorhabditis elegans and Drosophila melanogaster are uncovering cellular functions and mechanisms associated with mutant forms of the well-conserved gene products corresponding to DYT1, DYT5a, DYT5b, and DYT12 dystonias. Here we review recent findings from the invertebrate literature pertaining to molecular mechanisms of these gene products, torsinA, GTP cyclohydrolase I, tyrosine hydroxylase, and the alpha subunit of Na+/K ATPase, respectively. In each study, the application of powerful genetic tools developed over decades of intensive work with both of these invertebrate systems has led to mechanistic insights into these human disorders. These models are particularly amenable to large-scale genetic screens for modifiers or additional alleles, which are bolstering our understanding of the molecular functions associated with these gene products. Moreover, the use of invertebrate models for the evaluation of DYT genetic loci and their genetic interaction networks has predictive value and can provide a path forward for therapeutic intervention.

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Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1)

Abstract: The sequence change described here may be a novel pathogenic mutation of TOR1A in DYT1.

Cited by 72 publications

References 19 publications

Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

Earlier onset of motor deficits in mice with double mutations in Dyt1 and Sgce

Unraveling Cellular Phenotypes of NovelTorsinA/TOR1AMutations

Invertebrate Models of Dystonia

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