SUSCEPTIBILITY TO
            <i>DYT1</i>
            DYSTONIA IN EUROPEAN PATIENTS IS MODIFIED BY THE D216H POLYMORPHISM

Kamm, Christoph; Fischer, Harald; Garavaglia, Barbara; Kullmann, Stephanie; Sharma, Manu; Schrader, Christoph; Grundmann, Kathrin; Klein, Christine; Borggräfe, Ingo; Lobsien, Elmar; Kupsch, Andreas; Nardocci, Nardo; Gasser, Thomas

doi:10.1212/01.wnl.0000313838.05734.8a

Cited by 58 publications

(32 citation statements)

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“…The potential pathogenic nature of this mutation is in doubt, however, as this patient also had a mutation in the epsilon sarcoglycan gene responsible for myoclonus dystonia [Doheny et al, 2002]. An aspartic acid (D) 216 to histidine (H) (c.646G>C; p.Asp216His) change has been found to influence penetrance of the ΔGAG mutation, but is not independently associated with dystonia onset [Kock et al, 2006; Risch et al, 2007; Kamm et al, 2008]. A 4 bp deletion (c.934_937delAGAG; p.Arg312_Val313delinsPhefs) causing a frameshift truncation was identified in an anonymous control sample for whom no neurologic evaluation was available [Kabakci et al, 2004] and later also found in a patient with late onset myoclonic and dystonic features with signs of Parkinson’s disease [Ritz et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Cellular Analysis of Human Variants of the DYT1 Dystonia Protein, TorsinA/TOR1A

et al. 2014

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Early-onset dystonia is associated with the deletion of one of a pair of glutamic acid residues (c.904_906delGAG/c.907_909delGAG; p.Glu302del/Glu303del; ΔE 302/303) near the carboxyl-terminus of torsinA, a member of the AAA+ protein family that localizes to the endoplasmic reticulum (ER) lumen and nuclear envelope (NE). This deletion commonly underlies early-onset DYT1 dystonia. While the role of the disease-causing mutation, torsinAΔE, has been established through genetic association studies, it is much less clear whether other rare human variants of torsinA are pathogenic. Two missense variations have been described in single patients; R288Q (c.863G>A; p.Arg288Gln; R288Q) identified in a patient with onset of severe generalized dystonia and myoclonus since infancy, and F205I (c.613T>A, p.Phe205Ile; F205I) in a psychiatric patient with late-onset focal dystonia. In this study, we have undertaken a series of analyses comparing the biochemical and cellular effects of these rare variants to torsinAΔE and wild-type (wt) torsinA in order to reveal whether there are common dysfunctional features. The results revealed that the variants, R288Q and F205I, are more similar in their properties to torsinAΔE protein than to torsinAwt. These findings provide functional evidence for the potential pathogenic nature of these rare sequence variants in the TOR1A gene, thus implicating these pathologies in the development of dystonia.

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Section: Introductionmentioning

confidence: 99%

Biochemical and Cellular Analysis of Human Variants of the DYT1 Dystonia Protein, TorsinA/TOR1A

et al. 2014

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“…This finding suggests that rs1801968 may have a protective role against the effect of ΔGAG mutation and dystonia [45–47]. On the contrary, 216D allele in cis together with ΔGAG, may predispose for developing dystonia [46, 47]. Cheng et al reported that 216D allele was more abundant in patients with early-onset primary dystonia, while 216H allele was more frequent in the control group [41].…”

Section: Discussionmentioning

confidence: 99%

The Role of TOR1A Polymorphisms in Dystonia: A Systematic Review and Meta-Analysis

et al. 2017

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ImportanceA number of genetic loci were found to be associated with dystonia. Quite a few studies have been contacted to examine possible contribution of TOR1A variants to the risk of dystonia, but their results remain conflicting. The aim of the present study was to systematically evaluate the effect of TOR1A gene SNPs on dystonia and its phenotypic subtypes regarding the body distribution.MethodsWe performed a systematic review of Pubmed database to identify all available studies that reported genotype frequencies of TOR1A SNPs in dystonia. In total 16 studies were included in the quantitative analysis. Odds ratios (ORs) were calculated in each study to estimate the influence of TOR1A SNPs genotypes on the risk of dystonia. The fixed-effects model and the random effects model, in case of high heterogeneity, for recessive and dominant mode of inheritance as well as the free generalized odds ratio (ORG) model were used to calculate both the pooled point estimate in each study and the overall estimates.ResultsRs1182 was found to be associated with focal dystonia in recessive mode of inheritance [Odds Ratio, OR (95% confidence interval, C.I.): 1.83 (1.14–2.93), Pz = 0.01]. In addition, rs1801968 was associated with writer’s cramp in both recessive and dominant modes [OR (95%C.I.): 5.99 (2.08–17.21), Pz = 0.00009] and [2.48 (1.36–4.51), Pz = 0.003) respectively and in model free-approach [ORG (95%C.I.): 2.58 (1.45–4.58)].ConclusionsOur meta-analysis revealed a significant implication of rs1182 and rs1801968 TOR1A variants in the development of focal dystonia and writer’s cramp respectively. TOR1A gene variants seem to be implicated in dystonia phenotype.

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“…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]. Significantly, a polymorphism in torsinA at position 216, which changes an aspartic acid to a histidine, has been found at a higher frequency in healthy individuals who also harbor the (ΔE) mutation in the trans chromosomal configuration [52][53][54] (Fig. 2B).…”

Section: A Dyt1: Early-onset Torsion Dystoniamentioning

confidence: 90%

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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SUSCEPTIBILITY TO DYT1 DYSTONIA IN EUROPEAN PATIENTS IS MODIFIED BY THE D216H POLYMORPHISM

Cited by 58 publications

References 0 publications

Biochemical and Cellular Analysis of Human Variants of the DYT1 Dystonia Protein, TorsinA/TOR1A

Biochemical and Cellular Analysis of Human Variants of the DYT1 Dystonia Protein, TorsinA/TOR1A

The Role of TOR1A Polymorphisms in Dystonia: A Systematic Review and Meta-Analysis

Invertebrate Models of Dystonia

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