Missense mutations in DYT-TOR1A dystonia (original) (raw)
Related papers
High-throughput mutational analysis of TOR1A in primary dystonia
2009
Background: Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some ΔGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify TOR1A Exon 5 mutations in a large cohort of subjects with mainly nongeneralized primary dystonia.
Inherited and de novo mutations in sporadic cases of DYT1-dystonia
European Journal of Human Genetics, 2002
A study of Danish probands with primary torsion dystonia is presented. The probands were examined clinically and biochemically to exclude secondary dystonia. Mutation analyses for the GAG-deletion in the DYT1 gene were performed on 107 probands; and the mutation was detected in three. All three probands had the classical phenotype of DYT1-dystonia, but only one had a family history of dystonia. The other two probands had, obviously, sporadic DYT1-dystonia, one of which was caused by a de novo mutation, while the other one had a parent being an asymptomatic carrier. De novo mutations in the DYT1 gene are seldomly reported although independent founder mutations are known to have occurred. The frequency of DYT1dystonia was low in our study even though several probands had early onset generalised dystonia. None of the probands in our study with other types of dystonia had the GAG-deletion as reported in other studies. The difficulties in genetic counselling concerning the heterogeneity of dystonia examplified by DYT1dystonia are outlined.
Acta Neuropathologica Communications, 2014
Early onset isolated dystonia (DYT1) is linked to a three base pair deletion (ΔGAG) mutation in the TOR1A gene. Clinical manifestation includes intermittent muscle contraction leading to twisting movements or abnormal postures. Neuropathological studies on DYT1 cases are limited, most showing no significant abnormalities. In one study, brainstem intraneuronal inclusions immunoreactive for ubiquitin, torsinA and lamin A/C were described. Using the largest series reported to date comprising 7 DYT1 cases, we aimed to identify consistent neuropathological features in the disease and determine whether we would find the same intraneuronal inclusions as previously reported.
Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia
Journal of Medical Genetics, 2009
Background-TOR1A encodes a chaperone-like AAA-ATPase whose ΔGAG (ΔE) mutation is responsible for an early-onset, generalized dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalized dystonia (DYT1), a potential genetic contribution of TOR1A to the more prevalent and diverse presentations of late-onset, focal dystonia has been suggested.
Update on the Genetics of Dystonia
Mainly due to the advent of next-generation se-quencing (NGS), the field of genetics of dystonia has rapidly grown in recent years, which led to the discovery of a number of novel dystonia genes and the development of a new classification and nomenclature for inherited dystonias. In addition, new findings from both in vivo and in vitro studies have been published on the role of previously known dystonia genes, extending our understanding of the pathophysiology of dys-tonia. We here review the current knowledge and recent findings in the known genes for isolated dystonia TOR1A, THAP1, and GNAL as well as for the combined dystonias due to mutations in GCH1, ATP1A3, and SGCE. We present confirmatory evidence for a role of dystonia genes that had not yet been unequivocally established including PRKRA, TUBB4A, ANO3, and TAF1. We finally discuss selected novel genes for dystonia such as KMT2B and VAC14 along with the challenges for gene identification in the NGS era and the translational importance of dystonia genetics in clinical practice.
Biochemical and Cellular Analysis of Human Variants of the DYT1 Dystonia Protein, TorsinA.
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.
Neurogenetics, 2001
Dystonia is a movement disorder involving sustained muscle contractions and abnormal posturing with a strong hereditary predisposition and without a distinct neuropathology. In this study the TOR1A (DYT1) gene was screened for mutations in cases of early onset dystonia and early onset parkinsonism (EOP), which frequently presents with dystonic symptoms. In a screen of 40 patients, we identified three variations, none of which occurred in EOP patients. Two infrequent intronic single base pair (bp) changes of unknown consequences were found in a dystonia patient and the mother of an EOP patient. An 18-bp deletion (Phe323_Tyr328del) in the TOR1A gene was found in a patient with early onset dys-tonia and myoclonic features. This deletion would remove 6 amino acids close to the carboxy terminus, including a putative phosphorylation site of torsinA. This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia.
Review: Genetics and neuropathology of primary pure dystonia
Neuropathology and Applied Neurobiology, 2012
Neuropathology has been the key to understanding the aetiology of many neurological disorders such as Alzheimer's disease, Parkinson's disease, frontotemporal degeneration and cerebellar ataxias. Dystonia shares many clinical features with these conditions but research in general, has been unrewarding in providing information on disease processes. Neuropathological studies are few in number and only limited morphological abnormalities have been described. In the genetic literature, dystonia loci are represented as DYT and are assigned ascending numerals chronologically as they are identified. This review will concentrate on the neuropathology of primary pure dystonia, focusing on DYT1 and DYT6 and the correlation between clinical and genetic findings. Research in this area is incomplete and confounded by the rarity of post mortem brain tissue. However, recent findings, indicating a direct interaction between the torsinA (TOR1A) gene responsible for DYT1 and the thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) gene responsible for DYT6, have important implications in understanding these two entities and also for other members of this group of disorders.
Primary torsion dystonia: the search for genes is not over
Journal of Neurology, Neurosurgery & Psychiatry, 1999
A GAG deletion in the DYT1 gene accounts for most early, limb onset primary torsion dystonia (PTD). The genetic bases for the more common adult onset and focal PTD are less well delineated. Genetic loci for an "intermediate dystonia" phenotype and for torticollis, named DYT6 and DYT7 respectively, have recently been mapped in single families. To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions. There was no evidence of linkage to either locus in any family. These findings illustrate the genetic heterogeneity of the dystonias and indicate the existence of one or more as yet unmapped genes for dystonia. Large collaborative eVorts will be required to identify these, and additional genes, causing PTD. (J Neurol Neurosurg Psychiatry 1999;67:395-397)