Dystonia in Ashkenazi Jews: Clinical characterization of a founder mutation

Bressman, Susan; Leon, Deborah de; Kramer, Patricia L.; Ozelius, Laurie J.; Brin, Mitchell F.; Greene, Paul; Fahn, Stanley; Breakefield, Xandra O.; Risch, Neil

doi:10.1002/ana.410360514

Cited by 166 publications

(114 citation statements)

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“…Several interesting features of this disease bear on developmental plasticity of movement control in the central nervous system, including the tendency for the disorder to progress from lower to upper body regions and the positive correlation between younger age at onset and greater severity of disease (Bressman et al 1994b). The low penetrance in this autosomal dominant syndrome suggests that other genetic and/or environmental factors can modulate the outcome of mutations at the DYT1 locus.…”

Section: Discussionmentioning

confidence: 99%

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Fine Localization of the Torsion Dystonia Gene (DYT1) on Human Chromosome 9q34: YAC Map and Linkage Disequilibrium

Ozelius

Hewett

Kramer³

et al. 1997

Genome Res.

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The DYT1 gene, which maps to chromosome 9q34, appears to be responsible for most cases of early-onset torsion dystonia in both Ashkenazic Jewish (AJ) and non-Jewish families. This disease is inherited in an autosomal dominant mode with reduced penetrance (30%–40%). The abnormal involuntary movements associated with this disease are believed to be caused by unbalanced neural transmission in the basal ganglia. Previous linkage disequilibrium studies in the AJ population placed the DYT1 gene in a 2-cM region between the loci D9S62a and ASS. A YAC contig has now been created spanning 600 kb of this region including D9S62a. The location of the DYT1 gene has been refined within this contig using several new polymorphic loci to expand the linkage disequilibrium analysis of the AJ founder mutation. The most likely location of theDYT1 gene is within a 150 kb region between the lociD9S2161 and D9S63.

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Section: Discussionmentioning

confidence: 99%

“…Based on haplotype analysis in the immediate chromosomal region surrounding DYT1, it is clear that most cases of early-onset dystonia in the AJ population result from a founder mutation (Ozelius et al 1992a;Bressman et al 1994b;Risch et al 1995). …”

Section: Linkage Disequilibriummentioning

confidence: 99%

Fine Localization of the Torsion Dystonia Gene (DYT1) on Human Chromosome 9q34: YAC Map and Linkage Disequilibrium

Ozelius

Hewett

Kramer³

et al. 1997

Genome Res.

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“…Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2,3).…”

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confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

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“…DYT1 dystonia typically spares facial and laryngeal structures (present in~11-14% of cases), and involves the neck in a minority of cases (present in~25% of cases) [8][9][10]. This clinical picture of DYT1 dystonia is highly stereotyped, but exceptional cases and families have been reported, including with much earlier or later onset, onset in the larynx, or a phenotype of isolated writer's cramp [11,12].…”

Section: Dyt1mentioning

confidence: 99%