ε‐sarcoglycan mutations found in combination with other dystonia gene mutations

Klein, Christine; Liu, Liu; Doheny, Dana; Kock, Norman; Müller, Bettina; Aguiar, Patrícia Maria de Carvalho; Leung, Jessica C.; Leon, Deborah de; Bressman, Susan; Silverman, Jeremy M.; Smith, Christopher J.; Danisi, Fabio; Morrison, Chris; Walker, Ruth H.; Velickovic, Miodrag; Schwinger, E.; Kramer, Patricia L.; Breakefield, Xandra O.; Brin, Mitchell F.; Ozelius, Laurie J.

doi:10.1002/ana.10358

Cited by 83 publications

(58 citation statements)

References 19 publications

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“…A single mutation, an in-frame GAG deletion, in the DYT1 gene on chromosome 9q34 is a major cause of early onset primary dystonia. The GAG deletion results in the loss of a glutamic acid residue in the encoded protein TorsinA [Ozelius et al, 1997], and is the only DYT1 mutation identified that is unequivocally associated with dystonia [Leung et al, 2001;Klein et al, 2002;Kabakci et al, 2004;Clarimon et al, 2005;Hague et al, 2006]. Penetrance is estimated at only 30%; thus most mutation carriers are clinically normal, or at least unaffected with overt signs of dystonia [Kramer et al, 1994].…”

Section: Introductionmentioning

confidence: 99%

Obsessive‐compulsive disorder is not a clinical manifestation of the DYT1 dystonia gene

Heiman

Ottman

Saunders‐Pullman

et al. 2006

American J of Med Genetics Pt B

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Prior studies suggest that obsessive-compulsive symptoms (OCS) and disorder (OCD) are comorbid with dystonia. We tested if OCS/OCD is a clinical manifestation of the DYT1 dystonia mutation by interviewing members of families with an identified DYT1 mutation, and classifying by manifesting carriers (MC), non-manifesting carriers (NMC), and non-carriers (NC). We found that OCD/OCS are not increased in DYT1 mutation carriers compared with NC, nor is OCD associated with manifesting DYT1 dystonia.

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Section: Introductionmentioning

confidence: 99%

Obsessive‐compulsive disorder is not a clinical manifestation of the DYT1 dystonia gene

Heiman

Ottman

Saunders‐Pullman

et al. 2006

American J of Med Genetics Pt B

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“…It may also elucidate the mechanism of the penetrance and help to find potential approaches to prevent the onset of this disease. Previous studies reported two myoclonus-dystonia patients in a family with double mutations in DYT1 and SGCE (33,34). They inherited an 18 bp in-frame deletion in DYT1 from their mother and a 587T4G missense mutation (Leu196Arg) in SGCE from their father.…”

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confidence: 97%

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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“…(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).…”

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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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ε‐sarcoglycan mutations found in combination with other dystonia gene mutations

Cited by 83 publications

References 19 publications

Obsessive‐compulsive disorder is not a clinical manifestation of the DYT1 dystonia gene

Obsessive‐compulsive disorder is not a clinical manifestation of the DYT1 dystonia gene

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

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

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