The TOR1A (DYT1) Gene Family and Its Role in Early Onset Torsion Dystonia

Ozelius, Laurie J.; Page, Curtis E.; Klein, Christine; Hewett, Jeffrey; Mineta, Mari; Leung, Jessica C.; Shalish, Christo; Bressman, Susan; Leon, Deborah de; Brin, Mitchell F.; Fahn, Stanley; Corey, David P.; Breakefield, Xandra O.

doi:10.1006/geno.1999.6039

Cited by 144 publications

(113 citation statements)

References 38 publications

(42 reference statements)

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“…DYT1 codes for torsinA, a member of the AAA + superfamily of proteins, which typically forms 6-member oligomeric complexes and associates with additional protein species. The torsin family of proteins consists of torsinA, torsinB, torp2a, and torp3a in mammals (Ozelius et al, 1999;Neuwald et al, 1999). Three related genes exist in nematodes and one in Drosophila.…”

Section: Introductionmentioning

confidence: 99%

Developmental patterns of torsinA and torsinB expression

2006

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Early onset torsion dystonia is characterized by involuntary movements and distorted postures and is usually caused by a 3-bp (GAG) deletion in the DYT1 (TOR1A) gene. DYT1 codes for torsinA, a member of the AAA + family of proteins, implicated in membrane recycling and chaperone functions. A close relative, torsinB may be involved in similar cellular functions. We investigated torsinA and torsinB message and protein levels in the developing mouse brain. TorsinA expression was highest during prenatal and early postnatal development (until postnatal day 14; P14), whereas torsinB expression was highest during late postnatal periods (from P14 onwards) and in the adult. In addition, significant regional variation in the expression of the two torsins was seen within the developing brain. Thus, torsinA expression was highest in the cerebral cortex from embryonic day 15 (E15)-E17 and in the striatum from E17-P7, while torsinB was highest in the cerebral cortex between P7-P14 and in the striatum from P7-P30. TorsinA was also highly expressed in the thalamus from P0-P7 and in the cerebellum from P7-P14. Although functional significance of the patterns of torsinA and B expression in the developing brain remains to be established, our findings provide a basis for investigating the role of torsins in specific processes such as neurogenesis, neuronal migration, axon/dendrite development, and synaptogenesis.

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Section: Introductionmentioning

confidence: 99%

Developmental patterns of torsinA and torsinB expression

2006

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“…Related human proteins torsinB, torp2A, and torp3A also have N-terminal signal sequences to direct them to the lumen of the secretory pathway (12), as do three similar proteins in Caenorhabditis elegans (13,14) and one in Drosophila melanogaster. No protein clearly related to torsinA has been found in yeast or in prokaryotes.…”

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TorsinA in the nuclear envelope

Naismith

Heuser

Breakefield

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Early-onset torsion dystonia, a CNS-based movement disorder, is usually associated with a single amino acid deletion (⌬E302͞303) in the protein torsinA. TorsinA is an AAA؉ ATPase in the endoplasmic reticulum, but what it does is unknown. Here, we use torsinA mutants with defects in ATP hydrolysis (E171Q, ATP-bound) and ATP binding (K108A, ATP-free) to probe torsinA's normal cellular function. Surprisingly, ATP-bound torsinA is recruited to the nuclear envelope (NE) of transfected cells, where it alters connections between inner and outer nuclear membranes. In contrast, ATP-free torsinA is diffusely distributed throughout the endoplasmic reticulum and has no effect on the NE. Among AAA؉ ATPases, affinity for substrates is high in the ATP-bound and low in the ATP-free state, leading us to propose that component(s) of the NE may be substrates for torsinA. We also find that the disease-promoting ⌬E302͞303 mutant is in the NE, and that this relocalization, as well as the mutant's previously described ability to induce membranous inclusions, is eliminated by the K108A ATP-binding mutation. These results suggest that changes in interactions involving torsinA in the NE could be important for the pathogenesis of dystonia and point to torsinA and related proteins as a class of ATPases that may operate in the NE.

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“…2,3 These salusins are considered to be generated simultaneously through proteolytic processing of prosalusin, a commonly occurring alternatively spliced product of the TOR2A gene, which has structural homologies to torsion dystonia genes (DYT1 and DQ1). 4,5 Alternative splicing responsible for biosynthesis of salusin peptides is probably not a rare event, and salusins are expressed ubiquitously throughout human tissues. 1 Systemic administration of salusins to rats is associated with rapid and profound hypotension and bradycardia; the maximal hypotensive response to salusin-␤ in rats is almost equivalent to or even exceeds those of the hypotensive peptide hormones identified thus far.…”

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Synthetic Salusins as Cardiac Depressors in Rat

et al. 2005

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Abstract-Using bioinformatic analyses of full-length, enriched human cDNA libraries, we recently identified salusins, multifunctional related peptides ubiquitously expressed in major human tissues. Salusins cause transient and profound hypotension when injected intravenously to rats, the hypotensive effect of salusin-␤ being especially striking. However, the mechanisms of this hypotensive action remain elusive. To determine whether salusins modulate cardiac function in rats, we studied serial changes of systemic hemodynamics and functions of isolated perfused working and nonworking hearts before and after salusin administration. Intravenous salusin-␤ administration to intact anesthetized rats caused a temporary rapid, profound decrease in aortic blood flow concomitantly with hypotension and bradycardia without affecting systemic vascular resistance. Salusin-␤-induced hypotension and bradycardia were completely blocked by pretreatment with atropine, a muscarinic receptor antagonist, but not by propranolol. In isolated perfused working rat hearts, salusin-␤ significantly decreased cardiac output, aortic flow, and stroke work. However, it did not affect coronary flow in isolated working and nonworking hearts. Our results indicate that salusins induce potent hypotension via negative inotropic and chronotropic actions. Salusin-␤ promotes its actions by facilitating vagal outflows to the heart, whereas the negative inotropism of salusin-␤ is also mediated via a direct myotropic effect. Key Words: cardiac output Ⅲ heart rate Ⅲ blood pressure Ⅲ vascular resistance T he availability of a massive amount of information on human genome sequences has allowed for the faster elucidation of gene functions. Functional characterization of putative bioactive proteins is an indispensable process in elucidating the roles of secretory proteins. Very recently, we identified 2 novel multifunctional peptides of 28-and 20-residues that we designated as salusin-␣ and salusin-␤, respectively, 1 after screening a number of secretory proteinencoding cDNAs using receptor ligand-facilitated gene transfer protocols. 2,3 These salusins are considered to be generated simultaneously through proteolytic processing of prosalusin, a commonly occurring alternatively spliced product of the TOR2A gene, which has structural homologies to torsion dystonia genes (DYT1 and DQ1). 4,5 Alternative splicing responsible for biosynthesis of salusin peptides is probably not a rare event, and salusins are expressed ubiquitously throughout human tissues. 1 Systemic administration of salusins to rats is associated with rapid and profound hypotension and bradycardia; the maximal hypotensive response to salusin-␤ in rats is almost equivalent to or even exceeds those of the hypotensive peptide hormones identified thus far. Further, other potent endogenous hypotensive peptides do not induce hypotension and concomitant bradycardia with such a time course, implying an as yet undescribed mechanism for salusins. Although the expression of preprosalusin in heart is very limit...

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The TOR1A (DYT1) Gene Family and Its Role in Early Onset Torsion Dystonia

Cited by 144 publications

References 38 publications

Developmental patterns of torsinA and torsinB expression

Developmental patterns of torsinA and torsinB expression

TorsinA in the nuclear envelope

Synthetic Salusins as Cardiac Depressors in Rat

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