Human Molecular Genetics Advance Access originally published online on March 14, 2006
Human Molecular Genetics 2006 15(8):1355-1364; doi:10.1093/hmg/ddl055
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Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier
1Department of Neurology and 2Department of Radiology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA 02114, USA, 3Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid, Campus Box 8228, St Louis, MO 63110, USA, 4Molecular Genetics Department, Albert Einstein College of Medicine, New York, NY 10461, USA, 5Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA and 6Department of Neurology, University of Lübeck, Lübeck, Germany
* To whom correspondence should be addressed. Tel: +1 3147474233; Fax: +1 3143627463; Email: phanson22{at}wustl.edu
Received December 2, 2005; Accepted March 8, 2006
Four naturally occurring sequence variations have been found in the coding region of the DYT1 gene encoding torsinA. One of these, a 3 bp (
GAG) deletion, underlies dominantly inherited cases of early-onset torsion dystonia. Others, including a single nucleotide polymorphism that replaces aspartic acid (D) at residue 216 with histidine (H) in 12% of normal alleles and two other rare deletions, have not been clearly associated with disease. To gain insight into how these sequence variations affect torsinA, we used the structure of the related protein ClpB to provide a model of torsinA's AAA+ domain. Motifs important for ATP hydrolysis—sensor 1 and sensor 2—were identified, mutagenized and used to validate predictions of this model. Inspection revealed that the GAG deletion associated with dystonia removes one residue from an 
-helix in the C-terminal portion of the AAA+ domain. The resulting distortion in torsinA structure may underlie this mutant's known tendency to produce ER-derived inclusions as well as its proposed loss of function. The D/H polymorphism at residue 216 falls in the N-terminal portion of the AAA+ domain near the sensor 1 motif. Surprisingly, cells expressing torsinA with the polymorphic histidine developed inclusions similar to those associated with GAG-torsinA, indicating that this change may also affect torsinA structure. Introducing H216 into GAG-torsinA reduced its tendency to form inclusions, suggesting that the two changes offset each other. Our findings point to a structural basis for the defects associated with the disease-linked GAG deletion in torsinA. They also suggest possible connections between the allelic polymorphism at residue 216 and the penetrance of DYT1 dystonia, as well as a possible role for this polymorphism in related disease states.
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