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Human Molecular Genetics Advance Access published online on March 14, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl055
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 2, 2005
Revised March 8, 2006
Accepted March 8, 2006

Article

Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier

Norman Kock 1, Teresa V. Naismith 2, Heather E. Boston 3, Laurie J. Ozelius 4, David P. Corey 5, Xandra O. Breakefield 3, and Phyllis I. Hanson 6

1 Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts 02114; Department of Neurology, University of Lübeck, Lübeck GERMANY
2 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
3 Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts 02114
4 Molecular Genetics Department, Albert Einstein College of Medicine, New York, New York 10461
5 Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115
6 Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Campus Box 8228, St. Louis, Missouri 63110


  Abstract

Four naturally occurring sequence variations have been found in the coding region of the DYT1 gene encoding torsinA. One of these, a three base pair ({Delta}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 {Delta}GAG deletion associated with dystonia removes one residue from an {alpha}-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 {Delta}GAG-torsinA, indicating that this change may also affect torsinA structure. Interestingly, introducing H216 into {Delta}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 {Delta}GAG deletion in torsinA. They also suggest possible connections between the allelic polymorphism at residue 216 and penetrance of DYT1 dystonia, as well as a possible role for this polymorphism in related disease states.


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