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

Human Molecular Genetics
Norman KockP I Hanson

Abstract

Four naturally occurring sequence variations have been found in the coding region of the DYT1 gene encoding torsinA. One of these, a 3 bp (DeltaGAG) 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 DeltaGAG 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...Continue Reading

References

Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·W S PearD Baltimore
Sep 1, 1997·Nature Genetics·L J OzeliusX O Breakefield
Jan 25, 2000·Genomics·L J OzeliusX O Breakefield
May 10, 2000·Neurology·S B BressmanN J Risch
Jul 13, 2000·The Journal of Cell Biology·R D Vale
Jul 28, 2001·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·T Ogura, A J Wilkinson
Jul 6, 2002·Neuroscience Letters·Casey O'FarrellMark R Cookson
Oct 29, 2002·Annals of Neurology·Christine KleinLaurie J Ozelius
Nov 8, 2002·Journal of Neurochemistry·Pamela J McLeanBradley T Hyman
Jan 30, 2003·Human Molecular Genetics·Guy A CaldwellKim A Caldwell
Mar 1, 2003·Neurobiology of Disease·Kevin RostasyJohn C Hedreen
Apr 3, 2003·Journal of Neuroscience Research·Jeffrey HewettXandra O Breakefield
Oct 11, 2003·Neuroscience Letters·Rohini KunerArmin Schneider
Oct 29, 2003·The Journal of Cell Biology·Erik L SnappJennifer Lippincott-Schwartz
Oct 29, 2003·Neurology·D SibbingO Bandmann
Nov 18, 2003·Molecular Biology of the Cell·Seema DalalPhyllis I Hanson
Jan 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·Rose E Goodchild, William T Dauer
Feb 6, 2004·Journal of Neurochemistry·P ShashidharanC Warren Olanow
Feb 19, 2004·The Journal of Biological Chemistry·Christoph KammXandra O Breakefield
Mar 19, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Pedro Gonzalez-Alegre, Henry L Paulson
Mar 24, 2004·Journal of Structural Biology·Lakshminarayan M IyerL Aravind
May 12, 2004·Proceedings of the National Academy of Sciences of the United States of America·Teresa V NaismithPhyllis I Hanson
May 19, 2004·Journal of Neurochemistry·Jeffrey W HewettVijaya Ramesh
Jun 10, 2004·Proceedings of the National Academy of Sciences of the United States of America·Larry Gerace
Jul 31, 2004·Brain Research. Developmental Brain Research·Jianfeng XiaoMark S LeDoux
Aug 13, 2004·Brain Research. Molecular Brain Research·Casey O'FarrellMark R Cookson
Sep 30, 2004·Cell·Robert T SauerTania A Baker
Sep 30, 2004·Annals of Neurology·Kevin St P McNaughtC Warren Olanow
Oct 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·Gonzalo E TorresMarc G Caron
Nov 19, 2004·Human Molecular Genetics·P ShashidharanC W Olanow
Nov 24, 2004·Molecular and Cellular Neurosciences·D Cristopher BraggXandra O Breakefield
Mar 16, 2005·The Journal of Cell Biology·Rose E Goodchild, William T Dauer
Apr 15, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Songsong CaoGuy A Caldwell
Jun 3, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Nutan SharmaXandra O Breakefield
Aug 3, 2005·Nature Reviews. Molecular Cell Biology·Phyllis I Hanson, Sidney W Whiteheart

❮ Previous
Next ❯

Citations

Apr 29, 2010·Current Neurology and Neuroscience Reports·Norbert Brüggemann, Christine Klein
Feb 20, 2010·Cell Stress & Chaperones·Alexander J BurdetteKim A Caldwell
Jun 19, 2009·The Journal of Biological Chemistry·Lisa M GilesLih-Shen Chin
Aug 5, 2009·The Journal of Biological Chemistry·Teresa V NaismithPhyllis I Hanson
Sep 24, 2010·The Journal of Biological Chemistry·Li ZhuPhilip J Thomas
Apr 3, 2009·Molecular Biology of the Cell·Abigail B Vander HeydenPhyllis I Hanson
Jul 7, 2009·Brain : a Journal of Neurology·Ulrich Müller
Jun 2, 2007·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·K SzczalubaT Mazurczak
Jul 16, 2010·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·A Schmidt, C Klein
Nov 8, 2011·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·Y ChenH-F Shang
Dec 4, 2009·Journal of Medical Genetics·Nicole CalakosStephan Züchner
Mar 13, 2010·Disease Models & Mechanisms·Songsong CaoKim A Caldwell
Aug 7, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Miklos ArgyelanDavid Eidelberg
Jun 19, 2013·Brain : a Journal of Neurology·Gavin CharlesworthNicholas W Wood
Aug 26, 2014·ELife·Brian A SosaThomas U Schwartz
Aug 27, 2014·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·William Dauer
Dec 17, 2010·Neurochemical Research·Kara L GordonPedro Gonzalez-Alegre
Dec 21, 2010·Neurobiology of Disease·Laurie J Ozelius, Susan B Bressman
Dec 8, 2010·Neurobiology of Disease·D Cristopher BraggNutan Sharma
Jun 27, 2009·Neurologic Clinics·Cordelia S Schwarz, Susan B Bressman
Oct 19, 2006·Neuroscience Research·Mai T DangYuqing Li
May 22, 2009·Journal of Neurochemistry·Alessandra GranataThomas T Warner
Mar 5, 2009·Movement Disorders : Official Journal of the Movement Disorder Society·Mélissa Yana FrédéricGwenaëlle Collod-Beroud
Mar 6, 2013·Movement Disorders : Official Journal of the Movement Disorder Society·Justus L GroenMarina A J Tijssen
Jul 30, 2010·Movement Disorders : Official Journal of the Movement Disorder Society·Nutan SharmaLaurie J Ozelius
Jun 1, 2011·Movement Disorders : Official Journal of the Movement Disorder Society·Laurie J OzeliusSusan B Bressman
Jul 31, 2013·Movement Disorders : Official Journal of the Movement Disorder Society·Katja Lohmann, Christine Klein
Jul 31, 2013·Movement Disorders : Official Journal of the Movement Disorder Society·Mark S LedouxThomas T Warner
May 28, 2014·Movement Disorders : Official Journal of the Movement Disorder Society·Fu-Bo ChengKathrin Grundmann
Jun 30, 2006·Current Opinion in Cell Biology·Nica BorgeseErik Snapp
May 16, 2007·American Journal of Human Genetics·Neil J RischLaurie J Ozelius
Nov 19, 2008·Parkinsonism & Related Disorders·Susan B Bressman
Jan 24, 2009·Neuroscience·M Carbon, D Eidelberg
Oct 23, 2008·Neuroscience·K L Gordon, P Gonzalez-Alegre

❮ Previous
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