SIMPLEmutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation

Human MutationVolume 25, Issue 4 p. 372-383 Research Article SIMPLE mutations in Charcot-Marie-Tooth disease and the potential role of its protein product in protein degradation†‡ Gulam Mustafa Saifi, Gulam Mustafa Saifi Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasSearch for more papers by this authorKinga Szigeti, Kinga Szigeti Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasSearch for more papers by this authorWojciech Wiszniewski, Wojciech Wiszniewski Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasSearch for more papers by this authorMichael E. Shy, Michael E. Shy Department of Neurology, Wayne State University, Detroit, MichiganSearch for more papers by this authorKaren Krajewski, Karen Krajewski Department of Neurology, Wayne State University, Detroit, MichiganSearch for more papers by this authorIrena Hausmanowa-Petrusewicz, Irena Hausmanowa-Petrusewicz Neuromuscular Unit, Medical Research Centre, Polish Academy of Sciences, Warsaw, PolandSearch for more papers by this authorAndrzej Kochanski, Andrzej Kochanski Neuromuscular Unit, Medical Research Centre, Polish Academy of Sciences, Warsaw, PolandSearch for more papers by this authorSuzanne Reeser, Suzanne Reeser WellSpan Health System, York Hospital, York, PennsylvaniaSearch for more papers by this authorPedro Mancias, Pedro Mancias Department of Neurology, University of Texas–Houston Health Science Center Medical School, Houston, TexasSearch for more papers by this authorIan Butler, Ian Butler Department of Neurology, University of Texas–Houston Health Science Center Medical School, Houston, TexasSearch for more papers by this authorJames R. Lupski, Corresponding Author James R. Lupski jlupski@bcm.tmc.edu Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Department of Pediatrics, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, TexasOne Baylor Plaza, Room 604B, Houston, TX 77030Search for more papers by this author Gulam Mustafa Saifi, Gulam Mustafa Saifi Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasSearch for more papers by this authorKinga Szigeti, Kinga Szigeti Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasSearch for more papers by this authorWojciech Wiszniewski, Wojciech Wiszniewski Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TexasSearch for more papers by this authorMichael E. Shy, Michael E. Shy Department of Neurology, Wayne State University, Detroit, MichiganSearch for more papers by this authorKaren Krajewski, Karen Krajewski Department of Neurology, Wayne State University, Detroit, MichiganSearch for more papers by this authorIrena Hausmanowa-Petrusewicz, Irena Hausmanowa-Petrusewicz Neuromuscular Unit, Medical Research Centre, Polish Academy of Sciences, Warsaw, PolandSearch for more papers by this authorAndrzej Kochanski, Andrzej Kochanski Neuromuscular Unit, Medical Research Centre, Polish Academy of Sciences, Warsaw, PolandSearch for more papers by this authorSuzanne Reeser, Suzanne Reeser WellSpan Health System, York Hospital, York, PennsylvaniaSearch for more papers by this authorPedro Mancias, Pedro Mancias Department of Neurology, University of Texas–Houston Health Science Center Medical School, Houston, TexasSearch for more papers by this authorIan Butler, Ian Butler Department of Neurology, University of Texas–Houston Health Science Center Medical School, Houston, TexasSearch for more papers by this authorJames R. Lupski, Corresponding Author James R. Lupski jlupski@bcm.tmc.edu Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Department of Pediatrics, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, TexasOne Baylor Plaza, Room 604B, Houston, TX 77030Search for more papers by this author First published: 17 March 2005 https://doi.org/10.1002/humu.20153Citations: 71 † Communicated by Christine Van Broeckhoven ‡ The Supplementary Material referred to in this article can be accessed at http://www.interscience.wiley.com/jpages/1059-7794/suppmat. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive weakness and atrophy of distal limb muscles. Recently, SIMPLE/LITAF was shown to be responsible for an autosomal dominant demyelinating form of CMT linked to 16p (CMT1C). Although two transcripts encoding different proteins (SIMPLE and LITAF) have been reported from the same gene, we could not confirm the existence of LITAF. Here we show that the LITAF transcript appears to result from a DNA sequencing error. We screened the SIMPLE gene for mutations in a cohort of 192 patients with CMT or related neuropathies, each of whom tested negative for other known genetic causes of CMT. In 16 unrelated CMT families we identified nine different nucleotide variations in SIMPLE that were not detected in control chromosomes. SIMPLE mutations can occur de novo, associated with sporadic CMT1 and may convey both demyelinating and axonal forms. Bioinformatics analyses and other observations of SIMPLE suggest that 1) it could be a member of the RING finger motif–containing subfamily of E3 ubiquitin ligases that are associated with the ubiquitin-mediated proteasome processing pathway, 2) it could interact through its PPXY motifs with a WW domain containing protein, for instance with NEDD4, an E3 ubiquitin ligase, and 3) it could interact through the PSAP motif with TSG10, a protein associated with endosomal multivesicular protein sorting. Since both SIMPLE and Hrs are endosomal proteins and have both PPXY and P(S/T)AP motifs, we hypothesize that SIMPLE, like Hrs, is potentially a clathrin adaptor aiding in the retention of ubiquitinated proteins on to the endosomes. Thus the potential E3 ubiquitin ligase activity of SIMPLE, alteration in its interactions with NEDD4 or TSG101, or changes in its properties as a clathrin coat adaptor may underlie the pathogenesis of Charcot-Marie-Tooth disease. Hum Mutat 25:372–383, 2005. © 2005 Wiley-Liss, Inc. Citing Literature Supporting Information Filename Description jwsHUMU.v25.4.372.fig1.pdf98.3 KB Supporting Information file jwsHUMU.v25.4.372.fig1.pdf jwsHUMU.v25.4.372.fig2.pdf42 KB Supporting Information file jwsHUMU.v25.4.372.fig2.pdf Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume25, Issue4April 2005Pages 372-383 RelatedInformation