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    Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

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    Author
    Wagner, Matias
    Osborn, Daniel P S
    Gehweiler, Ina
    Nagel, Maike
    Ulmer, Ulrike
    Bakhtiari, Somayeh
    Amouri, Rim
    Boostani, Reza
    Hentati, Faycal
    Hockley, Maryam M
    Hölbling, Benedikt
    Schwarzmayr, Thomas
    Karimiani, Ehsan Ghayoor
    Kernstock, Christoph
    Maroofian, Reza
    Müller-Felber, Wolfgang
    Ozkan, Ege
    Padilla-Lopez, Sergio
    Reich, Selina
    Reichbauer, Jennifer
    Darvish, Hossein
    Shahmohammadibeni, Neda
    Tafakhori, Abbas
    Vill, Katharina
    Zuchner, Stephan
    Kruer, Michael C
    Winkelmann, Juliane
    Jamshidi, Yalda
    Schüle, Rebecca
    Show allShow less
    Affiliation
    Univ Arizona, Coll Med, Dept Child Hlth
    Univ Arizona, Coll Med, Dept Cellular & Mol Med
    Univ Arizona, Coll Med, Dept Genet
    Univ Arizona, Coll Med, Dept Neurol
    Issue Date
    2019-10-21
    
    Metadata
    Show full item record
    Publisher
    NATURE PUBLISHING GROUP
    Citation
    Wagner, M., Osborn, D.P.S., Gehweiler, I. et al. Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. Nat Commun 10, 4790 (2019) doi:10.1038/s41467-019-12620-9
    Journal
    NATURE COMMUNICATIONS
    Rights
    Copyright © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.
    Note
    Open access journal
    ISSN
    2041-1723
    PubMed ID
    31636353
    DOI
    10.1038/s41467-019-12620-9
    Version
    Final published version
    Sponsors
    E-RARE JTC grant "NEUROLIPID" (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1408B]; Horizon 2020 research and innovation programm [779257]; Horizon 2020 research and innovation programm via ERA-NET Cofund action by the BMBFFederal Ministry of Education & Research (BMBF) [643578, 01GM1607]; STC-TUNGER-2015 grant "TUNGER-GENE" [01DH16024]; National Institute of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01NS072248, 1R01NS075764, 5R01NS054132, 2U54NS065712, NS083739, 1K08NS083739, 1R01NS106298]; Doris Duke Charitable FoundationDoris Duke Charitable Foundation (DDCF) [CSDA2014112]; Valley Research Partnership award; Interdisciplinary Center for Clinical Research (IZKF) of the University of Tubingen Medical School [2017-1-16]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG); Open Access Publishing Fund of University of Tubingen; National Institute for Health Research University Collegel London Hospitals Biomedical Research Centre;[01GM1905]
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-019-12620-9
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