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

Wagner, M; Osborn, DPS; Gehweiler, I; Nagel, M; Ulmer, U; Bakhtiari, S; Amouri, R; Boostani, R; Hentati, F; Hockley, MM; et al. Wagner, M; Osborn, DPS; Gehweiler, I; Nagel, M; Ulmer, U; Bakhtiari, S; Amouri, R; Boostani, R; Hentati, F; Hockley, MM; Hölbling, B; Schwarzmayr, T; Karimiani, EG; Kernstock, C; Maroofian, R; Müller-Felber, W; Ozkan, E; Padilla-Lopez, S; Reich, S; Reichbauer, J; Darvish, H; Shahmohammadibeni, N; Tafakhori, A; Vill, K; Zuchner, S; Kruer, MC; Winkelmann, J; Jamshidi, Y; Schüle, R (2019) Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. Nat Commun, 10 (1). p. 4790. ISSN 2041-1723 https://doi.org/10.1038/s41467-019-12620-9
SGUL Authors: Jamshidi, Yalda Osborn, Daniel Peter Sayer

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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.

Item Type: Article
Additional Information: Open Access 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, visithttp://creativecommons.org/licenses/by/4.0/. © The Author(s) 2019
Keywords: MD Multidisciplinary
Journal or Publication Title: Nat Commun
ISSN: 2041-1723
Language: eng
Dates:
DateEvent
21 October 2019Published
18 September 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
01DH16024Bundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100002347
CSDA2014112Doris Duke Charitable Foundationhttp://dx.doi.org/10.13039/100000862
NS083739National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
01GM1408BBundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100002347
779257Horizon 2020UNSPECIFIED
01GM1607Bundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100002347
01GM1905Bundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100002347
5R01NS072248National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
1R01NS075764National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
5R01NS054132National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
2U54NS065712National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
1K08NS083739National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
1R01NS106298National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
PubMed ID: 31636353
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111325
Publisher's version: https://doi.org/10.1038/s41467-019-12620-9

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