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Wagner, M. ; Osborn, D.P.S.* ; Gehweiler, I.* ; Nagel, M.* ; Ulmer, U.* ; Bakhtiari, S.* ; Amouri, R.* ; Boostani, R.* ; Hentati, F.* ; Hockley, M.M.* ; Hölbling, B.* ; Schwarzmayr, T. ; Karimiani, E.G.* ; 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, M.C.* ; Winkelmann, J. ; Jamshidi, Y.* ; Schüle, R.*

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

Nat. Commun. 10:4790 (2019)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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-trispho-sphate 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dominant Sensory Ataxia; Ubiquitin Ligase; Receptor; Mutation; Degradation; Disease; Protein; Erlin2; Gene; Neurodegeneration
Sprache englisch
Veröffentlichungsjahr 2019
HGF-Berichtsjahr 2019
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 10, Heft: 1, Seiten: , Artikelnummer: 4790 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
G-503200-001
DOI 10.1038/s41467-019-12620-9
WOS ID WOS:000491223600005
Scopus ID 85073656623
PubMed ID 31636353
Erfassungsdatum 2019-10-24
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