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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
Korrespondenzautor
Schlagwörter Dominant Sensory Ataxia; Ubiquitin Ligase; Receptor; Mutation; Degradation; Disease; Protein; Erlin2; Gene; Neurodegeneration
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
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)