TY - JOUR
T1 - Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia
AU - Wagner, Matias
AU - Osborn, Daniel P.S.
AU - Gehweiler, Ina
AU - Nagel, Maike
AU - Ulmer, Ulrike
AU - Bakhtiari, Somayeh
AU - Amouri, Rim
AU - Boostani, Reza
AU - Hentati, Faycal
AU - Hockley, Maryam M.
AU - Hölbling, Benedikt
AU - Schwarzmayr, Thomas
AU - Karimiani, Ehsan Ghayoor
AU - Kernstock, Christoph
AU - Maroofian, Reza
AU - Müller-Felber, Wolfgang
AU - Ozkan, Ege
AU - Padilla-Lopez, Sergio
AU - Reich, Selina
AU - Reichbauer, Jennifer
AU - Darvish, Hossein
AU - Shahmohammadibeni, Neda
AU - Tafakhori, Abbas
AU - Vill, Katharina
AU - Zuchner, Stephan
AU - Kruer, Michael C.
AU - Winkelmann, Juliane
AU - Jamshidi, Yalda
AU - Schüle, Rebecca
N1 - Funding Information:
643578 by the BMBF under the frame of the E-Rare-3 network “PREPARE” (01GM1607: S.R. and associated partners S.Z., F.H.) and the STC-TUNGER-2015 grant “TUNGER-GENE” (01DH16024: R.S., R.A., F.H.) and via funding for the translational research consortium for HSP TreatHSP (01GM1905 to R.S.), the National Institute of Health (NIH) (grant 5R01NS072248 to R.S. and S.Z., grants 1R01NS075764, 5R01NS054132, 2U54NS065712 to S.Z., grants NS083739, 1K08NS083739 and 1R01NS106298 to M.C.K.), the Doris Duke Charitable Foundation (grant CSDA2014112 to MCK), a Valley Research Partnership award (SB) and the Interdisciplinary Center for Clinical Research (IZKF) of the University of Tübingen Medical School (scholarship 2017-1-16 to I.G.). We acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of University of Tübingen. R.M. would acknowledge the Queen Square Genomics group at University College London, which is supported by the National Institute for Health Research University Collegel London Hospitals Biomedical Research Centre.
Funding Information:
We thank the patients and their families for participation in this study. We thank the Helmholtz-Zentum Munich NGS core facility, especially Elisabeth Graf and Tim Strom as well as Gertrud Eckstein, Peter Lichtner, and Veronika Schwarzbauer for their excellent support. We are also grateful to Lisa Abreu and Matt Danzi from the Hussman Institute for Human Genomics in Miami for their expert support with handling of WGS samples and data files and we thank Katrin Dillmann from the University of Tübingen for excellent clinical coordination of this study. This study was supported by the E-RARE JTC grant “NEUROLIPID” (BMBF, 01GM1408B to R.S.), the Horizon 2020 research and innovation programm via grant 779257 “Solve-RD” to R.S. and via the ERA-NET Cofund action No.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073656623&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12620-9
DO - 10.1038/s41467-019-12620-9
M3 - Article
C2 - 31636353
AN - SCOPUS:85073656623
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4790
ER -