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

Matias Wagner, Daniel P. S. Osborn, Ina Gehweiler, Maike Nagel, Ulrike Ulmer, Somayeh Bakhtiari, Rim Amouri, Reza Boostani, Faycal Hentati, Maryam M. Hockley, Benedikt Hölbling, Thomas Schwarzmayr, Ehsan Ghayoor Karimiani, Christoph Kernstock, Reza Maroofian, Wolfgang Müller-Felber, Ege Ozkan, Sergio Padilla-Lopez, Selina Reich, Jennifer Reichbauer, Hossein Darvish, Neda Shahmohammadibeni, Abbas Tafakhori, Katharina Vill, Stephan Zuchner, Michael C. Kruer, Juliane Winkelmann, Yalda Jamshidi and Rebecca Schüle ()
Additional contact information
Matias Wagner: Technische Universität München
Daniel P. S. Osborn: St George’s University of London
Ina Gehweiler: University of Tübingen
Maike Nagel: University of Tübingen
Ulrike Ulmer: University of Tübingen
Somayeh Bakhtiari: Phoenix Children’s Hospital
Rim Amouri: Mongi Ben Hmida National Institute of Neurology
Reza Boostani: Department of Neurology
Faycal Hentati: Mongi Ben Hmida National Institute of Neurology
Maryam M. Hockley: University of Arizona College of Medicine
Benedikt Hölbling: University of Tübingen
Thomas Schwarzmayr: Helmholtz Zentrum München
Ehsan Ghayoor Karimiani: St George’s University of London
Christoph Kernstock: University of Tübingen
Reza Maroofian: St George’s University of London
Wolfgang Müller-Felber: Ludwig-Maximilians-University of Munich
Ege Ozkan: St George’s University of London
Sergio Padilla-Lopez: Phoenix Children’s Hospital
Selina Reich: University of Tübingen
Jennifer Reichbauer: University of Tübingen
Hossein Darvish: Semnan University of Medical Sciences
Neda Shahmohammadibeni: Semnan University of Medical Sciences
Abbas Tafakhori: Tehran University of Medical Sciences
Katharina Vill: Ludwig-Maximilians-University of Munich
Stephan Zuchner: Dr. John T. Macdonald Foundation, Department of Human Genetics
Michael C. Kruer: Phoenix Children’s Hospital
Juliane Winkelmann: Technische Universität München
Yalda Jamshidi: St George’s University of London
Rebecca Schüle: University of Tübingen

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12620-9

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