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

Nat Commun. 2019 Oct 21;10(1):4790. doi: 10.1038/s41467-019-12620-9.

Matias Wagner ¹ ² ³, Daniel P S Osborn ⁴, Ina Gehweiler ⁵ ⁶, Maike Nagel ⁵ ⁶, Ulrike Ulmer ⁵ ⁶, Somayeh Bakhtiari ⁷ ⁸, Rim Amouri ⁹ ¹⁰, Reza Boostani ¹¹, Faycal Hentati ⁹ ¹⁰, Maryam M Hockley ⁸, Benedikt Hölbling ⁵ ⁶, Thomas Schwarzmayr ³, Ehsan Ghayoor Karimiani ⁴ ¹², Christoph Kernstock ¹³, Reza Maroofian ⁴, Wolfgang Müller-Felber ¹⁴, Ege Ozkan ⁴, Sergio Padilla-Lopez ⁷ ⁸, Selina Reich ⁵ ⁶, Jennifer Reichbauer ⁵ ⁶, Hossein Darvish ¹⁵, Neda Shahmohammadibeni ¹⁵, Abbas Tafakhori ¹⁶, Katharina Vill ¹⁴, Stephan Zuchner ¹⁷ ¹⁸, Michael C Kruer ⁷ ⁸, Juliane Winkelmann ¹ ³ ¹⁹, Yalda Jamshidi ⁴, Rebecca Schüle ²⁰ ²¹

Affiliations

1 Institute of Human Genetics, Technische Universität München, Trogerstraße 32, 81675, Munich, Germany.
2 Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
3 Institut für Neurogenomik, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
4 Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK.
5 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
6 German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany.
7 Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, 85016, USA.
8 Departments of Child Health, Cellular & Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine, Phoenix, AZ, 85004, USA.
9 Neurology Department, Mongi Ben Hmida National Institute of Neurology, Tunis, Tunisia.
10 Neuroscience Department, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia.
11 Department of Neurology, Mashhad, Iran.
12 Next Generation Genetic Clinic, Mashhad, Iran.
13 Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
14 Department of Pediatric Neurology and Developmental Medicine, Ludwig-Maximilians-University of Munich, Lindwurmstraße 4, 80337, Munich, Germany.
15 Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.
16 Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
17 Dr. John T. Macdonald Foundation, Department of Human Genetics, FL33136, Miami, USA.
18 John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, FL33136, Miami, USA.
19 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
20 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. rebecca.schuele-freyer@uni-tuebingen.de.
21 German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany. rebecca.schuele-freyer@uni-tuebingen.de.

PMID: 31636353 DOI: 10.1038/s41467-019-12620-9

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.

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