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; Rebecca Schüle

doi:10.1038/s41467-019-12620-9

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

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.10(1), pp.4790-13

2019-10-21

DOI: https://doi.org/10.1038/s41467-019-12620-9

PMCID: PMC6803694

PMID: 31636353

Abstract

Spastic Paraplegia, Hereditary - genetics

Skin - cytology

Calcium - metabolism

Humans

Middle Aged

Child, Preschool

Endoplasmic Reticulum - metabolism

Male

Spastic Paraplegia, Hereditary - metabolism

Gene Knockdown Techniques

Inositol 1,4,5-Trisphosphate Receptors - metabolism

Adult

Female

Neurons - metabolism

Child

Fibroblasts - metabolism

Signal Transduction

Endoplasmic Reticulum-Associated Degradation - genetics

Zebrafish

Animals

Adolescent

Cell Line, Tumor

High-Throughput Nucleotide Sequencing

Primary Cell Culture

Ubiquitin-Protein Ligases - genetics

Inositol 1,4,5-Trisphosphate - metabolism

Alterations of Ca homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca 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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.951 Huntington's Disease
Web Of Science research areas: Biochemistry & Molecular Biology
ESI research areas: Biology & Biochemistry

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Title: Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia
Creators: Matias Wagner - Institut für Neurogenomik, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany
Daniel P S Osborn - Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK
Ina Gehweiler - German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany
Maike Nagel - German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany
Ulrike Ulmer - German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany
Somayeh Bakhtiari - Departments of Child Health, Cellular & Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine, Phoenix, AZ, 85004, USA
Rim Amouri - Neuroscience Department, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia
Reza Boostani - Department of Neurology, Mashhad, Iran
Faycal Hentati - Neuroscience Department, Faculty of Medicine of Tunis, University Tunis El Manar, Tunis, Tunisia
Maryam M Hockley - Departments of Child Health, Cellular & Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine, Phoenix, AZ, 85004, USA
Benedikt Hölbling - German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany
Thomas Schwarzmayr - Institut für Neurogenomik, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany
Ehsan Ghayoor Karimiani - Next Generation Genetic Clinic, Mashhad, Iran
Christoph Kernstock - Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
Reza Maroofian - Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK
Wolfgang Müller-Felber - Department of Pediatric Neurology and Developmental Medicine, Ludwig-Maximilians-University of Munich, Lindwurmstraße 4, 80337, Munich, Germany
Ege Ozkan - Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK
Sergio Padilla-Lopez - Departments of Child Health, Cellular & Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine, Phoenix, AZ, 85004, USA
Selina Reich - German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany
Jennifer Reichbauer - German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany
Hossein Darvish - Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Neda Shahmohammadibeni - Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Abbas Tafakhori - Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
Katharina Vill - Department of Pediatric Neurology and Developmental Medicine, Ludwig-Maximilians-University of Munich, Lindwurmstraße 4, 80337, Munich, Germany
Stephan Zuchner - John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, FL33136, Miami, USA
Michael C Kruer - Departments of Child Health, Cellular & Molecular Medicine, Genetics, and Neurology, University of Arizona College of Medicine, Phoenix, AZ, 85004, USA
Juliane Winkelmann - Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Yalda Jamshidi - Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK
Rebecca Schüle - German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076, Tübingen, Germany. rebecca.schuele-freyer@uni-tuebingen.de
Publication Details: Nature communications, Vol.10(1), pp.4790-13
Publisher: England
Grant note: K08 NS083739 / NINDS NIH HHS R01 NS106298 / NINDS NIH HHS R01 NS054132 / NINDS NIH HHS R01 NS072248 / NINDS NIH HHS R01 NS075764 / NINDS NIH HHS U54 NS065712 / NINDS NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 31636353
PMCID: PMC6803694
Record Identifier: 991031577463702976