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

Matias Wagner,Ege Ozkan,Rebecca Schüle,Fayçal Hentati ,Katharina Vill,Thomas Schwarzmayr,Daniel P S Osborn,Somayeh Bakhtiari,Neda Shahmohammadibeni,Wolfgang Müller‐Felber ,Jennifer Reichbauer,Ehsan Ghayoor Karimiani,Christoph Kernstock,Rim Amouri,Abbas Tafakhori,Maryam M Hockley,Michael C Kruer,Ina Gehweiler,Maike Nagel,Hossein Darvish,Selina Reich,Stephan Züchner ,Reza Maroofian,Sérgio Padilla-Lopez ,Juliane Winkelmann,Reza Boostani,Yalda Jamshidi,Ulrike Ulmer,Benedikt V Hölbling

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.

Highlights

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases
In two siblings of an apparently autosomal recessive German family with early-onset hereditary spastic paraplegia (HSP) complicated by axonal peripheral neuropathy we performed whole genome sequencing (WGS) to identify the causative mutation, after extensive genetic testing for mutations in known HSP genes had failed to confirm the molecular diagnosis
The homozygous splice region variant in RNF170 (NM_030954.3 [https://www.ncbi.nlm.nih.gov/nuccore/NM_030954.3]) c.396+3A > G is located within a haplotype shared between the apparently unrelated parents, pointing towards a potential founder effect consistent with the origin of both parents from the same small village in the Westerwald region in Germany

Summary

Introduction

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Activated inositol 1,4,5-trisphosphate receptors are 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 prioritize this pathway for therapeutic interventions. Our findings highlight inositol 1,4,5trisphosphate signaling as a candidate pathway for the development of future therapeutic interventions

Methods

Results

Conclusion