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 ReichbauerHossein Darvish, Neda Shahmohammadibeni, Abbas Tafakhori, Katharina Vill, Stephan Zuchner, Michael C. Kruer, Juliane Winkelmann, Yalda Jamshidi, Rebecca Schüle

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number4790
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Hereditary Spastic Paraplegia
inositols
Inositol 1,4,5-Trisphosphate Receptors
genes
Cerebellar Ataxia
Inositol 1,4,5-Trisphosphate
Genes
mutations
Degradation
ataxia
Mutation
endoplasmic reticulum
Endoplasmic Reticulum-Associated Degradation
Neurodegenerative diseases
degradation
Gene Knockdown Techniques
Gene encoding
Ubiquitin-Protein Ligases
Zebrafish
Fibroblasts

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Wagner, M., Osborn, D. P. S., Gehweiler, I., Nagel, M., Ulmer, U., Bakhtiari, S., ... Schüle, R. (2019). Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. Nature communications, 10(1), [4790]. https://doi.org/10.1038/s41467-019-12620-9

Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. / Wagner, Matias; Osborn, Daniel P.S.; Gehweiler, Ina; Nagel, Maike; Ulmer, Ulrike; Bakhtiari, Somayeh; Amouri, Rim; Boostani, Reza; Hentati, Faycal; Hockley, Maryam M.; Hölbling, Benedikt; Schwarzmayr, Thomas; Karimiani, Ehsan Ghayoor; Kernstock, Christoph; Maroofian, Reza; Müller-Felber, Wolfgang; Ozkan, Ege; Padilla-Lopez, Sergio; Reich, Selina; Reichbauer, Jennifer; Darvish, Hossein; Shahmohammadibeni, Neda; Tafakhori, Abbas; Vill, Katharina; Zuchner, Stephan; Kruer, Michael C.; Winkelmann, Juliane; Jamshidi, Yalda; Schüle, Rebecca.

In: Nature communications, Vol. 10, No. 1, 4790, 01.12.2019.

Research output: Contribution to journalArticle

Wagner, M, Osborn, DPS, Gehweiler, I, Nagel, M, Ulmer, U, Bakhtiari, S, Amouri, R, Boostani, R, Hentati, F, Hockley, MM, Hölbling, B, Schwarzmayr, T, Karimiani, EG, Kernstock, C, Maroofian, R, Müller-Felber, W, Ozkan, E, Padilla-Lopez, S, Reich, S, Reichbauer, J, Darvish, H, Shahmohammadibeni, N, Tafakhori, A, Vill, K, Zuchner, S, Kruer, MC, Winkelmann, J, Jamshidi, Y & Schüle, R 2019, 'Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia', Nature communications, vol. 10, no. 1, 4790. https://doi.org/10.1038/s41467-019-12620-9
Wagner M, Osborn DPS, Gehweiler I, Nagel M, Ulmer U, Bakhtiari S et al. Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. Nature communications. 2019 Dec 1;10(1). 4790. https://doi.org/10.1038/s41467-019-12620-9
Wagner, Matias ; Osborn, Daniel P.S. ; Gehweiler, Ina ; Nagel, Maike ; Ulmer, Ulrike ; Bakhtiari, Somayeh ; Amouri, Rim ; Boostani, Reza ; Hentati, Faycal ; Hockley, Maryam M. ; Hölbling, Benedikt ; Schwarzmayr, Thomas ; Karimiani, Ehsan Ghayoor ; Kernstock, Christoph ; Maroofian, Reza ; Müller-Felber, Wolfgang ; Ozkan, Ege ; Padilla-Lopez, Sergio ; Reich, Selina ; Reichbauer, Jennifer ; Darvish, Hossein ; Shahmohammadibeni, Neda ; Tafakhori, Abbas ; Vill, Katharina ; Zuchner, Stephan ; Kruer, Michael C. ; Winkelmann, Juliane ; Jamshidi, Yalda ; Schüle, Rebecca. / Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. In: Nature communications. 2019 ; Vol. 10, No. 1.
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