Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia
Osborn, Daniel P S
Hockley, Maryam M
Karimiani, Ehsan Ghayoor
Kruer, Michael C
AffiliationUniv Arizona, Coll Med, Dept Child Hlth
Univ Arizona, Coll Med, Dept Cellular & Mol Med
Univ Arizona, Coll Med, Dept Genet
Univ Arizona, Coll Med, Dept Neurol
MetadataShow full item record
PublisherNATURE PUBLISHING GROUP
CitationWagner, M., Osborn, D.P.S., Gehweiler, I. et al. Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia. Nat Commun 10, 4790 (2019) doi:10.1038/s41467-019-12620-9
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AbstractAlterations 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.
NoteOpen access journal
VersionFinal published version
SponsorsE-RARE JTC grant "NEUROLIPID" (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1408B]; Horizon 2020 research and innovation programm ; Horizon 2020 research and innovation programm via ERA-NET Cofund action by the BMBFFederal Ministry of Education & Research (BMBF) [643578, 01GM1607]; STC-TUNGER-2015 grant "TUNGER-GENE" [01DH16024]; National Institute of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01NS072248, 1R01NS075764, 5R01NS054132, 2U54NS065712, NS083739, 1K08NS083739, 1R01NS106298]; Doris Duke Charitable FoundationDoris Duke Charitable Foundation (DDCF) [CSDA2014112]; Valley Research Partnership award; Interdisciplinary Center for Clinical Research (IZKF) of the University of Tubingen Medical School [2017-1-16]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG); Open Access Publishing Fund of University of Tubingen; National Institute for Health Research University Collegel London Hospitals Biomedical Research Centre;[01GM1905]