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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Calcium / metabolism
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum-Associated Degradation / genetics*
  • Female
  • Fibroblasts / metabolism*
  • Gene Knockdown Techniques
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Male
  • Middle Aged
  • Neurons / metabolism*
  • Primary Cell Culture
  • Signal Transduction
  • Skin / cytology
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Zebrafish

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol 1,4,5-Trisphosphate
  • RNF170 protein, human
  • Ubiquitin-Protein Ligases
  • Calcium