CAPRIN1P512L causes aberrant protein aggregation and associates with early-onset ataxia

Cell Mol Life Sci. 2022 Sep 22;79(10):526. doi: 10.1007/s00018-022-04544-3.


CAPRIN1 is a ubiquitously expressed protein, abundant in the brain, where it regulates the transport and translation of mRNAs of genes involved in synaptic plasticity. Here we describe two unrelated children, who developed early-onset ataxia, dysarthria, cognitive decline and muscle weakness. Trio exome sequencing unraveled the identical de novo c.1535C > T (p.Pro512Leu) missense variant in CAPRIN1, affecting a highly conserved residue. In silico analyses predict an increased aggregation propensity of the mutated protein. Indeed, overexpressed CAPRIN1P512L forms insoluble ubiquitinated aggregates, sequestrating proteins associated with neurodegenerative disorders (ATXN2, GEMIN5, SNRNP200 and SNCA). Moreover, the CAPRIN1P512L mutation in isogenic iPSC-derived cortical neurons causes reduced neuronal activity and altered stress granule dynamics. Furthermore, nano-differential scanning fluorimetry reveals that CAPRIN1P512L aggregation is strongly enhanced by RNA in vitro. These findings associate the gain-of-function Pro512Leu mutation to early-onset ataxia and neurodegeneration, unveiling a critical residue of CAPRIN1 and a key role of RNA-protein interactions.

Keywords: CRISPR/Cas9; De novo variant; Neurodegeneration; Prion-like domain; Protein misfolding.

Publication types

  • Case Reports

MeSH terms

  • Ataxia
  • Cell Cycle Proteins* / metabolism
  • Child
  • Humans
  • Mutation
  • Protein Aggregates*
  • RNA, Messenger / metabolism


  • CAPRIN1 protein, human
  • Cell Cycle Proteins
  • Protein Aggregates
  • RNA, Messenger