A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures

Cell. 2018 Feb 22;172(5):924-936.e11. doi: 10.1016/j.cell.2018.02.006.


Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

Keywords: Ataxin-1; PADDAS; PRCA; Pumilio1; RNA-binding proteins; ataxia; chromosome 1p35.2; copy number variants; developmental delay; intellectual disability; seizures.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Aged, 80 and over
  • Animals
  • Base Sequence
  • Child
  • Child, Preschool
  • Developmental Disabilities / diagnostic imaging
  • Developmental Disabilities / genetics*
  • Evolution, Molecular
  • Female
  • Gene Deletion
  • Genetic Predisposition to Disease*
  • HEK293 Cells
  • Haploinsufficiency / genetics*
  • Humans
  • Infant
  • Male
  • Mice
  • Middle Aged
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Pedigree
  • Protein Stability
  • RNA-Binding Proteins / genetics*
  • Seizures / diagnostic imaging
  • Seizures / genetics*


  • PUM1 protein, human
  • RNA-Binding Proteins
  • pumilio 1 protein, mouse