Pathogenic Variants in NUP214 Cause "Plugged" Nuclear Pore Channels and Acute Febrile Encephalopathy

Am J Hum Genet. 2019 Jul 3;105(1):48-64. doi: 10.1016/j.ajhg.2019.05.003. Epub 2019 Jun 6.


We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs") in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.

Keywords: NUP214; NUP88; central channel particles; febrile encephalopathy; neurodegeneration; nuclear pore complex; nucleoporins.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Acute Febrile Encephalopathy / etiology*
  • Acute Febrile Encephalopathy / metabolism
  • Acute Febrile Encephalopathy / pathology
  • Apoptosis
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Frameshift Mutation*
  • Humans
  • Infant
  • Ion Channels / physiology*
  • Male
  • Mutation, Missense*
  • Nuclear Pore / genetics
  • Nuclear Pore / metabolism
  • Nuclear Pore / pathology*
  • Nuclear Pore Complex Proteins / chemistry
  • Nuclear Pore Complex Proteins / genetics*
  • Nuclear Pore Complex Proteins / metabolism
  • Pedigree
  • Protein Conformation


  • Ion Channels
  • NUP214 protein, human
  • Nuclear Pore Complex Proteins