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

Boris Fichtman, Tamar Harel, Nitzan Biran, Fadia Zagairy, Carolyn D. Applegate, Yuval Salzberg, Tal Gilboa, Somaya Salah, Avraham Shaag, Natalia Simanovsky, Houriya Ayoubieh, Nara Sobreira, Giuseppe Punzi, Ciro Leonardo Pierri, Ada Hamosh, Orly Elpeleg, Amnon Harel, Simon Edvardson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)48-64
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - 3 Jul 2019


  • NUP214
  • NUP88
  • central channel particles
  • febrile encephalopathy
  • neurodegeneration
  • nuclear pore complex
  • nucleoporins

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics


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