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

We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporinNUP214 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 porecomplexes remained normal. Nuclear transportassays 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 porechannels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear porechannel, 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 porelevel of functional changes linked to a human disease.