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 nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 p...

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Bibliographic Details
Published in:American journal of human genetics 2019-07, Vol.105 (1), p.48-64
Main Authors: Fichtman, Boris, Harel, Tamar, Biran, Nitzan, Zagairy, Fadia, Applegate, Carolyn D., Salzberg, Yuval, Gilboa, Tal, Salah, Somaya, Shaag, Avraham, Simanovsky, Natalia, Ayoubieh, Houriya, Sobreira, Nara, Punzi, Giuseppe, Pierri, Ciro Leonardo, Hamosh, Ada, Elpeleg, Orly, Harel, Amnon, Edvardson, Simon
Format: Article
Language:English
Subjects:
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
central channel particles
Child
Child, Preschool
febrile encephalopathy
Female
Fibroblasts - metabolism
Fibroblasts - pathology
Frameshift Mutation
Humans
Infant
Ion Channels - physiology
Male
Mutation, Missense
neurodegeneration
Nuclear Pore - genetics
Nuclear Pore - metabolism
Nuclear Pore - pathology
nuclear pore complex
Nuclear Pore Complex Proteins - chemistry
Nuclear Pore Complex Proteins - genetics
Nuclear Pore Complex Proteins - metabolism
nucleoporins
NUP214
NUP88
Pedigree
Protein Conformation
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2019.05.003