TY - JOUR
T1 - Pathogenic Variants in NUP214 Cause “Plugged” Nuclear Pore Channels and Acute Febrile Encephalopathy
AU - Fichtman, Boris
AU - Harel, Tamar
AU - Biran, Nitzan
AU - Zagairy, Fadia
AU - Applegate, Carolyn D.
AU - Salzberg, Yuval
AU - Gilboa, Tal
AU - Salah, Somaya
AU - Shaag, Avraham
AU - Simanovsky, Natalia
AU - Ayoubieh, Houriya
AU - Sobreira, Nara
AU - Punzi, Giuseppe
AU - Pierri, Ciro Leonardo
AU - Hamosh, Ada
AU - Elpeleg, Orly
AU - Harel, Amnon
AU - Edvardson, Simon
N1 - Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2019/7/3
Y1 - 2019/7/3
N2 - 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.
AB - 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.
KW - NUP214
KW - NUP88
KW - central channel particles
KW - febrile encephalopathy
KW - neurodegeneration
KW - nuclear pore complex
KW - nucleoporins
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U2 - 10.1016/j.ajhg.2019.05.003
DO - 10.1016/j.ajhg.2019.05.003
M3 - Article
C2 - 31178128
AN - SCOPUS:85068059765
SN - 0002-9297
VL - 105
SP - 48
EP - 64
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -