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.

Boris Fichtman ¹, Tamar Harel ², Nitzan Biran ¹, Fadia Zagairy ¹, Carolyn D Applegate ³, Yuval Salzberg ¹, Tal Gilboa ⁴, Somaya Salah ², Avraham Shaag ⁵, Natalia Simanovsky ⁶, Houriya Ayoubieh ⁷, Nara Sobreira ⁷, Giuseppe Punzi ⁸, Ciro Leonardo Pierri ⁸, Ada Hamosh ⁷, Orly Elpeleg ⁵, Amnon Harel ⁹, Simon Edvardson ¹⁰

Affiliations

1 Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel.
2 Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
3 McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4 Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91240, Israel.
5 Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
6 Department of Medical Imaging, Hadassah Medical Center, Jerusalem 91240, Israel.
7 McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Baylor-Hopkins Center for Mendelian Genomics, Jerusalem 91240, Israel, Jerusalem 91240, Israel.
8 Laboratory of Biochemistry, Molecular and Computational Biology; Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy.
9 Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel. Electronic address: amnon.harel@biu.ac.il.
10 Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91240, Israel; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.

PMID: 31178128 DOI: 10.1016/j.ajhg.2019.05.003

Abstract

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.

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