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In Vivo Expression of NUP93 and Its Alteration by NUP93 Mutations Causing Focal Segmental Glomerulosclerosis

Authors :
Kiyoshi Hayasaka
Hideki Ishida
Keiichi Takizawa
Seiya Urae
Motoshi Hattori
Daisuke Ogino
Tetsuo Mitsui
Yutaka Harita
Shigeru Horita
Taeko Hashimoto
Kiyonobu Ishizuka
Kenichiro Miura
Gen Tamiya
Source :
Kidney International Reports, Kidney International Reports, Vol 4, Iss 9, Pp 1312-1322 (2019)
Publication Year :
2019
Publisher :
Elsevier BV, 2019.

Abstract

Introduction: Mutations in genes encoding nucleoporins (NUPs; components of nuclear pore complexes [NPCs]), such as NUP93, have been reported to cause steroid-resistant nephrotic syndrome (SRNS) or focal segmental glomerulosclerosis (FSGS), which often progresses to end-stage renal disease (ESRD) in childhood. The expression of NUP93 in renal or extrarenal tissues, and the mechanism by which NUP93 mutations cause this renal phenotype, remain unclear. Methods: The expression of NUP93 in normal control kidney and in a patient with FSGS carrying NUP93 mutations was examined by immunofluorescence analysis. The expression of NUP93 in blood cells was analyzed by Western blot analysis. Results: Immunofluorescence analysis detected NUP93 expression in nuclei of all glomerular and tubulointerstitial cells in human kidneys. Whole-exome sequencing identified a compound heterozygous NUP93 mutation comprising a novel missense mutation p.Arg525Trp, and a previously reported mutation, p.Tyr629Cys, in a patient with FSGS that developed ESRD at the age of 6 years. In the patient’s kidney, the intensity of NUP93 immunofluorescence was significantly decreased in the nuclei of both glomerular and extraglomerular cells. The expression of CD2-associated protein (CD2AP) and nephrin in the patient’s podocytes was relatively intact. The amount of NUP93 protein was not significantly altered in the peripheral blood mononuclear cells of the patient. Conclusion: NUP93 is expressed in the nuclei of all the cell types of the human kidney. Altered NUP93 expression in glomerular cells as well as extraglomerular cells by NUP93 mutations may underlie the pathogenic mechanism of SRNS or FSGS. Keywords: focal segmental glomerulosclerosis, nuclear pore complex, nucleoporin, NUP93, steroid-resistant nephrotic syndrome

Details

ISSN :
24680249
Volume :
4
Database :
OpenAIRE
Journal :
Kidney International Reports
Accession number :
edsair.doi.dedup.....75a6b3ab09954cdcbff92e946d6d99e9
Full Text :
https://doi.org/10.1016/j.ekir.2019.05.1157