Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy-Reference-Cited by-同舟云学术

Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy

Published:2023-07-25 Issue:1 Volume:13 Page:
ISSN:2045-2322
Container-title:Scientific Reports
language:en
Short-container-title:Sci Rep

Author:

Ueda Hiroko,Tran Quynh Thuy Huong,Tran Linh Nguyen Truc,Higasa Koichiro,Ikeda Yoshiki,Kondo Naoyuki,Hashiyada Masaki,Sato Chika,Sato Yoshinori,Ashida Akira,Nishio Saori,Iwata Yasunori,Iida Hiroyuki,Matsuoka Daisuke,Hidaka Yoshihiko,Fukui Kenji,Itami Suzu,Kawashita Norihito,Sugimoto Keisuke,Nozu Kandai,Hattori Motoshi,Tsukaguchi Hiroyasu

Abstract

AbstractFocal segmental glomerulosclerosis (FSGS) is a common glomerular injury leading to end-stage renal disease. Monogenic FSGS is primarily ascribed to decreased podocyte integrity. Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes (Charcot–Marie–Tooth CMT/FSGS). To understand the molecular basis for INF2 disorders, we compared structural and cytoskeletal effects of INF2 variants classified into two subgroups: One (G73D, V108D) causes the CMT/FSGS phenotype, and the other (T161N, N202S) produces monogenic FSGS. Molecular dynamics analysis revealed that all INF2 variants show distinct flexibility compared to the wild-type INF2 and could affect stability of an intramolecular interaction between their N- and C-terminal segments. Immunocytochemistry of cells expressing INF2 variants showed fewer actin stress fibers, and disorganization of cytoplasmic microtubule arrays. Notably, CMT/FSGS variants caused more prominent changes in mitochondrial distribution and fragmentation than FSGS variants and these changes correlated with the severity of cytoskeletal disruption. Our results indicate that CMT/FSGS variants are associated with more severe global cellular defects caused by disrupted cytoskeleton-organelle interactions than are FSGS variants. Further study is needed to clarify tissue-specific pathways and/or cellular functions implicated in FSGS and CMT phenotypes

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

Link

https://www.nature.com/articles/s41598-023-38588-7.pdf

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