RRC ID 76682
Author Ueda H, Tran QTH, Tran LNT, Higasa K, Ikeda Y, Kondo N, Hashiyada M, Sato C, Sato Y, Ashida A, Nishio S, Iwata Y, Iida H, Matsuoka D, Hidaka Y, Fukui K, Itami S, Kawashita N, Sugimoto K, Nozu K, Hattori M, Tsukaguchi H.
Title Characterization of cytoskeletal and structural effects of INF2 variants causing glomerulopathy and neuropathy.
Journal Sci Rep
Abstract Focal 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.
Volume 13(1)
Pages 12003
Published 2023-7-25
DOI 10.1038/s41598-023-38588-7
PII 10.1038/s41598-023-38588-7
PMID 37491439
PMC PMC10368640
MeSH Actins / genetics Cytoskeleton / metabolism Formins / genetics Glomerulosclerosis, Focal Segmental* / complications Humans Microfilament Proteins / metabolism Mutation Podocytes* / metabolism
IF 3.998
Human and Animal Cells HeLa(RCB0007), COS-7(RCB0539)