Mutations in the Gene That Encodes the F-Actin Binding Protein Anillin Cause FSGS

Abstract

FSGS is characterized by segmental scarring of the glomerulus and is a leading cause of kidney failure. Identification of genes causing FSGS has improved our understanding of disease mechanisms and points to defects in the glomerular epithelial cell, the podocyte, as a major factor in disease pathogenesis. Using a combination of genome-wide linkage studies and whole-exome sequencing in a kindred with familial FSGS, we identified a missense mutation R431C in anillin (ANLN), an F-actin binding cell cycle gene, as a cause of FSGS. We screened 250 additional families with FSGS and found another variant, G618C, that segregates with disease in a second family with FSGS. We demonstrate upregulation of anillin in podocytes in kidney biopsy specimens from individuals with FSGS and kidney samples from a murine model of HIV-1-associated nephropathy. Overexpression of R431C mutant ANLN in immortalized human podocytes results in enhanced podocyte motility. The mutant anillin displays reduced binding to the slit diaphragmassociated scaffold protein CD2AP. Knockdown of the ANLN gene in zebrafish morphants caused a loss of glomerular filtration barrier integrity, podocyte foot process effacement, and an edematous phenotype. Collectively, these findings suggest that anillin is important in maintaining the integrity of the podocyte actin cytoskeleton.

KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

“…This is consistent with the finding that some of the recently identified recessive genetic causes of NS are exceedingly rare (1,20,21). In addition, we identified two families with NS with KANK2 variants.…”

Asymmetric inheritance of the apical domain and self-renewal of retinal ganglion cell progenitors depend on Anillin function

“…Anillin knockdown causes cytokinesis defects that affect early vertebrate development (Gbadegesin et al, 2014;Reyes et al, 2014) (supplementary material Movie 2). We therefore generated anillin hypomorphic conditions (supplementary material Fig.…”

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

“…The important role of the podocyte actin cytoskeleton and podocyte-glomerular basement membrane (GBM) interactions for the development of foot process effacement is supported by several genetic lossor gain-of-function models affecting the cytoskeleton and recapitulating genetic human diseases [14][15][16][17][18][19]. It would therefore seem reasonable to search for supportive therapies that would directly interfere with pathways regulating slit diaphragm protein expression and cytoskeletal pathways that activate or support the recovery potential of stressed podocytes.…”