Mutations in the Gene That Encodes the F-Actin Binding Protein Anillin Cause FSGS
Year: 2014
Type: article
Study design: Observational Study
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 diaphragm-associated 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.
Authors: Rasheed A. Gbadegesin, Gentzon Hall, Adebowale Adeyemo, Nils Hanke, Irini Tossidou, James Burchette, Guanghong Wu, Alison Homstad, Matthew A. Sparks, Jose Gomez, Ruiji Jiang, Andrea Alonso, Peter Lavin, Peter Conlon, Ron Korstanje, M. Christine Stander, Ghaidan Shamsan, Moumita Barua, Robert Spurney, Pravin C. Singhal, Jeffrey B. Kopp, Hermann Haller, David Howell, Martin R. Pollak, Andrey S. Shaw, Mario Schiffer, Michelle P. Winn
Institutions: Duke University, Duke Medical Center, Pediatrics and Genetics, National Institutes of Health, National Human Genome Research Institute, Mount Desert Island Biological Laboratory, Medizinische Hochschule Hannover, Trinity College Dublin, Tallaght University Hospital, Beaumont Hospital, Jackson Laboratory, Howard Hughes Medical Institute, Washington University in St. Louis, Beth Israel Deaconess Medical Center, Northwell Health, Feinstein Institute for Medical Research, National Institute of Diabetes and Digestive and Kidney Diseases
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Mount Desert Island Biological Laboratory, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G1050801880, Comparative Biology of Tissue Repair, Regeneration and Aging, ADCC Genomic Medicine Approach to MCI and Dementia, George M. O'Brien Kidney Research Core Centers, Determinants of protection in HIV-exposed seronegative men , Characterization of TRPC6 As A Cause for Focal and Segmental Glomerulosclerosis, Functional and Phenotypic Characterization of a New FSGS Gene, Gene Discovery in Autosomal Dominant Focal Segmental Glomerulosclerosis, Duke Training Grant in Nephrology, G6531385732, A New Locus for Hereditary FSGS on Chromosome 2p, Regulation of Podocyte Function By Angiotensin II, The Genetic Basis of FSGS, Role of Gq Signaling in Promoting Podocyte Injury in Diabetes Mellitus, Full Human Genome Sequencing in ALS, Functional and Phenotypic Characterization of a New FSGS Gene, Whole-genome sequencing for rare highly penetrant gene variants in schizophrenia
OpenAlex ID: W2148617543