title: 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 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.affiliation: Departments of Pediatrics, Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; rasheed.gbadegesin@duke.edu.
authors.forename: Rasheed A
authors.initials: RA
authors.lastname: Gbadegesin
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Medicine, and.
authors.forename: Gentzon
authors.initials: G
authors.lastname: Hall
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine;
authors.forename: Nils
authors.initials: N
authors.lastname: Hanke
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany;
authors.forename: Irini
authors.initials: I
authors.lastname: Tossidou
authors.affiliation: Pathology, and.
authors.forename: James
authors.initials: J
authors.lastname: Burchette
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Medicine, and.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wu
authors.affiliation: Departments of Pediatrics, Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: Alison
authors.initials: A
authors.lastname: Homstad
authors.affiliation: Medicine, and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sparks
authors.affiliation: Medicine, and.
authors.forename: Jose
authors.initials: J
authors.lastname: Gomez
authors.affiliation: Departments of Pediatrics, Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: Ruiji
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Departments of Pediatrics, Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: Andrea
authors.initials: A
authors.lastname: Alonso
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Medicine, and Trinity Health Kidney Centre, Tallaght Hospital, Trinity College, Dublin, Ireland;
authors.forename: Peter
authors.initials: P
authors.lastname: Lavin
authors.affiliation: Department of Nephrology, Beaumont Hospital, Dublin, Ireland;
authors.forename: Peter
authors.initials: P
authors.lastname: Conlon
authors.affiliation: Mount Desert Island Biological Laboratory, Salisbury Cove, Maine; The Jackson Laboratory, Bar Harbor, Maine;
authors.forename: Ron
authors.initials: R
authors.lastname: Korstanje
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: M Christine
authors.initials: MC
authors.lastname: Stander
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Ghaidan
authors.initials: G
authors.lastname: Shamsan
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
authors.forename: Moumita
authors.initials: M
authors.lastname: Barua
authors.affiliation: Medicine, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Spurney
authors.affiliation: Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
authors.affiliation: Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine;
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Pathology, and.
authors.forename: David
authors.initials: D
authors.lastname: Howell
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri;
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine;
authors.forename: Mario
authors.initials: M
authors.lastname: Schiffer
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Medicine, and.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D017124:Conserved Sequence; D003285:Contractile Proteins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D059472:Exome; D005260:Female; D055785:Gene Knockdown Techniques; D060730:Glomerular Filtration Barrier / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D050199:Podocytes / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: C000591059:ANLN protein, human; D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003285:Contractile Proteins; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D050505:Mutant Proteins; D029961:Zebrafish Proteins; C095886:anillin