Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS

J Am Soc Nephrol. 2014 Sep;25(9):1991-2002. doi: 10.1681/ASN.2013090976.

Rasheed A Gbadegesin ¹, Gentzon Hall ², Adebowale Adeyemo ³, Nils Hanke ⁴, Irini Tossidou ⁵, James Burchette ⁶, Guanghong Wu ², Alison Homstad ⁷, Matthew A Sparks ⁸, Jose Gomez ⁸, Ruiji Jiang ⁷, Andrea Alonso ⁷, Peter Lavin ⁹, Peter Conlon ¹⁰, Ron Korstanje ¹¹, M Christine Stander ¹², Ghaidan Shamsan ¹², Moumita Barua ¹³, Robert Spurney ⁸, Pravin C Singhal ¹⁴, Jeffrey B Kopp ¹⁵, Hermann Haller ⁴, David Howell ⁶, Martin R Pollak ¹³, Andrey S Shaw ¹², Mario Schiffer ⁴, Michelle P Winn ²

Affiliations

1 Departments of Pediatrics, Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; rasheed.gbadegesin@duke.edu.
2 Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Medicine, and.
3 Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;
4 Department of Nephrology, Hannover Medical School, Hannover, Germany; Mount Desert Island Biological Laboratory, Salisbury Cove, Maine;
5 Department of Nephrology, Hannover Medical School, Hannover, Germany;
6 Pathology, and.
7 Departments of Pediatrics, Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
8 Medicine, and.
9 Center for Human Genetics, Duke University Medical Center, Durham, North Carolina; Medicine, and Trinity Health Kidney Centre, Tallaght Hospital, Trinity College, Dublin, Ireland;
10 Department of Nephrology, Beaumont Hospital, Dublin, Ireland;
11 Mount Desert Island Biological Laboratory, Salisbury Cove, Maine; The Jackson Laboratory, Bar Harbor, Maine;
12 Howard Hughes Medical Institute, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri;
13 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
14 Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York; and.
15 Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

PMID: 24676636 DOI: 10.1681/ASN.2013090976

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.

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