title: Defects of CRB2 cause steroid-resistant nephrotic syndrome.
abstract: Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, 751 85 Uppsala, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Lwaki
authors.initials: L
authors.lastname: Ebarasi
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Children's and Academic Renal Unit, University of Bristol, Bristol BS1 5NB, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bierzynska
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Children's and Academic Renal Unit, University of Bristol, Bristol BS1 5NB, UK.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: McCarthy
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Lovric
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Sadowski
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Werner
authors.initials: W
authors.lastname: Pabst
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Vega-Warner
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fang
authors.affiliation: Department of Experimental Immunobiology, Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Ania
authors.initials: A
authors.lastname: Koziell
authors.affiliation: Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Departments of Pediatric Nephrology and Rheumatology, Erciyes University, Kayseri 38039, Turkey.
authors.forename: Ismail
authors.initials: I
authors.lastname: Dursun
authors.affiliation: Department of Pediatric Nephrology, Dr. Behcet Uz Children Hospital, Izmir 35210, Turkey.
authors.forename: Erkin
authors.initials: E
authors.lastname: Serdaroglu
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.affiliation: Children's and Academic Renal Unit, University of Bristol, Bristol BS1 5NB, UK.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, 751 85 Uppsala, Sweden. Electronic address: arindam.majumdar@igp.uu.se.
authors.forename: Arindam
authors.initials: A
authors.lastname: Majumdar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D059472:Exome; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009404:Nephrotic Syndrome / Q000150:complications / Q000235:genetics*; D050199:Podocytes; D051381:Rats; D015027:Zebrafish / Q000235:genetics
chemical_list: C492531:CRB2 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; C113267:nephrin