title: Mutations in EMP2 cause childhood-onset nephrotic syndrome.
abstract: Nephrotic syndrome (NS) is a genetically heterogeneous group of diseases that are divided into steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS). SRNS inevitably leads to end-stage kidney disease, and no curative treatment is available. To date, mutations in more than 24 genes have been described in Mendelian forms of SRNS; however, no Mendelian form of SSNS has been described. To identify a genetic form of SSNS, we performed homozygosity mapping, whole-exome sequencing, and multiplex PCR followed by next-generation sequencing. We thereby detected biallelic mutations in EMP2 (epithelial membrane protein 2) in four individuals from three unrelated families affected by SRNS or SSNS. We showed that EMP2 exclusively localized to glomeruli in the kidney. Knockdown of emp2 in zebrafish resulted in pericardial effusion, supporting the pathogenic role of mutated EMP2 in human NS. At the cellular level, we showed that knockdown of EMP2 in podocytes and endothelial cells resulted in an increased amount of CAVEOLIN-1 and decreased cell proliferation. Our data therefore identify EMP2 mutations as causing a recessive Mendelian form of SSNS.
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wan
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: Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Esteve-Rudd
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Lovric
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fang
authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Toby W
authors.initials: TW
authors.lastname: Hurd
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Carolin E
authors.initials: CE
authors.lastname: Sadowski
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Allen
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.affiliation: Nephrogenetics Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
authors.forename: Emine
authors.initials: E
authors.lastname: Korkmaz
authors.affiliation: Biomedical Research Core Facilities, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Washburn
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.affiliation: Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.affiliation: Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara 06570, Turkey.
authors.forename: Sevcan A
authors.initials: SA
authors.lastname: Bakkaloglu
authors.affiliation: New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Zolotnitskaya
authors.affiliation: Nephrogenetics Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey; Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey; Center for Biobanking and Genomics, Hacettepe University, Ankara 06100, Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital and 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
mesh_terms: D000483:Alleles; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism; D049109:Cell Proliferation; D002675:Child, Preschool; D002874:Chromosome Mapping; D042783:Endothelial Cells / Q000473:pathology; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006720:Homozygote; D006801:Humans; D007223:Infant; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009404:Nephrotic Syndrome / Q000150:complications / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D051242:Caveolin 1; C486403:EMP2 protein, human; D008562:Membrane Glycoproteins