PUBLICATION

Mutations in EMP2 Cause Childhood-Onset Nephrotic Syndrome

Authors
Gee, H.Y., Ashraf, S., Wan, X., Vega-Warner, V., Esteve-Rudd, J., Lovric, S., Fang, H., Hurd, T.W., Sadowski, C.E., Allen, S.J., Otto, E.A., Korkmaz, E., Washburn, J., Levy, S., Williams, D.S., Bakkaloglu, S.A., Zolotnitskaya, A., Ozaltin, F., Zhou, W., Hildebrandt, F.
ID
ZDB-PUB-140513-5
Date
2014
Source
American journal of human genetics   94(6): 884-90 (Journal)
Registered Authors
Wan, Xiaoyang, Zhou, Weibin
Keywords
none
MeSH Terms
  • Alleles
  • Animals
  • Caveolin 1/metabolism
  • Cell Proliferation
  • Child, Preschool
  • Chromosome Mapping
  • Endothelial Cells/pathology
  • Gene Expression Regulation
  • Genetic Loci
  • Homozygote
  • Humans
  • Infant
  • Kidney/pathology
  • Kidney Failure, Chronic/etiology
  • Kidney Failure, Chronic/genetics
  • Membrane Glycoproteins/genetics*
  • Membrane Glycoproteins/metabolism
  • Mutation*
  • Nephrotic Syndrome/complications
  • Nephrotic Syndrome/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed
24814193 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes