ZFIN ID: ZDB-PUB-150707-1
In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress
Anderson, B.R., Howell, D.N., Soldano, K., Garrett, M.E., Katsanis, N., Telen, M.J., Davis, E.E., Ashley-Koch, A.E.
Date: 2015
Source: PLoS Genetics   11: e1005349 (Journal)
Registered Authors: Davis, Erica, Katsanis, Nicholas
Keywords: Zebrafish, Embryos, Edema, Larvae, Kidneys, Dextran, Chronic kidney disease, Anemia
MeSH Terms:
  • Animals
  • Apolipoproteins/genetics*
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Flow Cytometry
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease
  • Genetic Variation/genetics
  • Glomerular Filtration Rate/genetics
  • Glomerulonephritis, Membranous/genetics*
  • Humans
  • Kidney Glomerulus/embryology
  • Kidney Glomerulus/growth & development
  • Kidney Glomerulus/pathology*
  • Lipoproteins, HDL/genetics*
  • Microscopy, Electron, Transmission
  • Molecular Motor Proteins/genetics*
  • Morpholinos/genetics
  • Myosin Heavy Chains/genetics*
  • Zebrafish
PubMed: 26147622 Full text @ PLoS Genet.
African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.