Show simple item record

In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.

dc.contributor.author Anderson, BR
dc.contributor.author Ashley-Koch, A
dc.contributor.author Davis, EE
dc.contributor.author Garrett, ME
dc.contributor.author Howell, DN
dc.contributor.author Katsanis, N
dc.contributor.author Soldano, Karen L
dc.contributor.author Telen, MJ
dc.coverage.spatial United States
dc.date.accessioned 2015-11-06T19:15:07Z
dc.date.issued 2015-07
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/26147622
dc.identifier PGENETICS-D-15-01120
dc.identifier.uri http://hdl.handle.net/10161/10832
dc.description.abstract 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.
dc.language eng
dc.relation.ispartof PLoS Genet
dc.relation.isversionof 10.1371/journal.pgen.1005349
dc.subject Animals
dc.subject Apolipoproteins
dc.subject Clustered Regularly Interspaced Short Palindromic Repeats
dc.subject Flow Cytometry
dc.subject Gene Knockdown Techniques
dc.subject Genetic Predisposition to Disease
dc.subject Genetic Variation
dc.subject Glomerular Filtration Rate
dc.subject Glomerulonephritis, Membranous
dc.subject Humans
dc.subject Kidney Glomerulus
dc.subject Lipoproteins, HDL
dc.subject Microscopy, Electron, Transmission
dc.subject Molecular Motor Proteins
dc.subject Morpholinos
dc.subject Myosin Heavy Chains
dc.subject Zebrafish
dc.title In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/26147622
pubs.begin-page e1005349
pubs.issue 7
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biostatistics & Bioinformatics
pubs.organisational-group Cell Biology
pubs.organisational-group Center for Child and Family Policy
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group Duke Molecular Physiology Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Hematology
pubs.organisational-group Medicine, Nephrology
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pathology
pubs.organisational-group Pediatrics
pubs.organisational-group Pediatrics, Neonatology
pubs.organisational-group Sanford School of Public Policy
pubs.organisational-group School of Medicine
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published online
pubs.volume 11
dc.identifier.eissn 1553-7404


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record