Modeling Implicates in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress
African Americans have a disproportionate risk for developing chronic kidney disease compared to European Americans. Previous studies have identified a region on chromosome 22 containing two genes, MYH9 and APOL1, which likely accounts for nearly all of this difference. Previous reports provided strong statistical evidence implicating APOL1 as the major contributor to nephropathy risk in African Americans, driven by two coding variants, termed G1 and G2. However, other groups still report statistical evidence for MYH9 association in kidney disease, and animal models have demonstrated biological relevance for MYH9 function in the kidney. Here, we show that suppressing apol1 in zebrafish embryos results in perturbed kidney function. Importantly, using this in vivo assay, we show that the G1 variant appears to cause a loss of APOL1 function, while the G2 variant results in an altered protein that may be acting antagonistically in the presence of normal APOL1. We also report a genetic interaction between apol1 and myh9 under anemic stress, which is consistent with our previous findings in sickle cell disease (SCD) nephropathy patients. Finally, we provide functional evidence in vivo that the G2-altered APOL1 may be interacting with MYH9 to confer nephropathy risk.
Vyšlo v časopise:
Modeling Implicates in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005349
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1005349
Souhrn
African Americans have a disproportionate risk for developing chronic kidney disease compared to European Americans. Previous studies have identified a region on chromosome 22 containing two genes, MYH9 and APOL1, which likely accounts for nearly all of this difference. Previous reports provided strong statistical evidence implicating APOL1 as the major contributor to nephropathy risk in African Americans, driven by two coding variants, termed G1 and G2. However, other groups still report statistical evidence for MYH9 association in kidney disease, and animal models have demonstrated biological relevance for MYH9 function in the kidney. Here, we show that suppressing apol1 in zebrafish embryos results in perturbed kidney function. Importantly, using this in vivo assay, we show that the G1 variant appears to cause a loss of APOL1 function, while the G2 variant results in an altered protein that may be acting antagonistically in the presence of normal APOL1. We also report a genetic interaction between apol1 and myh9 under anemic stress, which is consistent with our previous findings in sickle cell disease (SCD) nephropathy patients. Finally, we provide functional evidence in vivo that the G2-altered APOL1 may be interacting with MYH9 to confer nephropathy risk.
Zdroje
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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