In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
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DOI：
10.1371/journal.pgen.1005349
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发表时间：
2015-07
期刊：
影响因子：
4.5
通讯作者：
Ashley-Koch AE
中科院分区：
文献类型：
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作者：
Anderson BR;Howell DN;Soldano K;Garrett ME;Katsanis N;Telen MJ;Davis EE;Ashley-Koch AE
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. 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.
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DOI：
10.1126/science.1193032
发表时间：
2010-08-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Genovese G;Friedman DJ;Ross MD;Lecordier L;Uzureau P;Freedman BI;Bowden DW;Langefeld CD;Oleksyk TK;Uscinski Knob AL;Bernhardy AJ;Hicks PJ;Nelson GW;Vanhollebeke B;Winkler CA;Kopp JB;Pays E;Pollak MR
通讯作者：
Pollak MR
影响因子：
13.6
作者：
Hall, Gentzon;Gbadegesin, Rasheed A.;Winn, Michelle P.
通讯作者：
Winn, Michelle P.
DOI：
10.1073/pnas.1308335110
发表时间：
2013-08-20
影响因子：
11.1
作者：
Jao, Li-En;Wente, Susan R.;Chen, Wenbiao
通讯作者：
Chen, Wenbiao
影响因子：
13.2
作者：
Collins, Allan J.;Foley, Robert N.;Agodoa, Lawrence
通讯作者：
Agodoa, Lawrence
影响因子：
46.9
作者：
通讯作者：
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