Modeling Implicates in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress

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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

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1. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Johansen K, et al. 'United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States. American journal of kidney diseases: the official journal of the National Kidney Foundation. 2012;59(1 Suppl 1):A7, e1–420. doi: 10.1053/j.ajkd.2011.11.015 22177944.

2. Byrne C, Nedelman J, Luke RG. Race, socioeconomic status, and the development of end-stage renal disease. American journal of kidney diseases: the official journal of the National Kidney Foundation. 1994;23(1):16–22. 8285192.

3. Kopp JB, Winkler C. HIV-associated nephropathy in African Americans. Kidney international Supplement. 2003;(83):S43-9. 12864874.

4. Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. American journal of kidney diseases: the official journal of the National Kidney Foundation. 2004;44(5):815–25. 15492947.

5. Ashley-Koch AE, Okocha EC, Garrett ME, Soldano K, De Castro LM, Jonassaint JC, et al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. British journal of haematology. 2011;155(3):386–94. doi: 10.1111/j.1365-2141.2011.08832.x 21910715.

6. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841–5. doi: 10.1126/science.1193032 20647424; PubMed Central PMCID: PMC2980843.

7. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. Journal of the American Society of Nephrology: JASN. 2011;22(11):2129–37. doi: 10.1681/ASN.2011040388 21997394; PubMed Central PMCID: PMC3231787.

8. Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nature genetics. 2008;40(10):1175–84. doi: 10.1038/ng.226 18794856; PubMed Central PMCID: PMC2827354.

9. Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nature genetics. 2008;40(10):1185–92. doi: 10.1038/ng.232 18794854; PubMed Central PMCID: PMC2614692.

10. Freedman BI, Kopp JB, Langefeld CD, Genovese G, Friedman DJ, Nelson GW, et al. The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans. Journal of the American Society of Nephrology: JASN. 2010;21(9):1422–6. doi: 10.1681/ASN.2010070730 20688934.

11. Grabhorn R, Kopp W, Gitzinger I, von Wietersheim J, Kaufhold J. [Differences between female and male patients with eating disorders—results of a multicenter study on eating disorders (MZ-Ess)]. Psychotherapie, Psychosomatik, medizinische Psychologie. 2003;53(1):15–22. doi: 10.1055/s-2003-36479 12514763.

12. Conti MA, Even-Ram S, Liu C, Yamada KM, Adelstein RS. Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice. The Journal of biological chemistry. 2004;279(40):41263–6. doi: 10.1074/jbc.C400352200 15292239.

13. Matsushita T, Hayashi H, Kunishima S, Hayashi M, Ikejiri M, Takeshita K, et al. Targeted disruption of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia with different organ involvement: hematological, nephrological, and otological studies of heterozygous KO mice. Biochemical and biophysical research communications. 2004;325(4):1163–71. doi: 10.1016/j.bbrc.2004.10.147 15555549.

14. Suzuki N, Kunishima S, Ikejiri M, Maruyama S, Sone M, Takagi A, et al. Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability. PloS one. 2013;8(8):e71187. doi: 10.1371/journal.pone.0071187 23976996; PubMed Central PMCID: PMC3748045.

15. Zhang Y, Conti MA, Malide D, Dong F, Wang A, Shmist YA, et al. Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A. Blood. 2012;119(1):238–50. doi: 10.1182/blood-2011-06-358853 21908426; PubMed Central PMCID: PMC3251230.

16. Johnstone DB, Zhang J, George B, Leon C, Gachet C, Wong H, et al. Podocyte-specific deletion of Myh9 encoding nonmuscle myosin heavy chain 2A predisposes mice to glomerulopathy. Molecular and cellular biology. 2011;31(10):2162–70. doi: 10.1128/MCB.05234-11 21402784; PubMed Central PMCID: PMC3133349.

17. Muller T, Rumpel E, Hradetzky S, Bollig F, Wegner H, Blumenthal A, et al. Non-muscle myosin IIA is required for the development of the zebrafish glomerulus. Kidney international. 2011;80(10):1055–63. doi: 10.1038/ki.2011.256 21849970.

18. Madhavan SM O'Toole JF, Konieczkowski M, Ganesan S, Bruggeman LA, Sedor JR. APOL1 localization in normal kidney and nondiabetic kidney disease. Journal of the American Society of Nephrology: JASN. 2011;22(11):2119–28. doi: 10.1681/ASN.2011010069 21997392; PubMed Central PMCID: PMC3231786.

19. Ma L, Shelness GS, Snipes JA, Murea M, Antinozzi PA, Cheng D, et al. Localization of APOL1 Protein and mRNA in the Human Kidney: Nondiseased Tissue, Primary Cells, and Immortalized Cell Lines. Journal of the American Society of Nephrology: JASN. 2014. doi: 10.1681/ASN.2013091017 25012173.

20. Lan X, Jhaveri A, Cheng K, Wen H, Saleem MA, Mathieson PW, et al. APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability. American journal of physiology Renal physiology. 2014;307(3):F326–36. doi: 10.1152/ajprenal.00647.2013 24899058; PubMed Central PMCID: PMC4121568.

21. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. The New England journal of medicine. 1994;330(23):1639–44. doi: 10.1056/NEJM199406093302303 7993409.

22. Elmariah H, Garrett ME, De Castro LM, Jonassaint JC, Ataga KI, Eckman JR, et al. Factors associated with survival in a contemporary adult sickle cell disease cohort. American journal of hematology. 2014;89(5):530–5. doi: 10.1002/ajh.23683 24478166; PubMed Central PMCID: PMC3988218.

23. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364(9442):1343–60. doi: 10.1016/S0140-6736(04)17192-4 15474138.

24. Drummond IA. Zebrafish kidney development. Methods in cell biology. 2004;76 : 501–30. 15602890.

25. Ebarasi L, Oddsson A, Hultenby K, Betsholtz C, Tryggvason K. Zebrafish: a model system for the study of vertebrate renal development, function, and pathophysiology. Current opinion in nephrology and hypertension. 2011;20(4):416–24. doi: 10.1097/MNH.0b013e3283477797 21519251.

26. Monajemi H, Fontijn RD, Pannekoek H, Horrevoets AJ. The apolipoprotein L gene cluster has emerged recently in evolution and is expressed in human vascular tissue. Genomics. 2002;79(4):539–46. doi: 10.1006/geno.2002.6729 11944986.

27. Ko WY, Rajan P, Gomez F, Scheinfeldt L, An P, Winkler CA, et al. Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations. American journal of human genetics. 2013;93(1):54–66. doi: 10.1016/j.ajhg.2013.05.014 23768513; PubMed Central PMCID: PMC3710747.

28. Zhou W, Hildebrandt F. Inducible podocyte injury and proteinuria in transgenic zebrafish. Journal of the American Society of Nephrology: JASN. 2012;23(6):1039–47. doi: 10.1681/ASN.2011080776 22440901; PubMed Central PMCID: PMC3358760.

29. Traka M, Millen KJ, Collins D, Elbaz B, Kidd GJ, Gomez CM, et al. WDR81 is necessary for purkinje and photoreceptor cell survival. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2013;33(16):6834–44. doi: 10.1523/JNEUROSCI.2394-12.2013 23595742.

30. Hentschel DM, Mengel M, Boehme L, Liebsch F, Albertin C, Bonventre JV, et al. Rapid screening of glomerular slit diaphragm integrity in larval zebrafish. American journal of physiology Renal physiology. 2007;293(5):F1746–50. doi: 10.1152/ajprenal.00009.2007 17699558.

31. Jao LE, Wente SR, Chen W. Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(34):13904–9. doi: 10.1073/pnas.1308335110 23918387; PubMed Central PMCID: PMC3752207.

32. Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ, Sander JD, et al. Efficient genome editing in zebrafish using a CRISPR-Cas system. Nature biotechnology. 2013;31(3):227–9. doi: 10.1038/nbt.2501 23360964; PubMed Central PMCID: PMC3686313.

33. Lipkowitz MS, Freedman BI, Langefeld CD, Comeau ME, Bowden DW, Kao WH, et al. Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. Kidney international. 2013;83(1):114–20. doi: 10.1038/ki.2012.263 22832513; PubMed Central PMCID: PMC3484228.

34. Genovese G, Friedman DJ, Pollak MR. APOL1 variants and kidney disease in people of recent African ancestry. Nature reviews Nephrology. 2013;9(4):240–4. doi: 10.1038/nrneph.2013.34 23438974.

35. O'Seaghdha CM, Parekh RS, Hwang SJ, Li M, Kottgen A, Coresh J, et al. The MYH9/APOL1 region and chronic kidney disease in European-Americans. Human molecular genetics. 2011;20(12):2450–6. doi: 10.1093/hmg/ddr118 21429915; PubMed Central PMCID: PMC3098737.

36. Lindstrand A, Davis EE, Carvalho CM, Pehlivan D, Willer JR, Tsai IC, et al. Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome. American journal of human genetics. 2014;94(5):745–54. doi: 10.1016/j.ajhg.2014.03.017 24746959; PubMed Central PMCID: PMC4067552.

37. Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, et al. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. The New England journal of medicine. 2013;368(21):1992–2003. doi: 10.1056/NEJMoa1215993 23656588; PubMed Central PMCID: PMC3738065.

38. Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nature genetics. 2011;43(3):189–96. doi: 10.1038/ng.756 21258341; PubMed Central PMCID: PMC3071301.

39. Khanna H, Davis EE, Murga-Zamalloa CA, Estrada-Cuzcano A, Lopez I, den Hollander AI, et al. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nature genetics. 2009;41(6):739–45. doi: 10.1038/ng.366 19430481; PubMed Central PMCID: PMC2783476.

40. Chassaing N, Sorrentino S, Davis EE, Martin-Coignard D, Iacovelli A, Paznekas W, et al. OTX2 mutations contribute to the otocephaly-dysgnathia complex. Journal of medical genetics. 2012;49(6):373–9. doi: 10.1136/jmedgenet-2012-100892 22577225.

41. Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. Journal of the American Society of Nephrology: JASN. 2006;17(8):2228–35. doi: 10.1681/ASN.2002010084 16837635.

42. Haymann JP, Stankovic K, Levy P, Avellino V, Tharaux PL, Letavernier E, et al. Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature. Clinical journal of the American Society of Nephrology: CJASN. 2010;5(5):756–61. doi: 10.2215/CJN.08511109 20185605; PubMed Central PMCID: PMC2863976.

43. Shah DI, Takahashi-Makise N, Cooney JD, Li L, Schultz IJ, Pierce EL, et al. Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature. 2012;491(7425):608–12. doi: 10.1038/nature11536 23135403; PubMed Central PMCID: PMC3504625.

44. Leet JK, Lindberg CD, Bassett LA, Isales GM, Yozzo KL, Raftery TD, et al. High-content screening in zebrafish embryos identifies butafenacil as a potent inducer of anemia. PloS one. 2014;9(8):e104190. doi: 10.1371/journal.pone.0104190 25090246; PubMed Central PMCID: PMC4121296.

45. Gbadegesin RA, Hall G, Adeyemo A, Hanke N, Tossidou I, Burchette J, et al. Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS. Journal of the American Society of Nephrology: JASN. 2014;25(9):1991–2002. doi: 10.1681/ASN.2013090976 24676636; PubMed Central PMCID: PMC4147982.

46. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308(5729):1801–4. doi: 10.1126/science.1106215 15879175.

47. Hall G, Gbadegesin RA, Lavin P, Wu G, Liu Y, Oh EC, et al. A Novel Missense Mutation of Wilms' Tumor 1 Causes Autosomal Dominant FSGS. Journal of the American Society of Nephrology: JASN. 2015;26(4):831–43. doi: 10.1681/ASN.2013101053 25145932.

48. Parsa A, Kao WH, Xie D, Astor BC, Li M, Hsu CY, et al. APOL1 risk variants, race, and progression of chronic kidney disease. The New England journal of medicine. 2013;369(23):2183–96. doi: 10.1056/NEJMoa1310345 24206458.

49. Foster MC, Coresh J, Fornage M, Astor BC, Grams M, Franceschini N, et al. APOL1 variants associate with increased risk of CKD among African Americans. Journal of the American Society of Nephrology: JASN. 2013;24(9):1484–91. doi: 10.1681/ASN.2013010113 23766536; PubMed Central PMCID: PMC3752955.

50. Cooke JN, Bostrom MA, Hicks PJ, Ng MC, Hellwege JN, Comeau ME, et al. Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association. 2012;27(4):1505–11. doi: 10.1093/ndt/gfr522 21968013; PubMed Central PMCID: PMC3315672.

51. Ito K, Bick AG, Flannick J, Friedman DJ, Genovese G, Parfenov MG, et al. Increased burden of cardiovascular disease in carriers of APOL1 genetic variants. Circulation research. 2014;114(5):845–50. doi: 10.1161/CIRCRESAHA.114.302347 24379297; PubMed Central PMCID: PMC3982584.

52. Wan G, Zhaorigetu S, Liu Z, Kaini R, Jiang Z, Hu CA. Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death. The Journal of biological chemistry. 2008;283(31):21540–9. doi: 10.1074/jbc.M800214200 18505729; PubMed Central PMCID: PMC2490785.

53. Hartleben B, Godel M, Meyer-Schwesinger C, Liu S, Ulrich T, Kobler S, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. The Journal of clinical investigation. 2010;120(4):1084–96. doi: 10.1172/JCI39492 20200449; PubMed Central PMCID: PMC2846040.

54. Schmitt F, Martinez F, Brillet G, Giatras I, Choukroun G, Girot R, et al. Early glomerular dysfunction in patients with sickle cell anemia. American journal of kidney diseases: the official journal of the National Kidney Foundation. 1998;32(2):208–14. 9708603.

55. Limou S, Nelson GW, Kopp JB, Winkler CA. APOL1 Kidney Risk Alleles: Population Genetics and Disease Associations. Advances in chronic kidney disease. 2014;21(5):426–33. doi: 10.1053/j.ackd.2014.06.005 25168832; PubMed Central PMCID: PMC4157456.

56. Yang Z, Tong Z, Chen Y, Zeng J, Lu F, Sun X, et al. Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS genetics. 2010;6(2):e1000836. doi: 10.1371/journal.pgen.1000836 20140183; PubMed Central PMCID: PMC2816682.

57. Niederriter AR, Davis EE, Golzio C, Oh EC, Tsai IC, Katsanis N. In vivo modeling of the morbid human genome using Danio rerio. Journal of visualized experiments: JoVE. 2013;(78):e50338. doi: 10.3791/50338 23995499; PubMed Central PMCID: PMC3856313.

58. Wang D, Jao LE, Zheng N, Dolan K, Ivey J, Zonies S, et al. Efficient genome-wide mutagenesis of zebrafish genes by retroviral insertions. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(30):12428–33. doi: 10.1073/pnas.0705502104 17640903; PubMed Central PMCID: PMC1924792.

59. Ma L, Murea M, Snipes JA, Marinelarena A, Kruger J, Hicks PJ, et al. An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects. PloS one. 2013;8(2):e56193. doi: 10.1371/journal.pone.0056193 23460794; PubMed Central PMCID: PMC3584087.