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Abstract
Homozygous Apolipoprotein L1 (APOL1) variants G1 and G2 cause APOL1-mediated kidney disease, purportedly acting as surface cation channels in podocytes. APOL1-G0 exhibits various single nucleotide polymorphisms, most commonly haplotype E150K, M228I and R255K (“KIK”; the Reference Sequence is “EMR”), whereas variants G1 and G2 are mostly found in a single “African” haplotype background (“EIK”). Several labs reported cytotoxicity with risk variants G1 and G2 in KIK or EIK background haplotypes, but used HEK-293 cells and did not verify equal surface expression. To see if haplotype matters in a more relevant cell type, we induced APOL1-G0, G1 and G2 EIK, KIK and EMR at comparable surface levels in immortalized podocytes. G1 and G2 risk variants (but not G0) caused dose-dependent podocyte death within 48h only in their native African EIK haplotype and correlated with K+ conductance (thallium FLIPR). We ruled out differences in localization and trafficking, except for possibly greater surface clustering of cytotoxic haplotypes. APOL1 surface expression was required, since Brefeldin A rescued cytotoxicity; and cytoplasmic isoforms vB3 and vC were not cytotoxic. Thus, APOL1-EIK risk variants kill podocytes in a dose and haplotype-dependent manner (as in HEK-293 cells), whereas unlike in HEK-293 cells the KIK risk variants did not.
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1 Genentech, Department of Discovery Immunology, South San Francisco, USA (ISNI:0000 0004 5899 3818); Genentech, Department of Molecular Biology, South San Francisco, USA (ISNI:0000 0004 5899 3818)
2 Genentech, Department of Discovery Immunology, South San Francisco, USA (ISNI:0000 0004 5899 3818); University of Michigan, Department of Cell and Developmental Biology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000 0004 1936 7347)
3 Genentech, Department of Biochemical and Cellular Pharmacology, South San Francisco, USA (GRID:grid.214458.e) (ISNI:0000 0004 5899 3818)
4 Utrecht University, Section of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234)
5 Genentech, Department of Human Genetics, South San Francisco, USA (GRID:grid.5477.1) (ISNI:0000 0004 5899 3818)
6 Genentech, Department of Biochemical and Cellular Pharmacology, South San Francisco, USA (GRID:grid.5477.1) (ISNI:0000 0004 5899 3818)
7 Genentech, Department of Discovery Immunology, South San Francisco, USA (GRID:grid.5477.1) (ISNI:0000 0004 5899 3818); Genentech, Department of Molecular Biology, South San Francisco, USA (GRID:grid.5477.1) (ISNI:0000 0004 5899 3818)