Self-defense of the kidney: Probing monoallelic expression and functional effects of proteinuria-associated CUBN variants

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The benefits of diploidy are considered to involve masking partially recessive mutations and to increase genetic diversity, which in turn may promote stress resilience and cellular plasticity. Glomerular injury, such as in nephrotic syndrome and diabetic nephropathy, can lead to tubulointerstitial fibrosis, a major driver of disease progression. Key cell types in this context are proximal tubular cells (PTCs), because they have a high metabolic demand and are continuously overloaded by the reabsorption of the proteins and lipids passing the leaky glomerulus. Particularly, saturated fatty acids carried by albumin are metabolized by the PTCs but can also cause ER stress and cell damage upon uptake. Here, I hypothesize that the combination of high functional genetic diversity and monoallelic expression at the CUBN locus, encoding for the uptake receptor cubilin, is an ancient mechanism for the protection against kidney disease. This hypothesis is based on our recent finding that CUBN mutations are very well tolerated by humans and may even confer selective heterozygote advantages in evolution despite causing urinary protein loss (or proteinuria). To address this hypothesis, we will first explore whether monoallelic CUBN expression generates beneficial cell competition among PTCs under different stress conditions. For this, we will use heterozygous CUBN-GFP cell culture and mice, in which monoallelic expression previously could be generated. Second, we will functionally validate the identified CUBN variants in the mouse and test their potency in protecting against glomerular proteinuria. Altogether, we aim to establish a novel paradigm for kidney protection with high relevance for the diagnosis, prognosis and treatment of proteinuric kidney disease.