ADPKD-Causing Missense Variants in Polycystin-1 Disrupt Cell Surface Localization or Polycystin Channel Function
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Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of this monogenic disorder, our limited mechanistic understanding of ADPKD has hindered therapeutic development. Here, we successfully developed bioassays that functionally classify missense variants in polycystin-1 (PC1). Strikingly, ADPKD pathogenic missense variants cluster into two major categories: 1) those that disrupt polycystin cell surface localization or 2) those that attenuate polycystin ion channel activity. We found that polycystin channels with defective surface localization could be rescued with a small molecule. We propose that small-molecule-based strategies to improve polycystin cell surface localization and channel function will be effective therapies for ADPKD patients.
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classify ADPKD-causing missense variants
Have you ever taken a look to see whether any of these variants, particularly the ones that affect localization, are naturally occurring in other species. I'm curious whether there could be clues in biology as to how such variants are compensated for elsewhere. Would be fun to check! Let us know if we can help at Arcadia.
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In contrast, one small molecule, C3, also known as VRT-325, increased ciliary localization of PC1 R2215W and L4317P (Figure 5A,B, Supplementary Figure 3)
This is really exciting. Curious whether you ever got to test this in any in vivo model to see whether it affects disease traits? (or maybe this is next up in your plans!)
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Moreover, the 5 pathogenic PC1 variants
Did you happen to check whether the other 3/8 had this effect too? Wondering if they might still impact primary cilia, despite not exhibiting the same detectable phenotype in your previous assay.
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In contrast, 5 out of 8 tested pathogenic variants (N77S, W139C, R2215W, T3135M, L4137P) attenuated localization to the plasma membrane (Figure 1C, magenta dots).
This is super interesting. For the 3 pathogenic variants that did not make it to this phenotype list, curious if you saw any other localization defects besides quantitative levels at the PM, i.e. specific spatial patterns at the PM?
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