Disruption of Polycystin Ciliary Localization and Channel Function by Autosomal Dominant Polycystic Kidney Disease–Causing Polycystin-1 Variants
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Abstract
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We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease.
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All tested pathogenic variants disrupted either polycystin-1 ciliary trafficking or channel function.
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Trafficking and channel function of some pathogenic variants was restored by low temperature culture to promote polycystin folding.
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of ADPKD, limited mechanistic understanding has hindered therapeutic development. Most ADPKD is caused by loss-of-function variants in polycystin-1 (PC1).
Methods
We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and polycystin channel function.
Results
We evaluated 29 nontruncating variants in PC1 and found that pathogenic variants disrupt two molecular phenotypes: ( 1 ) localization of PC1 at the primary cilium or ( 2 ) polycystin ion channel activity. Ciliary localization of a subset of polycystin variants was restored when cells were cultured at low temperature. A subset of variants with localization restored by low temperature formed functional channels.
Conclusions
This study demonstrated that disruptions in polycystin ciliary trafficking and channel function are common causes of ADPKD. Defects in ciliary trafficking and channel function can be rescued for a subset of pathogenic variants, establishing a foundation for polycystin-targeted therapies in ADPKD.
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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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