ADPKD-Causing Missense Variants in Polycystin-1 Disrupt Cell Surface Localization or Polycystin Channel Function.

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is the primary monogenic cause of kidney failure, impacting millions globally.
• Limited understanding of ADPKD mechanisms has impeded the development of effective therapeutic strategies.
• Polycystin-1 (PC1) is a key protein implicated in ADPKD pathogenesis.

Purpose of the Study:

• To develop functional bioassays for classifying missense variants in polycystin-1 (PC1).
• To elucidate the mechanistic basis of ADPKD pathogenesis by categorizing PC1 variants.
• To identify potential therapeutic targets for ADPKD.

Main Methods:

• Development of novel bioassays to assess polycystin-1 (PC1) function.
• Functional classification of ADPKD-associated missense variants in PC1.
• Investigation of small molecule effects on polycystin localization and channel activity.

Main Results:

• ADPKD pathogenic missense variants were categorized into two main groups: those affecting cell surface localization and those impacting ion channel activity.
• Bioassays successfully classified the functional impact of various PC1 missense variants.
• A small molecule was identified that could rescue defective polycystin surface localization.

Conclusions:

• Missense variants in polycystin-1 (PC1) contribute to ADPKD through distinct mechanisms affecting protein localization or channel function.
• Targeting polycystin-1 (PC1) cell surface localization and ion channel activity represents a promising therapeutic avenue for ADPKD.
• Small-molecule interventions hold potential for treating autosomal dominant polycystic kidney disease (ADPKD).