A Novel TRPC6 Mutation Causes Autosomal Dominant FSGS

Abstract

FSGS is the most common primary glomerular lesion that causes kidney failure in the US. FSGS results from injury or loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic variants in TRPC6 can cause FSGS through dysregulated calcium conductance and associated disturbances in podocyte physiology. Here, we describe a 5-generation kindred with FSGS caused by a novel compound C-terminal TRPC6 mutation. Analysis of patient-specific iPSC-derived podocytes and glomerular capillary wall-on-a-chip systems revealed that the compound variants disrupt TRPC6 protein structure, intermolecular interactions, and membrane localization. Combined therapy with Sildenafil and Losartan ameliorated these disturbances compared to conventional immunosuppressive treatment.