Autosomal Recessive Polycystic Kidney Disease: The complete molecular architecture for the PKHD1 gene and its protein

Fibrocystin/polyductin is a large single-pass transmembrane glycoprotein involved in tubulogenesis and maintenance of the epithelium, where disease-causing variants in its encoding gene PKHD1 cause autosomal recessive polycystic kidney disease (ARPKD).While enormous experimental efforts have been taken to characterize proteins involved in autosomal dominant polycystic kidney disease, the structural and molecular basis of fibrocystin has lagged behind with no known mechanistic models.Here, our study introduces the first idealized molecular model of fibrocystin, where we confirm the established domain architecture and refine the nomenclature of unresolved regions.Using our molecular model, we show that disease-causing missense variants tend to be buried and impose significant loss-of-function effects to the monomer.Furthermore, our molecular model suggests that the protective kidney survival outcomes associated with missense variants from amino acids 709-1837 are likely a result of their surface exposure on the IPT domains.Likewise, the protective hepatic outcomes of missense variants occurring in amino acids 1838-2624 are predicted to impose weakly destabilizing effects compared to all other functional classes of variants.Overall, our idealized model is the first to provide potential hypotheses addressing the broad diversity of phenotypes, thereby laying a foundation for basic and translational efforts for ARPKD.