Synergistic Genetic Interactions between <i>Pkhd1</i> and <i>Pkd1</i> Result in an ARPKD-Like Phenotype in Murine Models.

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes <i>PKD1</i> or <i>PKD2</i> (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by <i>PKHD1</i> (encoding fibrocystin/polyductin [FPC]). Primary cilia have been considered central to PKD pathogenesis due to protein localization and common cystic phenotypes in syndromic ciliopathies, but their relevance is questioned in the simple PKDs. ARPKD's mild phenotype in murine models versus in humans has hampered investigating its pathogenesis. To study the interaction between <i>Pkhd1</i> and <i>Pkd1</i>, including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes. The genetic interaction was synergistic in both species, with digenic animals exhibiting phenotypes of rapidly progressive PKD and early lethality resembling classic ARPKD. Genetic interaction between <i>Pkhd1</i> and <i>Pkd1</i> depended on dosage in the digenic murine models, with no significant enhancement of the monogenic phenotype until a threshold of reduced expression at the second locus was breached. <i>Pkhd1</i> loss did not alter expression, maturation, or localization of the ADPKD polycystin proteins, with no interaction detected between the ARPKD FPC protein and polycystins. RNA-seq analysis in the digenic and monogenic mouse models highlighted the ciliary compartment as a common dysregulated target, with enhanced ciliary expression and length changes in the digenic models. These data indicate that FPC and the polycystins work independently, with separate disease-causing thresholds; however, a combined protein threshold triggers the synergistic, cystogenic response because of enhanced dysregulation of primary cilia. These insights into pathogenesis highlight possible common therapeutic targets.