Synergistic Genetic Interactions between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models. J Am Soc Nephrol 2019 Nov;30(11):2113-2127
Date
08/21/2019Pubmed ID
31427367Pubmed Central ID
PMC6830782DOI
10.1681/ASN.2019020150Scopus ID
2-s2.0-85074378541 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes PKD1 or PKD2 (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by PKHD1 (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.
METHODS: To study the interaction between Pkhd1 and Pkd1, including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes.
RESULTS: 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 Pkhd1 and Pkd1 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. Pkhd1 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.
CONCLUSIONS: 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.
Author List
Olson RJ, Hopp K, Wells H, Smith JM, Furtado J, Constans MM, Escobar DL, Geurts AM, Torres VE, Harris PCAuthor
Aron Geurts PhD Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCilia
Disease Models, Animal
Female
Gene Expression Profiling
Male
Mice
Mice, Inbred C57BL
Phenotype
Polycystic Kidney, Autosomal Recessive
Rats
Rats, Inbred Lew
Rats, Sprague-Dawley
Receptors, Cell Surface
TRPP Cation Channels
