{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:57:28Z","timestamp":1793692648804,"version":"4.5.1"},"reference-count":95,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","funder":[{"name":"Mayo Graduate School of Biomedical Sciences Initiative for Maximizing Student Development","award":["DK109597"],"award-info":[{"award-number":["DK109597"]}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK058816"],"award-info":[{"award-number":["DK058816"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK59597"],"award-info":[{"award-number":["DK59597"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mayo Translational PKD Center","award":["DK090728"],"award-info":[{"award-number":["DK090728"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>The lack of rapidly progressive murine models reflecting the more severe end of the spectrum of autosomal recessive polycystic kidney disease (ARPKD) inhibits progress to understanding ARPKD pathogenesis. Defects in primary cilia have been implicated in polycystic kidney disease, but their potential role is poorly understood. The authors generated and characterized new mouse and rat models of ARPKD and autosomal dominant polycystic kidney disease (ADPKD) and investigated the interaction between causative genes for these two conditions. Their digenic models demonstrated a synergistic interaction that better reflects the early-onset disease characteristic of ARPKD. Analysis of mRNA expression in the models highlighted different disrupted pathways, but with a commonality of dysregulated mechanisms associated with primary cilia. These models may improve understanding of ARPKD and preclinical testing for this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes\n                      <jats:italic toggle=\"yes\">PKD1<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">PKD2<\/jats:italic>\n                      (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by\n                      <jats:italic toggle=\"yes\">PKHD1<\/jats:italic>\n                      (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\u2019s mild phenotype in murine models versus in humans has hampered investigating its pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To study the interaction between\n                      <jats:italic toggle=\"yes\">Pkhd1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Pkd1<\/jats:italic>\n                      , including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">Pkhd1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Pkd1<\/jats:italic>\n                      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.\n                      <jats:italic toggle=\"yes\">Pkhd1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2019020150","type":"journal-article","created":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T16:34:04Z","timestamp":1566232444000},"page":"2113-2127","source":"Crossref","is-referenced-by-count":55,"title":["Synergistic Genetic Interactions between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models"],"prefix":"10.1681","volume":"30","author":[{"given":"Rory J.","family":"Olson","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Graduate School of Biomedical Sciences, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2420-2358","authenticated-orcid":false,"given":"Katharina","family":"Hopp","sequence":"additional","affiliation":[{"name":"Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harrison","family":"Wells","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Furtado","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Graduate School of Biomedical Sciences, Rochester, Minnesota;"},{"name":"Biological and Biomedical Sciences Program, Yale University School of Medicine, New Haven, Connecticut; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Constans","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana L.","family":"Escobar","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aron M.","family":"Geurts","sequence":"additional","affiliation":[{"name":"Gene Editing Rat Resource Center, Medical College of Wisconsin, Milwaukee, Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente E.","family":"Torres","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-6593","authenticated-orcid":false,"given":"Peter C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Graduate 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