{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:30:43Z","timestamp":1786480243657,"version":"build-2736575974"},"reference-count":0,"publisher":"Ovid Technologies (Wolters Kluwer Health)","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"abstract":"\n Background<\/jats:title>\n Polycystic kidney disease (PKD) encompasses a group of genetic disorders characterized by the proliferation of fluid-filled renal cysts, leading to progressive renal failure and death. A key feature of PKD is its variable expressivity across patients, even when caused by the same variant, highlighting the importance of genetic background in PKD expression.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We identified an ostensibly healthy Sprague Dawley rat line with a variant that modifies PKD expressivity in Han:SPRD-\n Cy<\/jats:italic>\n rats (caused by a missense variant [p.Arg717Trp] in the ankyrin repeat and sterile alpha motif domain-containing 6 [\n Anks6<\/jats:italic>\n ] gene), which we named\n mcy<\/jats:italic>\n (modifier of\n Cy<\/jats:italic>\n ). We used whole genome sequencing and segregation analysis to identify the\n mcy<\/jats:italic>\n variant, quantitative PCR and mRNA sequencing to evaluate its effects on gene expression, western blotting and immunohistochemistry to assess its protein consequences, and ultrasound and histology to examine its impact on rat embryonic development.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We identified a nonsense variant in the\n Anks6<\/jats:italic>\n gene as the genetic basis of the\n mcy<\/jats:italic>\n phenotype (c.1126G>T [p.Glu376X]). While\n mcy<\/jats:italic>\n +\/\u2212<\/jats:sup>\n rats are ostensibly healthy and do not develop PKD,\n mcy<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n rats exhibit laterality defects and die prenatally at E16.5 due to apparent perturbations in cardiovascular development. Notably,\n mcy<\/jats:italic>\n +\/\u2212<\/jats:sup>\n Cy<\/jats:italic>\n +\/\u2212<\/jats:sup>\n rats develop PKD much more rapidly than\n Cy<\/jats:italic>\n +\/\u2212<\/jats:sup>\n rats and in a timeframe consistent with\n Cy<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n rats<\/jats:italic>\n . Transcripts with the\n mcy<\/jats:italic>\n variant allele appear to undergo nonsense-mediated decay, and no ANKS6 protein is detected. However, gene expression patterns in the kidneys did not differ significantly between age-matched\n mcy<\/jats:italic>\n +\/+<\/jats:sup>\n and\n mcy<\/jats:italic>\n +\/\u2212<\/jats:sup>\n rats, indicating that ANKS6 insufficiency does not cause PKD.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n We identified a novel nonsense variant in\n Anks6<\/jats:italic>\n . The findings indicate that the absence of wild-type ANKS6 accelerates PKD development in the Han:SPRD-\n Cy<\/jats:italic>\n rat, and that complete ANKS6 deficiency prevents normal embryonic development in rats.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.34067\/kid.0000001168","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T16:02:57Z","timestamp":1773244977000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Anks6 Nonsense Variant Promotes Polycystic Kidney Disease in Han:SPRD-Cy Rats and its Homozygosity is Prenatally Lethal"],"prefix":"10.34067","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-1146","authenticated-orcid":false,"given":"Trevor J.","family":"Pemberton","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4133-7526","authenticated-orcid":false,"given":"Tanja","family":"Winter","sequence":"additional","affiliation":[{"name":"Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada"},{"name":"Canadian Centre for Research in Agri-Food Research in Health and Medicine, St Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6841-8473","authenticated-orcid":false,"given":"Richard","family":"Hemming","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2265-8144","authenticated-orcid":false,"given":"Alexandra","family":"Blant","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes L.","family":"Fresnoza","sequence":"additional","affiliation":[{"name":"Central Animal Care Services, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1025-4142","authenticated-orcid":false,"given":"Emily N.","family":"Barker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8317-402X","authenticated-orcid":false,"given":"Mehrafarin","family":"Ashiri","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5191-4628","authenticated-orcid":false,"given":"Vernon W.","family":"Dolinsky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-6779","authenticated-orcid":false,"given":"Barbara","family":"Triggs-Raine","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6982-7239","authenticated-orcid":false,"given":"Harold M.","family":"Aukema","sequence":"additional","affiliation":[{"name":"Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada"},{"name":"Canadian Centre for Research in Agri-Food Research in Health and Medicine, St Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,3,11]]},"container-title":["Kidney360"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000001168","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T19:59:37Z","timestamp":1786478377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000001168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,11]]},"references-count":0,"URL":"https:\/\/doi.org\/10.34067\/kid.0000001168","relation":{},"ISSN":["2641-7650"],"issn-type":[{"value":"2641-7650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,11]]},"assertion":[{"value":"2025-12-04","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-25","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}