{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:51:28Z","timestamp":1790319088218,"version":"4.1.0"},"reference-count":70,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>All tested pathogenic variants disrupted either polycystin-1 ciliary trafficking or channel function.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Trafficking and channel function of some pathogenic variants was restored by low temperature culture to promote polycystin folding.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of ADPKD, limited mechanistic understanding has hindered therapeutic development. Most ADPKD is caused by loss-of-function variants in polycystin-1 (PC1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and polycystin channel function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We evaluated 29 nontruncating variants in PC1 and found that pathogenic variants disrupt two molecular phenotypes: (\n                      <jats:italic toggle=\"yes\">1<\/jats:italic>\n                      ) localization of PC1 at the primary cilium or (\n                      <jats:italic toggle=\"yes\">2<\/jats:italic>\n                      ) polycystin ion channel activity. Ciliary localization of a subset of polycystin variants was restored when cells were cultured at low temperature. A subset of variants with localization restored by low temperature formed functional channels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrated that disruptions in polycystin ciliary trafficking and channel function are common causes of ADPKD. Defects in ciliary trafficking and channel function can be rescued for a subset of pathogenic variants, establishing a foundation for polycystin-targeted therapies in ADPKD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.0000001008","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:03:01Z","timestamp":1770742981000},"page":"1661-1673","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":4,"title":["Disruption of Polycystin Ciliary Localization and Channel Function by Autosomal Dominant Polycystic Kidney Disease\u2013Causing Polycystin-1 Variants"],"prefix":"10.1681","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0866-0842","authenticated-orcid":false,"given":"Kotdaji","family":"Ha","sequence":"first","affiliation":[{"name":"Department of Physiology, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8514-8180","authenticated-orcid":false,"given":"Gabriel B.","family":"Loeb","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California"},{"name":"Cardiovascular Research Institute and Institute for Human Genetics, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2695-0894","authenticated-orcid":false,"given":"Meyeon","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0659-2919","authenticated-orcid":false,"given":"Mohona","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4987-3628","authenticated-orcid":false,"given":"Yukako","family":"Akiyama","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jillian","family":"Argiris","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aide","family":"Pinedo","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8984-575X","authenticated-orcid":false,"given":"Christine Haewon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0510-2546","authenticated-orcid":false,"given":"Nadav","family":"Brandes","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fnu","family":"Ritu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6560-3783","authenticated-orcid":false,"given":"Chun Jimmie","family":"Ye","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, Department of Epidemiology and Biostatistics, Department of Bioengineering and Therapeutic Sciences, Bakar Computation Health Sciences Institute, Parker Institute for Cancer Immunotherapy, Gladstone-UCSF Institute of Genomic Immunology, Institute for Human Genetics, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9614-5340","authenticated-orcid":false,"given":"Willow","family":"Coyote-Maestas","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences and Quantitative Biosciences Institute, University of California San Francisco, San Francisco, California"},{"name":"Chan Zuckerberg Biohub, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6512-320X","authenticated-orcid":false,"given":"Jeremy F.","family":"Reiter","sequence":"additional","affiliation":[{"name":"Chan Zuckerberg Biohub, San Francisco, California"},{"name":"Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9556-2097","authenticated-orcid":false,"given":"Markus","family":"Delling","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California San Francisco, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"issue":"1","key":"B1-20260826","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/ki.2015.59","article-title":"Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference","volume":"88","author":"Chapman","year":"2015","journal-title":"Kidney Int."},{"issue":"6","key":"B3-20260826","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1681\/ASN.2012070650","article-title":"Type of PKD1 mutation influences renal outcome in 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