{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:42:15Z","timestamp":1791380535835,"version":"4.3.3"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2018,10]]},"abstract":"\n Background<\/jats:title>\n \n The major form of autosomal dominant polycystic kidney disease is caused by heterozygous mutations in\n PKD1<\/jats:italic>\n , the gene that encodes polycystin-1 (PC1). Unlike\n PKD1<\/jats:italic>\n genes in the mouse and most other mammals, human\n PKD1<\/jats:italic>\n is unusual in that it contains two long polypyrimidine tracts in introns 21 and 22 (2.5 kbp and 602 bp, respectively; 97% cytosine and thymine). Although these polypyrimidine tracts have been shown to form thermodynamically stable segments of triplex DNA that can cause DNA polymerase stalling and enhance the local mutation rate, the efficiency of transcription and splicing across these cytosine- and thymine-rich introns has been unexplored.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We used RT-PCR and Western blotting (using an mAb to the N terminus) to probe splicing events over exons 20\u201324 in the mouse and human\n PKD1<\/jats:italic>\n genes as well as Nanopore sequencing to confirm the presence of multiple splice forms.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Analysis of PC1 indicates that humans, but not mice, have a smaller than expected protein product, which we call Trunc_PC1. The findings show that Trunc_PC1 is the protein product of abnormal differential splicing across introns 21 and 22 and that 28.8%\u201361.5% of\n PKD1<\/jats:italic>\n transcripts terminate early.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n The presence of polypyrimidine tracts decreases levels of full-length\n PKD1<\/jats:italic>\n mRNA from normal alleles. In heterozygous individuals, low levels of full-length PC1 may reduce polycystin signaling below a critical \u201ccystogenic\u201d threshold.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2018040442","type":"journal-article","created":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T10:57:28Z","timestamp":1536145048000},"page":"2482-2492","source":"Crossref","is-referenced-by-count":17,"title":["Human-Specific Abnormal Alternative Splicing of Wild-Type PKD1 Induces Premature Termination of Polycystin-1"],"prefix":"10.1681","volume":"29","author":[{"given":"Wendy A.","family":"Lea","sequence":"first","affiliation":[{"name":"The Jared Grantham Kidney Institute and Departments of"},{"name":"Internal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Parnell","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute and Departments of"},{"name":"Biochemistry and Molecular Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4616-7669","authenticated-orcid":false,"given":"Darren P.","family":"Wallace","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute and Departments of"},{"name":"Internal Medicine,"},{"name":"Molecular and Integrative Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Calvet","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute and Departments of"},{"name":"Biochemistry and Molecular Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesya V.","family":"Zelenchuk","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute and Departments of"},{"name":"Internal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nehemiah S.","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas; and"},{"name":"De Novo Genomics, Kansas City, Kansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Ward","sequence":"additional","affiliation":[{"name":"The Jared Grantham Kidney Institute and Departments of"},{"name":"Internal Medicine,"},{"name":"Biochemistry and Molecular Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,9,5]]},"reference":[{"key":"B1-20230829","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/S0272-6386(83)80044-4","article-title":"Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980","volume":"2","author":"Iglesias","year":"1983","journal-title":"Am J Kidney Dis"},{"key":"B2-20230829","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1681\/ASN.2011101032","article-title":"Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing","volume":"23","author":"Rossetti","year":"2012","journal-title":"J Am Soc Nephrol"},{"key":"B3-20230829","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/ng0697-179","article-title":"PKD1 interacts with PKD2 through a probable coiled-coil domain","volume":"16","author":"Qian","year":"1997","journal-title":"Nat Genet"},{"key":"B4-20230829","doi-asserted-by":"crossref","first-page":"31559","DOI":"10.1074\/jbc.M805452200","article-title":"Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin","volume":"283","author":"Kim","year":"2008","journal-title":"J Biol Chem"},{"key":"B5-20230829","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1128\/MCB.00072-07","article-title":"Fibrocystin\/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia","volume":"27","author":"Wang","year":"2007","journal-title":"Mol Cell Biol"},{"key":"B6-20230829","doi-asserted-by":"crossref","first-page":"16981","DOI":"10.1073\/pnas.252484899","article-title":"Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations","volume":"99","author":"Qian","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B7-20230829","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/ng0695-151","article-title":"The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains","volume":"10","author":"Hughes","year":"1995","journal-title":"Nat Genet"},{"key":"B8-20230829","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0014-5793(03)00130-3","article-title":"Structure\u2013function relationships of the extracellular domain of the autosomal dominant polycystic kidney disease-associated protein, polycystin-1","volume":"538","author":"Weston","year":"2003","journal-title":"FEBS letters"},{"key":"B9-20230829","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1042\/BJ20101810","article-title":"When a module is not a domain: the case of the REJ module and the redefinition of the architecture of polycystin-1","volume":"435","author":"Schr\u00f6der","year":"2011","journal-title":"Biochem J"},{"key":"B10-20230829","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1097\/01.ASN.0000029587.47950.25","article-title":"The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia","volume":"13","author":"Yoder","year":"2002","journal-title":"J Am Soc Nephrol"},{"key":"B11-20230829","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1681\/ASN.2008060564","article-title":"Characterization of PKD Protein-Positive Exosome-Like Vesicles","volume":"20","author":"Hogan","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"B12-20230829","first-page":"317","article-title":"A 2.5 kb polypyrimidine tract in the PKD1 gene contains at least 23 H-DNA-forming sequences","volume":"1","author":"Van Raay","year":"1996","journal-title":"Microb Compar Gen"},{"key":"B13-20230829","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s003359900969","article-title":"Murine Pkd1 introns 21 and 22 lack the extreme polypyrimidine bias present in human PKD1","volume":"10","author":"Piontek","year":"1999","journal-title":"Mammalian genome"},{"key":"B14-20230829","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1093\/nar\/27.13.2610","article-title":"DNA structural transitions within the PKD1 gene","volume":"27","author":"Blaszak","year":"1999","journal-title":"Nucleic Acids Res"},{"key":"B15-20230829","doi-asserted-by":"crossref","first-page":"33412","DOI":"10.1074\/jbc.M112.402503","article-title":"Replication fork stalling and checkpoint activation by a PKD1 locus mirror repeat polypurine-polypyrimidine (Pu-Py) tract","volume":"287","author":"Liu","year":"2012","journal-title":"J Biol Chem"},{"key":"B16-20230829","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/S0092-8674(00)81793-6","article-title":"The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I","volume":"87","author":"Qian","year":"1996","journal-title":"Cell"},{"key":"B17-20230829","doi-asserted-by":"crossref","first-page":"4536","DOI":"10.2741\/2408","article-title":"Triplex DNA and human disease","volume":"12","author":"Bissler","year":"2007","journal-title":"Front Biosci"},{"key":"B18-20230829","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/0092-8674(94)90137-6","article-title":"The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16","volume":"77","year":"1994","journal-title":"Cell"},{"key":"B19-20230829","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1086\/316939","article-title":"Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications","volume":"68","author":"Rossetti","year":"2001","journal-title":"Am J Hum Genet"},{"key":"B20-20230829","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1681\/ASN.2006121387","article-title":"Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease","volume":"18","author":"Rossetti","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"B21-20230829","first-page":"2091","article-title":"Characterisation and expression of the PKD-1 protein, polycystin, in renal and extrarenal tissues","volume":"55","author":"Ong","year":"1999","journal-title":"Kidney Int"},{"key":"B22-20230829","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1172\/JCI76972","article-title":"Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner","volume":"125","author":"Gainullin","year":"2015","journal-title":"J Clin Invest"},{"key":"B23-20230829","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1093\/hmg\/4.4.575","article-title":"Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat: The AMERICAN PKD1 Consortium (APKD1 Consortium)","volume":"4","author":"Burn","year":"1995","journal-title":"Hum Mol Genet"},{"key":"B24-20230829","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1093\/hmg\/9.18.2617","article-title":"A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype","volume":"9","author":"Pritchard","year":"2000","journal-title":"Hum Mol Genet"},{"key":"B25-20230829","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1681\/ASN.2014040354","article-title":"Identification of biomarkers for PKD1 using urinary exosomes","volume":"26","author":"Hogan","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"B26-20230829","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/ng0697-179","article-title":"PKD1 interacts with PKD2 through a probable coiled-coil domain","volume":"16","author":"Qian","year":"1997","journal-title":"Nat Genet"},{"key":"B27-20230829","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s003359900429","article-title":"The mouse homolog of PKD1: sequence analysis and alternative splicing","volume":"8","author":"L\u00f6hning","year":"1997","journal-title":"Mammalian genome"},{"key":"B28-20230829","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1073\/pnas.89.1.104","article-title":"Construction of a map of chromosome 16 by using radiation hybrids","volume":"89","author":"Ceccherini","year":"1992","journal-title":"PNAS"},{"key":"B29-20230829","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1093\/nar\/gkh312","article-title":"PKD1 intron 21: triplex DNA formation and effect on replication","volume":"32","author":"Patel","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"B30-20230829","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1006\/geno.1999.5927","article-title":"Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q","volume":"60","author":"Loftus","year":"1999","journal-title":"Genomics"},{"key":"B31-20230829","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1093\/hmg\/ddh336","article-title":"Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease","volume":"13","author":"van Leeuwen","year":"2004","journal-title":"Hum Mol Genet"},{"key":"B32-20230829","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1128\/MCB.26.4.1538-1548.2006","article-title":"Overexpression of PKD1 causes polycystic kidney disease","volume":"26","author":"Thivierge","year":"2006","journal-title":"Mol Cell Biol"},{"key":"B33-20230829","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1093\/hmg\/ddt081","article-title":"Progressive development of polycystic kidney disease in the mouse model expressing Pkd1 extracellular domain","volume":"22","author":"Kurbegovic","year":"2013","journal-title":"Hum Mol Genet"},{"key":"B34-20230829","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/ncb3363","article-title":"The polycystin complex mediates Wnt\/Ca2+ signalling","volume":"18","author":"Kim","year":"2016","journal-title":"Nat Cell Biol"},{"key":"B35-20230829","doi-asserted-by":"crossref","first-page":"e","DOI":"10.1371\/journal.pone.0028926","article-title":"Resveratrol, by modulating RNA processing factor levels, can influence the alternative splicing of pre-mRNAs","volume":"6","author":"Markus","year":"2011","journal-title":"PLoS One"},{"key":"B36-20230829","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1073\/pnas.93.4.1524","article-title":"Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney","volume":"93","author":"Ward","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"B37-20230829","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1172\/JCI119147","article-title":"Loss of the polycystic kidney disease (PKD1) region of chromosome 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis","volume":"99","author":"Brasier","year":"1997","journal-title":"The Journal of clinical investigation"},{"key":"B38-20230829","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1093\/hmg\/11.16.1845","article-title":"Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease","volume":"11","author":"Wu","year":"2002","journal-title":"Hum Mol Genet"},{"key":"B39-20230829","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/ng.860","article-title":"A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation","volume":"43","author":"Fedeles","year":"2011","journal-title":"Nat Genet"}],"container-title":["Journal of the American Society of Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/00001751-201810000-00009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:31:59Z","timestamp":1786131119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/00001751-201810000-00009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,5]]},"references-count":39,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2018]]}},"URL":"https:\/\/doi.org\/10.1681\/asn.2018040442","relation":{},"ISSN":["1046-6673","1533-3450"],"issn-type":[{"value":"1046-6673","type":"print"},{"value":"1533-3450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,5]]}}}