{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T06:00:58Z","timestamp":1773036058637,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:00:00Z","timestamp":1663113600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in <jats:italic>PKD1<\/jats:italic> and <jats:italic>PKD2<\/jats:italic> (<jats:italic>PKD1\/2<\/jats:italic>), has unexplained phenotypic variability likely affected by environmental and other genetic factors. Approximately 10% of individuals with ADPKD phenotype have no causal mutation detected, possibly due to unrecognized risk variants of <jats:italic>PKD1\/2<\/jats:italic>. This study was designed to identify risk variants of PKD genes through population genetic analyses. We used Wright's F\u2010statistics (Fst) to evaluate common single nucleotide variants (SNVs) potentially favored by positive natural selection in <jats:italic>PKD1<\/jats:italic> from 1000 Genomes Project (1KG) and genotyped 388 subjects from the Rogosin Institute ADPKD Data Repository. The variants with &gt;90<jats:sup>th<\/jats:sup> percentile Fst scores underwent further investigation by <jats:italic>in silico<\/jats:italic> analysis and molecular genetics analyses. We identified a deep intronic SNV, rs3874648G&gt;\u2009A, located in a conserved binding site of the splicing regulator Tra2\u2010\u03b2 in <jats:italic>PKD1<\/jats:italic> intron 30. Reverse\u2010transcription PCR (RT\u2010PCR) of peripheral blood leukocytes (PBL) from an ADPKD patient homozygous for rs3874648\u2010A identified an atypical <jats:italic>PKD1<\/jats:italic> splice form. Functional analyses demonstrated that rs3874648\u2010A allele increased Tra2\u2010\u03b2 binding affinity and activated a cryptic acceptor splice\u2010site, causing a frameshift that introduced a premature stop codon in mRNA, thereby decreasing <jats:italic>PKD1<\/jats:italic> full\u2010length transcript level. <jats:italic>PKD1<\/jats:italic> transcript levels were lower in PBL from rs3874648\u2010G\/A carriers than in rs3874648\u2010G\/G homozygotes in a small cohort of normal individuals and patients with <jats:italic>PKD2<\/jats:italic> inactivating mutations. Our findings indicate that rs3874648G\u2009&gt;\u2009A is a <jats:italic>PKD1<\/jats:italic> expression modifier attenuating <jats:italic>PKD1<\/jats:italic> expression through Tra2\u2010\u03b2, while the derived G allele advantageously maintains <jats:italic>PKD1<\/jats:italic> expression and is predominant in all subpopulations.<\/jats:p>","DOI":"10.1111\/cge.14214","type":"journal-article","created":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T10:08:13Z","timestamp":1661594893000},"page":"483-493","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A common intronic single nucleotide variant modifies <scp><i>PKD1<\/i><\/scp> expression level"],"prefix":"10.1111","volume":"102","author":[{"given":"Zhengmao","family":"Zhang","sequence":"first","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Levine","sequence":"additional","affiliation":[{"name":"The Rogosin Institute  New York New York USA"},{"name":"Department of Biochemistry Weill Cornell Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Parker","sequence":"additional","affiliation":[{"name":"The Rogosin Institute  New York New York USA"},{"name":"Department of Biochemistry Weill Cornell Medicine  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna","family":"Rennert","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine Weill Cornell Medicine  New York New York 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