{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:23:53Z","timestamp":1792027433470,"version":"4.4.0"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Autosomal dominant polycystic kidney disease (ADPKD) is frequently complicated by intracranial aneurysms (IAs). However, the genetic factors driving the elevated IA risk in ADPKD remain poorly understood. In this study, we identified a novel <jats:italic>PKD1<\/jats:italic> mutation associated with a remarkably high IA incidence in a large Chinese ADPKD family.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted whole\u2010exome sequencing in a three\u2010generation Chinese ADPKD family (<jats:italic>n<\/jats:italic>\u2009=\u200924) characterized by an unusually high IA prevalence. The pathogenicity of the identified <jats:italic>PKD1<\/jats:italic> variant was validated through comprehensive functional studies, including protein localization, calcium signaling, and endothelial cell behavior analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We discovered a novel <jats:italic>PKD1<\/jats:italic> mutation (c.G10086T) that co\u2010segregated with disease in all affected family members. Notably, 38.1% (8\/21) of the mutation carriers developed IAs, a significantly higher rate than reported in general ADPKD populations (4%\u201311.5%). Functional studies revealed that this mutation disrupted polycystin\u20101 trafficking and impaired calcium signaling, leading to endothelial dysfunction. In\u00a0vitro experiments demonstrated enhanced angiogenic potential and compromised vascular integrity in cells expressing mutant <jats:italic>PKD1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The newly identified <jats:italic>PKD1<\/jats:italic>:c.G10086T mutation represents a high\u2010risk genetic variant for IA development in ADPKD. Our findings provide new insights into the vascular complications of ADPKD and suggest that <jats:italic>PKD1<\/jats:italic> genotyping may help identify patients requiring intensive IA surveillance. This study supports the development of mutation\u2010specific screening strategies for ADPKD\u2010associated vascular complications.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.70086","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T10:10:47Z","timestamp":1740046247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel <scp><i>PKD1<\/i><\/scp> Mutation (c.<scp>G10086T<\/scp>) Drives High Intracranial Aneurysm Risk in Autosomal Dominant Polycystic Kidney Disease"],"prefix":"10.1111","volume":"32","author":[{"given":"Lili","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Neurology Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9015-1350","authenticated-orcid":false,"given":"Chenghan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuansheng","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuopeng","family":"Lin","sequence":"additional","affiliation":[{"name":"Wuhan Kindstar Clinical Diagnostic Co., Kindstar Globalgene Technology, Inc Wuhan 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