{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T22:37:34Z","timestamp":1762900654958,"version":"3.41.2"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T00:00:00Z","timestamp":1731715200000},"content-version":"vor","delay-in-days":320,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["CRI 88413","MOP-136913"],"award-info":[{"award-number":["CRI 88413","MOP-136913"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chaire Jonathan-Bouchard"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hydrocephalus and Dandy\u2013Walker malformation are amongst the most common congenital brain anomalies. We identified three consanguineous families with both obstructive hydrocephalus and Dandy\u2013Walker malformation. To understand the molecular basis of these anomalies, we conducted genome-wide sequencing in these families. We identified three homozygous truncating variants in the PLAT gene in the four affected family members. All of them showed tetraventricular hydrocephalus. In two individuals, a membrane at the inferior aspect of the fourth ventricle was likely the cause of their hydrocephalus. Three cases exhibited Dandy\u2013Walker malformation, whereas the two oldest individuals displayed intellectual disability. PLAT encodes the tissue-type plasminogen activator, a serine protease whose main function is to cleave the proenzyme plasminogen to produce active plasmin. Interestingly, plasminogen deficiency has also been shown to cause obstructive hydrocephalus and Dandy\u2013Walker malformation, suggesting that loss of PLAT causes these defects by disrupting plasmin production. In summary, we describe a recessive disorder characterized by obstructive hydrocephalus, Dandy\u2013Walker malformation and intellectual disability in individuals with loss-of-function variants in PLAT. This discovery further strengthens the involvement of the plasminogen pathway in the pathogenesis of these developmental disorders.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae408","type":"journal-article","created":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T10:02:07Z","timestamp":1731751327000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss of tissue-type plasminogen activator causes multiple developmental anomalies"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6744-2837","authenticated-orcid":false,"given":"Kevin","family":"Uguen","sequence":"first","affiliation":[{"name":"CHU Sainte-Justine Azrieli Research Centre , Montreal H3T 1C5 ,","place":["Canada"]},{"name":"Department of Medical Genetics, CHRU Brest , Brest F 29200 ,","place":["France"]},{"name":"Univ Brest, Inserm, EFS, UMR 1078, GGB , Brest F-29200 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