Loss of tissue-type plasminogen activator causes multiple developmental anomalies

• Published in: Brain communications 2024, Vol.6 (6), p.fcae408
• Main Authors: Uguen, Kevin, Frey, Tanja, Muthaffar, Osama, Décarie, Jean-Claude, Ameziane, Najim, Boissel, Sarah, Baradaran-Heravi, Yalda, Rauch, Anita, Oprea, Gabriela, Rad, Aboulfazl, Steindl, Katharina, Michaud, Jacques L
• Format: Article
• Language: English
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcae408

Abstract Hydrocephalus and Dandy–Walker malformation are amongst the most common congenital brain anomalies. We identified three consanguineous families with both obstructive hydrocephalus and Dandy–Walker 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–Walker 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–Walker 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–Walker 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. Uguen et al. report four cases presenting with hydrocephalus and Dandy–Walker malformations harbouring homozygous loss-of-function variants in the PLAT gene. PLAT encodes the tissue plasminogen activator, and, based on the phenotype associated with plasminogen deficiency, authors propose that the disruption of the plasminogen pathway is responsible of brain malformations. Graphical Abstract Graphical Abstract