title: A lethal phenotype associated with tissue plasminogen deficiency in humans.
abstract: The role of plasminogen in preventing thrombosis requires activation by tissue plasminogen activator (t-PA) encoded by PLAT. While case-control associations have been pursued for common variants in PLAT, no disease-causing mutations have been reported. We describe a consanguineous family with two children who died shortly after birth due to complications related to severe hydranencephaly and diaphragmatic hernia. A combined exome/autozygome analysis was carried out with informed consent. We identified a homozygous null mutation in PLAT that abrogated t-PA level in patient cells. This is the first reported human knockout mutation of PLAT. The apparent association with hydranencephaly, diaphragmatic hernia and postnatal lethality requires further validation.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hanan E
authors.initials: HE
authors.lastname: Shamseldin
authors.affiliation: Department of Internal Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Aldeeri
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Babay
authors.affiliation: Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alsultan
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.identifier: 0000-0003-4158-341X
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D055786:Gene Knockout Techniques; D020022:Genetic Predisposition to Disease; D006548:Hernia, Diaphragmatic / Q000235:genetics / Q000401:mortality; D006720:Homozygote; D006801:Humans; D006832:Hydranencephaly / Q000235:genetics / Q000401:mortality; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D013927:Thrombosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000235:genetics*
chemical_list: C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator