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.
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Acknowledgments
We thank the study family for their enthusiastic participation. We also thank the Genotyping and Sequencing Core Facilities at KFSHRC for their technical help. This work was supported in part by a KACST grant 13-BIO1113-20 (FSA).
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Shamseldin, H.E., Aldeeri, A., Babay, Z. et al. A lethal phenotype associated with tissue plasminogen deficiency in humans. Hum Genet 135, 1209–1211 (2016). https://doi.org/10.1007/s00439-016-1711-5
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DOI: https://doi.org/10.1007/s00439-016-1711-5