16.11.2024Loss of tissue-type plasminogen activator causes multiple developmental anomalies.

Hydrocephalus and Dandy-Walker malformation are among 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.

Topic:

Congenital abnormality, hydrocephalus, alteplase, dandy-walker syndrome, developmental disabilities, enzyme precursors, fourth ventricle, genes, genome, homozygote, tissue membrane, intellectual disability, plasmin, plasminogen, obstructive hydrocephalus, hypoplasminogenemia, congenital anomaly of brain, serine proteases

Keywords:

hydrocephalus, Dandy-Walker malformation, PLAT, plasminogen, intellectual disability

Read the full publication here:

Loss of tissue-type plasminogen activator causes multiple developmental anomalies. 
DOI: 10.1093/braincomms/fcae408, S2CID: 274124366. Brain Communications, fcae408:1-20. 2024, Nov. 16. Epub ahead of print.

Authors:

Kevin Uguen, Tanja Frey, Osama Muthaffar, Jean-Claude Décarie, Najim Ameziane, Sarah Boissel, Yalda Baradaran-Heravi, Anita Rauch, Gabriela Oprea, Aboulfazl Rad, Katharina Steindl, Jacques L Michaud.