A lethal phenotype associated with tissue plasminogen deficiency in humans

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Tissue plasminogen activator (t-PA), encoded by PLAT, is essential for plasminogen activation and thrombosis prevention.
• Previous studies focused on common PLAT variants, but no disease-causing mutations were identified.
• Severe congenital anomalies like hydranencephaly and diaphragmatic hernia can lead to postnatal lethality.

Purpose of the Study:

• To investigate the genetic basis of severe congenital anomalies and early postnatal death in a consanguineous family.
• To identify novel mutations in the PLAT gene and their functional consequences.

Main Methods:

• Whole exome and autozygome sequencing were performed on affected individuals from a consanguineous family.
• Patient-derived cells were analyzed to assess tissue plasminogen activator (t-PA) levels.
• Genetic analysis focused on identifying homozygous null mutations in the PLAT gene.

Main Results:

• A homozygous null mutation in the PLAT gene was identified in affected siblings.
• The identified mutation abrogated t-PA levels in patient cells, confirming a functional knockout.
• This represents the first reported human knockout mutation of PLAT.

Conclusions:

• The study reports the first human PLAT knockout mutation, leading to absent t-PA.
• The findings suggest a potential association between PLAT deficiency and severe congenital anomalies, including hydranencephaly, diaphragmatic hernia, and postnatal lethality.
• Further validation is required to confirm the causal link between PLAT mutations and these severe phenotypes.