MAST2 is a member of the microtubule associated serine/threonine (MAST) kinase family of proteins that remains poorly studied.
One variant, p.Arg89Gln, in MAST2 was reported in 4 members of a family with unknown thrombophilia (Morange et al., PMID: 33465109).
The mechanism of disorder is not completely clear, however, it has been proposed that mutant MAST2 increases TFPI expression and reduces that of PAI-1. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (functional alteration in non-patient cells).
Summary of Case Level Data: 0.5 POINTS Variants in this gene have been reported in 1 proband in 1 publication (PMID: 33465109). Affected patients show thrombophilia, lower plasma levels of the anticoagulant protein free-Tissue Factor Pathway Inhibitor (f-TFPI) and higher of the antifibrinolytic protein Plasminogen Activator Inhibitor-1 (PAI-1).
Summary of Experimental Data: 1.5 POINTS Morange et al showed that the expression of some genes known to regulate some hemostatic properties of endothelial cells (SERPINE1, PLAU, TFPI, SERPINB8) was altered by MAST2 knockdown (PMID: 33465109). Moreover, they showed that PAI-1 accumulated in the supernatant of ECV304 cells expressing mutant MAST2 (PMID: 33465109). Finally, silencing of MAST2 significantly increased TFPI promoter activity and reduced that of SERPINE1, while overexpression of Gln89 MAST2 decreased TFPI promoter activity and increased that of SERPINE1. Moreover, phosphorylation of AKT is increased (PMID: 33465109).
In summary, we obtained limited association of MAST2 with unclassified bleeding disorder.
This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on June 4th 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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