MASTL

Inheritance Pattern: AD

Disease ID:MONDO:0015679

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0002049

Submitter: ClinGen

The MASTL gene encodes a serine/threonine kinase that plays a crucial role in mitosis by inhibiting protein phosphatase-2 (PP-2) B55 complexes through activation of ENSA and ARPP19. Dysregulation of MASTL has been linked to various types of cancer. In platelets, MASTL plays a cell-cycle–independent role that is the regulation of focal adhesion and actin dynamics. Indeed, MASTL inhibits PP-2 that in turn is an inhibitor of the outside-in signaling pathway downstream of αIIbβ3, and dephosphorylates critical signaling molecules during platelet activation, such as PKCζ or VASP. As a consequence, mutant gain of function MASTL induces increased αIIbβ3 activation and aberrant platelet function. A MASTL variant, c.501G>C (p.Glu167Asp), was reported in relation to thrombocytopenia in 2003 by Gandhi et al (PMID:12890928) in a large family (51 family members) with thrombocytopenia and normal platelet volume inherited in an autosomal-dominant manner. This family was previously described in 2000 by the same group. Patients showed thrombocytopenia, small and less polyploid megakaryocytes, increased neutrophil count and slightly increased TPO. In the same paper the authors mapped the genetic locus segregating with thrombocytopenia in this family: 10p11.1-p12, stating that this was the locus segregating with thrombocytopenia type 2 (THC2) (PMID:10891439). These are the only patients and the only MASTL variant described so far in patients with thrombocytopenia. However, in the same locus, Pippucci et al identified in 2010 the gene causative for THC2, that is ANKRD26 (PMID: 21211618, not curated). Patients with ANKRD26 variants show characteristics very similar to the family described with the MASTL variant that are: autosomal dominant inheritance, thrombocytopenia with normal platelet volume, small and less polyploid megakaryocytes, increased neutrophil count and slightly increased TPO. However, experimental evidenced (see below) suggest a role of MASTL in platelet formation and function. Finally, a recent publication (PMID: 37746810, not curated) described two members of a family with thrombocytopenia and normal platelet volume, in which exome sequencing identified a 1006 kb deletion in the 10p12.1. Therefore, a deletion involving both MASTL and ANKRD26 segregates with familial thrombocytopenia, which suggests that haploinsufficiency of one or both genes might be the cause. The mechanism of disorder is (probably) gain of function (PMID: 19460416). Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (expression (A), function (B), functional alteration in patient cells, non-human model organism). Summary of Case Level Data: 3.1 POINTS One variant in this gene has been reported in one family in 1 publication (PMID:12890928). Affected patients show thrombocytopenia, normal platelet volume, mild bleeding, small and less polyploid megakaryocytes, increased neutrophil count and slightly increased TPO. Lod score was 6.63. Summary of Experimental Data: 4.75 POINTS Johnson et al. showed that MASTL is expressed in human hematopoietic and cancer cell lines (PMID: 19460416) (Expression A). Mochida et al. showed that MASTL phosphorylates EMSA and ARPP19. These in turn inhibit PP2A-B55. (PMID: 21164013) (Biochemical Function B). Johnson et al. demonstrated, by transient knockdown of MASTL with antisense morpholino oligomers in zebrafish, that ablation of Mastl causes thrombocytopenia suggesting that it is necessary for thrombocyte development (PMID: 19460416) (Model Systems). Drachman JG et al, cultured megakaryocytes (Mks) from CD34+ cells from patients with the MASTL p.Glu167Asp variant, they showed diminished differentiation of Mks, moreover Mks were smaller and less polyploid respect to controls (PMID: 10891439) (Functional Alteration - Patient cells). Hurtado et al. generated two mouse models, one was a conditional KO in which Mastl was knocked down only in megakaryocytes and platelets, the other was a knock-in model expressing the MASTL p.Glu167Asp variant (PMID: 30252678). KO mice showed thrombocytopenia and a reduced number of Mks. Mutant p.Glu167Asp mice showed thrombocytopenia but normal Mks differentiation, prolonged bleeding time but reduced survival after induction of pulmonary embolism or FeCl3-induced carotid artery injury. By studying platelet activation and function the authors showed normal platelet aggregation, increased αIIbβ3 activation, increased actin polymerization and impaired spreading. Moreover, there was enhanced activation of critical regulatory kinases such as protein kinase C, Src or Fak resulting in increased phosphorylation of Vasp, known to increase stress fiber and filopodia formation and of the regulatory light chain of myosin II (Mlc2), a reporter of active reorganization of the actomyosin cytoskeleton (PMID: 30252678) (Model Systems). All these findings suggest that thrombocytopenia in MASTL mutant mice is caused by aberrant platelet activation and consequent destruction, differently from patients. In summary, with a score of 7.85, we obtained moderate association of MASTL with thrombocytopenia, that however was downgraded at limited due to the fact that only one family was described with variants in MASTL and thrombocytopenia. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on ..... (SOP Version 11).