MPL – Familial Thrombocytosis

Familial thrombocytosis is an autosomal dominant haematological disorder marked by persistent platelet overproduction and increased thrombotic risk. Germline variants in the thrombopoietin receptor gene MPL have been causally linked to familial thrombocytosis.

Genetic analyses identified the recurrent c.1514G>A (p.Ser505Asn) variant in eight Italian pedigrees, affecting 21 probands (PMID:19713221) and segregating with thrombocytosis in 20 additional relatives (PMID:19608689). A second heterozygous variant, c.305G>C (p.Arg102Pro), was reported in two cases from one family with mild thrombocytosis and elevated thrombopoietin (PMID:28979237).

Variant spectrum in familial thrombocytosis is dominated by gain-of-function missense changes in the transmembrane domain, including c.1514G>A (p.Ser505Asn) and c.305G>C (p.Arg102Pro). Recurrent or founder effects are documented for p.Ser505Asn in Italian cohorts, estimated to originate ~23 generations ago (PMID:19608689).

Functional studies demonstrate that p.Ser505Asn induces constitutive MPL homodimerization and ligand-independent JAK2-STAT activation in the absence of thrombopoietin (PMID:19483125). The p.Arg102Pro change disrupts receptor trafficking, reduces cell-surface clearance of thrombopoietin, and paradoxically increases circulating ligand to drive megakaryocyte proliferation (PMID:28979237).

No studies to date have refuted these associations. The concordant genetic segregation across multiple families and mechanistic data support a gain-of-function model of MPL-mediated thrombocytosis.

Accurate identification of MPL variants in patients with unexplained thrombocytosis informs risk stratification, guides family counseling, and avoids unnecessary cytoreductive therapy. Key take-home: screening for c.1514G>A (p.Ser505Asn) and related MPL variants is clinically actionable in familial thrombocytosis.

References

• Haematologica • 2010 • Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. PMID:19713221
• Haematologica • 2009 • Evidence for a founder effect of the MPL-S505N mutation in eight Italian pedigrees with hereditary thrombocythemia. PMID:19608689
• Blood • 2009 • The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-MPL protein due to strong amino acid polarity. PMID:19483125
• Frontiers in endocrinology • 2017 • Identification of MPL R102P Mutation in Hereditary Thrombocytosis. PMID:28979237

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