A new form of inherited thrombocytopenia due to monoallelic loss of function mutation in the thrombopoietin gene

Thrombopoietin (THPO) is an essential regulator of haemopoiesis that is required for the maintenance of haemopoietic progenitors and their differentiation into megakaryocytes (Mks). Moreover, it modulates the events that drive Mk maturation and allows the release of platelets into bone marrow sinusoids. THPO plays these roles by binding the MPL receptor, which is expressed in bone marrow stem cells, Mks, platelets and many other human cells. Until recently, no inherited THPO defect was known to cause thrombocytopenia or bone marrow aplasia. However, it was recently shown that microdeletions encompassing the THPO gene in chromosome 3 result in a complex clinical picture, including mild congenital thrombocytopenia. Moreover, a Micronesian family carrying the homozygous c.112C>T (p.Arg38Cys or p.Arg17Cys in the mature protein) missense mutation in THPO presents inherited bone marrow aplasia. No THPO mutation associated with isolated thrombocytopenia has been reported to date, but the application of whole exome sequencing (WES) in a cohort of patients with inherited thrombocytopenias (ITs) of unknown origin revealed that monoallelic changes in this gene identify a new form of IT. In fact, WES identified two unrelated individuals carrying the heterozygous variant c.91C>T (p. Arg31*), which is expected to result in mutant protein degradation and THPO haploinsufficiency.