S. Van Den Oudenrijn et al., Mutations in the thrombopoietin receptor, Mpl, in children with congenitalamegakaryocytic thrombocytopenia, BR J HAEM, 110(2), 2000, pp. 441-448
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder of un
defined aetiology. The disease presents with severe thrombocytopenia and ab
sence of megakaryocytes in the bone marrow. Furthermore, CAMT patients may
develop bone marrow aplasia. To obtain more insight into the mechanism unde
rlying CAMT, five children were analysed. All patients had increased plasma
thrombopoietin (Tpo) levels, indicating a platelet production defect. Bone
marrow-derived CD34(+) stem cells from three patients were cultured in an
in vitro liquid culture system to study megakaryocytopoiesis. CD34(+) cells
from two of the three patients failed to differentiate into megakaryocytes
. The lack of megakaryocyte formation could imply that a defect in the c-mp
l gene, encoding the Tpo receptor, exists. Sequencing of c-mpl revealed mut
ations in four of five patients. Three patients had point mutations and/or
a deletion in the coding regions of c-mpl. All point mutations led to an am
ino acid substitution or to a premature stop codon. In one patient, a homoz
ygous mutation in the last base of intron 10 was found that resulted in los
s of a splice site. This study showed that mutations in c-mpl could be the
cause of thrombocytopenia in CAMT in the majority of patients. Furthermore,
Tpo has been shown to have an anti-apoptotic effect on stem cells. Therefo
re, mutations in c-mpl might not only affect megakaryocyte formation but ma
y also impair stem cell survival, which could explain the occurrence of bon
e marrow failure as final outcome in patients with CAMT.