In addition to the clinical importance of recognizing this disorder, characterization of mutations identified in patients with CAMT has led to insights into thrombopoietin receptor structure and function.
Surprisingly, complimentary transduction of MPL into normal or CAMT iPSCs using a retroviral vector showed that MPL overexpression promoted erythropoiesis in normal CD34+ hematopoietic progenitor cells (HPCs), but impaired erythropoiesis and increased aberrant megakaryocyte production in CAMT iPSC-derived CD34+ HPCs, reflecting a difference in the expression of the transcription factor FLI1.
Recently, we and others could define the molecular cause of the rare disease congenital amegakaryocytic thrombocytopenia (CAMT) as mutations in the c-mpl gene (Blood 97: 139, 2001).
Using in vitro assays with hematopoietic progenitors from patients of both patient groups we could provide experimental evidence for a residual activity of the thrombopoietin receptor in CAMT II patients.
We describe a CAMT patient with compound heterozygous mutations of the causative MPL gene (one being a previously unreported splice site mutation in intron 11) who developed pancytopenia within the first month of life.
Because the c-mpl gene was considered as one of the candidate genes for this disorder, we analyzed the genomic sequence of the c-mpl gene of a 10-year-old Japanese girl with CAMT.
Most of the cases of congenital amegakaryocytic thrombocytopenia are caused by defective expression or function of the thrombopoietin receptor due to homozygous or compound heterozygous mutations in the gene MPL.
Here, we report for the first time two different MPL amino-acid substitutions in a 2-year-old Italian boy with CAMT and compound heterozygosis for two (c-mpl point mutations.
Germline loss-of-function (LOF) JAK3 and MPL mutations cause severe combined immunodeficiency and congenital amegakaryocytic thrombocytopenia, respectively.
F104S c-Mpl responds to a transmembrane domain-binding thrombopoietin receptor agonist: proof of concept that selected receptor mutations in congenital amegakaryocytic thrombocytopenia can be stimulated with alternative thrombopoietic agents.
The marrow findings and a significantly elevated plasma thrombopoietin (Tpo) level were consistent with congenital amegakaryocytic thrombocytopenia; we sought a genetic mutation that could explain this phenotype.
Recently, two heterozygous truncating mutations of the thrombopoietin (TPO) receptor MPL, coded by the c-mpl gene, were identified in a 10-year-old Japanese patient with CAMT transmitted in an autosomal recessive manner.
The <i>MPL</i> R102P mutation was first described in congenital amegakaryocytic thrombocytopenia in a homozygous state with a loss-of-function activity.
Congenital amegakaryocytic thrombocytopenia (CAMT) and thrombocytopenia with absent radii (TAR) share features of isolated thrombocytopenia, reduced or absent marrow megakaryocytes, impaired responsiveness to thrombopoietin (TPO), and high plasma TPO levels.