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Congenital amegakaryocytic thrombocytopenia (CAMT) is a severe inherited thrombocytopenia due to loss-of-function mutations affecting the thrombopoietin (TPO) receptor, MPL. Here, we report a new homozygous MPL variant responsible for CAMT in one consanguineous family. The propositus and her sister presented with severe thrombocytopenia associated with mild anemia. NGS revealed the presence of a homozygous MPLR464G mutation resulting in a weak cell surface expression of the receptor in platelets. In cell lines, we observed a defect in MPLR464G maturation associated to its retention in the endoplasmic reticulum. The low cell surface expression of MPLR464G induced very limited signaling with TPO stimulation, leading to survival and reduced proliferation of cells. Overexpression of a myeloproliferative neoplasm-associated calreticulin mutant did not rescue trafficking of MPLR464G to the cell surface and did not induce constitutive signaling. However, it unexpectedly restored a normal response to eltrombopag (ELT), but not to TPO. This effect was only partially mimicked by the purified recombinant calreticulin mutant protein. Finally, the endogenous calreticulin mutant was able to restore the megakaryocyte differentiation of patient CD34+ cells carrying MPLR464G in response to ELT.

Original publication




Journal article



Publication Date



INSERM 1287, Villejuif, France.