Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor ( c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT)

Abstract

Congenital amegakaryocytic thrombocytopenia (CAMT) without physical anomalies is a rare disease, presenting isolated thrombocytopenia and megakaryocytopenia in infancy, which can evolve into aplastic anemia and leukemia. 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. 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. C-to-T transitions were detected on exons 5 and 12 at the 769 and 1904 cDNA nucleotide positions, respectively. The mutation in exon 5 substitutes an arginine with a cysteine (R257C) in the extracellular domain, 11 amino acids distant from the WSXWS motif conserved in the cytokine-receptor superfamily. The mutation in exon 12 substitutes a proline with a leucine (P635L) in the last amino acid of the C-terminal intracellular domain, responsible for signal transduction. As in the Japanese family, the mutations were both transmitted from the parents. TPO plasma levels were highly increased in the patient. The patient's 7-year-old brother, who was a candidate donor for allografting, turned out to be an asymptomatic heterozygous carrier of P635L and showed defective megakaryocyte colony formation from bone-marrow progenitor cells. The present study provides important confirmation that CAMT can be associated with (c-mpl) mutations.

Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

“…1,[4][5][6][7][8][9][10][11] However, the diagnosis of five patients in two centers during the last 2 years raises the suspicion that the incidence of the disease is underestimated, presumably because the initial presentation of CAMT with isolated thrombocytopenia can be easily misdiagnosed with idiopathic thrombocytopenic purpura, while the late pancytopenic phase is indistinguishable from aplastic anemia. Thus, bone marrow examination should be part of the diagnostic work-up in all children with severe thrombocytopenia since birth and screening of the c-MPL gene should be performed when a reduced number of megakaryocytes is observed.…”

“…3 At least 28 different c-MPL mutated alleles have been so far identified from 32 unrelated CAMT families. 1,[4][5][6][7][8][9][10][11] Beside these mutations associated with CAMT, a gain-of-function mutation of c-MPL is responsible for familial essential thrombocythemia. 12 Interestingly, different types of mutations have been associated with different phenotypes, allowing patients to be subdivided into two groups.…”

Hematopoietic cytokines, transcription factors and lineage commitment

“…When an exogenous MEK1 (MAP kinase/ERK kinase 1) inhibitor was administrated, the production of hemoglobin-harboring cells was increased (Uchida et al, 2001). Mutations in the TpoR gene have been repeatedly found in the patients with congenital amegkaryocytic thrombocytopenia and TpoR 7/7 mice displayed a phenotype of selective thrombocytopenia (Gurney et al, 1994;Tonelli et al, 2000), indicating its selective role in the commitment or maturation of megakaryocyte. It has been shown that the activation of ERKs by Tpo/TpoR coupling could be mediated by multiple pathways, including Jak/Stat and Ras/Raf/MAPK pathways as well as PI3K and PKCzeta (Rojnuckarin et al, 2001).…”

Congenital amegakaryocytic thrombocytopenia—Report of a new c‐mpl gene missense mutation

“…The hallmark is absence of megakaryocytes [1], high serum thrombopoietin (tpo) levels, and in vitro megakaryocyte culture insensitivity to tpo stimulation [2]. CAMT is due to the germline mutations of both tpo receptor alleles, c-mpl [3][4][5]. c-mpl knock-out mice not only lack megakaryopoiesis but also have pluripotent stem cell defects [1].…”