Original Investigation

Human Genetics

, Volume 107, Issue 3, pp 225-233

First online:

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

  • Roberto TonelliAffiliated withDepartment of Pediatrics, University of Bologna, Bologna, Italy
  • , Anna Lisa ScardoviAffiliated withDepartment of Pediatrics, University of Bologna, Bologna, Italy
  • , Andrea PessionAffiliated withDepartment of Pediatrics, University of Bologna, Bologna, Italy
  • , Pierluigi StrippoliAffiliated withInstitute of Istology, Faculty of Medicine, University of Bologna, Italy
  • , Laura BonsiAffiliated withInstitute of Istology, Faculty of Medicine, University of Bologna, Italy
  • , Lorenza VitaleAffiliated withInstitute of Istology, Faculty of Medicine, University of Bologna, Italy
  • , Arcangelo PreteAffiliated withDepartment of Pediatrics, University of Bologna, Bologna, Italy
  • , Franco LocatelliAffiliated withDepartment of Pediatrics, University of Pavia, Pavia, Italy
  • , Gian Paolo BagnaraAffiliated withInstitute of Istology, Faculty of Medicine, University of Bologna, Italy
    • , Guido PaolucciAffiliated withDepartment of Pediatrics, University of Bologna, Bologna, Italy

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

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.