Human Genetics

, Volume 107, Issue 3, pp 225–233

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

  • Roberto Tonelli
  • Anna Lisa Scardovi
  • Andrea Pession
  • Pierluigi Strippoli
  • Laura Bonsi
  • Lorenza Vitale
  • Arcangelo Prete
  • Franco Locatelli
  • Gian Paolo Bagnara
  • Guido Paolucci
Original Investigation

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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • Roberto Tonelli
    • 1
  • Anna Lisa Scardovi
    • 1
  • Andrea Pession
    • 1
  • Pierluigi Strippoli
    • 2
  • Laura Bonsi
    • 2
  • Lorenza Vitale
    • 2
  • Arcangelo Prete
    • 1
  • Franco Locatelli
    • 3
  • Gian Paolo Bagnara
    • 2
  • Guido Paolucci
    • 1
  1. 1.Department of Pediatrics, University of Bologna, Bologna, Italy
  2. 2.Institute of Istology, Faculty of Medicine, University of Bologna, Italy
  3. 3.Department of Pediatrics, University of Pavia, Pavia, Italy

Personalised recommendations