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

R. Tonelli, A. L. Scardovi, A. Pession, P. Strippoli, L. Bonsi, L. Vitale, A. Prete, F. Locatelli, G. P. Bagnara, G. Paolucci

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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.

Original languageEnglish
Pages (from-to)225-233
Number of pages9
JournalHuman Genetics
Volume107
Issue number3
Publication statusPublished - 2000

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Thrombopoietin Receptors
Amino Acid Substitution
Mutation
Exons
Genes
Thrombopoietin
Amino Acids
Cytokine Receptors
Megakaryocytes
Aplastic Anemia
Homologous Transplantation
Rare Diseases
Point Mutation
Proline
Leucine
Bone Marrow Cells
Thrombocytopenia
Cysteine
Arginine
Siblings

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Tonelli, R., Scardovi, A. L., Pession, A., Strippoli, P., Bonsi, L., Vitale, L., ... Paolucci, G. (2000). Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT). Human Genetics, 107(3), 225-233.

Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT). / Tonelli, R.; Scardovi, A. L.; Pession, A.; Strippoli, P.; Bonsi, L.; Vitale, L.; Prete, A.; Locatelli, F.; Bagnara, G. P.; Paolucci, G.

In: Human Genetics, Vol. 107, No. 3, 2000, p. 225-233.

Research output: Contribution to journalArticle

Tonelli, R, Scardovi, AL, Pession, A, Strippoli, P, Bonsi, L, Vitale, L, Prete, A, Locatelli, F, Bagnara, GP & Paolucci, G 2000, 'Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT)', Human Genetics, vol. 107, no. 3, pp. 225-233.
Tonelli, R. ; Scardovi, A. L. ; Pession, A. ; Strippoli, P. ; Bonsi, L. ; Vitale, L. ; Prete, A. ; Locatelli, F. ; Bagnara, G. P. ; Paolucci, G. / Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT). In: Human Genetics. 2000 ; Vol. 107, No. 3. pp. 225-233.
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AU - Tonelli, R.

AU - Scardovi, A. L.

AU - Pession, A.

AU - Strippoli, P.

AU - Bonsi, L.

AU - Vitale, L.

AU - Prete, A.

AU - Locatelli, F.

AU - Bagnara, G. P.

AU - Paolucci, G.

PY - 2000

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