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

Congenital amegakaryocytic thrombocytopenia (CAMT) without physical anomali es is a rare disease, presenting isolated thrombocytopenia and megakaryocyt openia in infancy, which can evolve into aplastic anemia and leukemia. Rece ntly, two heterozygous truncating mutations of the thrombopoietin (TPO) rec eptor MPL, coded by the c-mpl gene, were identified in a 10-year-old Japane se 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 p oint mutations. C-to-T transitions were detected on exons 5 and 12 at the 7 69 and 1904 cDNA nucleotide positions, reespectively. The mutation in exon 5 substitutes an arginine with a cysteine (R257C) in the extracellular doma in, 11 amino acids distant from the WSXWS motif conserved in the cytokine-r eceptor superfamily. The mutation in exon 12 substitutes a proline with a l eucine (P635L) in the last amino acid of the C-terminal intracellular domai n, responsible for signal transduction. As in the Japanese family, the muta tions 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 cand idate 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 confirma tion that CAMT can be associated with c-mpl mutations.