[Show abstract][Hide abstract] ABSTRACT: Hereditary thrombocythemia is a rare disease characterized by increased megakaryopoiesis and overproduction of platelets. Germ line mutations have been identified in the genes for thrombopoietin (THPO) and its receptor, MPL. A clustering of familial cases with the MPL-G1073A mutation that results in a serine to asparagine substitution (S505N) has been recently reported in Italy. Here we performed haplotype analysis in nine families (eight Italian and one Japanese) with hereditary thrombocythemia carrying the MPL-S505N mutation in the MPL gene.
The MPL gene was examined by genomic DNA sequencing. Haplotype analysis was performed using microsatellites and single nucleotide polymorphisms.
Analysis of microsatellite markers and single nucleotide polymorphisms in the eight Italian families with hereditary thrombocythemia revealed the presence of a common haplotype compatible with a founder effect, which may have originated 23 generations ago. This haplotype was rarely observed in 132 unrelated individuals and was absent in a Japanese family with the MPL-S505N mutation.
The recurrent MPL-S505N mutation found in the eight Italian families with hereditary thrombocythemia is likely due to a founder effect.
[Show abstract][Hide abstract] ABSTRACT: Background Hereditary thrombocythemia is an autosomal dominant disorder with clinical features resem- bling sporadic essential thrombocythemia. Germline mutations in families with hereditary throm- bocythemia ha ve been identified in the gene for thrombopoietin (TPHO) and its receptor, MPL. Design and Methods Here we characterized a THPO mutation in a hereditary thrombocythemia pedigree with 11 affected family members. Results Affected family members carry a G→C transversion in the splice donor of intron 3 of THPO that co-segregated with thrombocytosis within the pedigree. W e previously described the identical mutation in a Dutch family with hereditary thrombocythemia. Haplotype analysis using single nucleotide polymorphisms surrounding the mutation indicated that the mutations arose inde- pendently in the two families. MPL protein levels, but not mRNA levels, were low in platelets from affected family members. Bone marrow histology showed features compatible with those of essential thrombocythemia, but the megakaryocytes were unusually compact, as assessed by planimetric analysis. Impaired microcirculation resulting in brief episodes of fainting and dizzi- ness that responded well to aspirin were the predominant clinical features in a total of 23 affect- ed family members studied. Disease onset is earlier in patients with hereditary thrombocythemia than in those with essential thrombocythemia, but the frequencies of thrombotic, vascular and hemorrhagic events are similar in the two groups. Conclusions A mutation in THPO occurred de novo in the same position as in a previously described family with hereditar y thrombocythemia. Patients with this mutation have elevated serum levels of thrombopoietin and a phenotype that responds to aspirin and does not require cytoreductive treatment.