Evidence for a founder effect of the MPL-S505N mutation in eight Italian pedigrees with hereditary thrombocythemia.

BACKGROUND 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. DESIGN AND METHODS The MPL gene was examined by genomic DNA sequencing. Haplotype analysis was performed using microsatellites and single nucleotide polymorphisms. RESULTS 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. CONCLUSIONS The recurrent MPL-S505N mutation found in the eight Italian families with hereditary thrombocythemia is likely due to a founder effect.