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

1 Experimental Hematology, Department of Biomedicine, Basel University Hospital, Basel, Switzerland 2 The Departments of Hematology and Pathology, Catholic University, Rome, Italy 3 Department of Pharmacology, Catholic University School of Medicine, Rome, Italy 4 Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, USA 5 Division of Hematology, Department of Cellular Biotechnologies and Hematology, "La Sapienza" University, Rome, Italy 6 Department of Medical Oncology and Immunology, Graduate School of Medical Sciences, Nagoya City University, Japan Correspondence: Radek C. Skoda, MD, Department of Biomedicine, Experimental Hematology, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland. E-mail: radek.skoda{at}unibas.ch 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. Key words: hereditary thrombocythemia, MPL, mutation, founder effect, TPO.