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

• Published in: Haematologica (Roma) Vol. 94; no. 10; pp. 1368 - 1374
• Main Authors: Liu, Kun, Martini, Maurizio, Rocca, Bianca, Amos, Christopher I, Teofili, Luciana, Giona, Fiorina, Ding, Jianmin, Komatsu, Hirokazu, Larocca, Luigi M, Skoda, Radek C
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01.10.2009
• Subjects: Adolescent; Adult; Asian Continental Ancestry Group - genetics; Biological and medical sciences; Child; Child, Preschool; European Continental Ancestry Group - genetics; Evidence-Based Medicine; Female; Founder Effect; Haplotypes - genetics; Hematologic and hematopoietic diseases; Humans; Infant; Italy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Microsatellite Repeats - genetics; Middle Aged; Mutation - genetics; Original; Pedigree; Platelet diseases and coagulopathies; Receptors, Thrombopoietin - genetics; Thrombocytosis - genetics; Thrombopoietin - genetics; Young Adult; Italy; Europe; Thrombopoietin receptor; Hematology; Family study; founder effect; MPL; Hemopathy; Hereditary; Thrombopoietin; Thrombocythemia; Myeloproliferative syndrome; Growth factor receptor; TPO; Pedigree; C-Onc gene; Genetics; hereditary thrombocythemia; Mutation; Protooncogene
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2009.005918

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.