title: Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin.
abstract: One Japanese pedigree of familial essential thrombocythemia (FET) inherited in an autosomal-dominant manner is presented. A unique point mutation, serine 505 to asparagine 505 (Ser505Asn), was identified in the transmembrane domain of the c-MPL gene in all of the 8 members with thrombocythemia, but in none of the other 8 unaffected members in this FET family. The Ba/F3 cells expressing the mutant Asn505 acquired interleukin 3 (IL-3)-independent survival capacity, whereas those expressing wild-type Ser505 did not. The autonomous phosphorylation of Mek1/2 and Stat5b was observed in the mutant Ba/F3 cells in the absence of IL-3. The former was also found in platelets derived from the affected individual in the absence of thrombopoietin. These results show that the Asn505 is an activating mutation with respect to the intracellular signaling and survival of the cells. This is the first report of FET deriving from a dominant-positive activating mutation of the c-MPL gene.
authors.affiliation: Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science, 1-Kawasumi, Mizuho-cho, Mizuho-Ku, Nagoya 467-8601, Japan.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Ding
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Komatsu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Wakita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kato-Uranishi
authors.forename: Masato
authors.initials: M
authors.lastname: Ito
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satoh
authors.forename: Kazuya
authors.initials: K
authors.lastname: Tsuboi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nitta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
mesh_terms: D002478:Cells, Cultured; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007564:Japan; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010766:Phosphorylation; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics* / Q000378:metabolism; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction / Q000502:physiology; D013920:Thrombocythemia, Essential / Q000235:genetics*; D013926:Thrombopoietin / Q000378:metabolism; D014162:Transfection
chemical_list: D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin