title: Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene.
abstract: Familial thrombosis (FT) has been described as a rare autosomal-dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene (MPL), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL. Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C > T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3.3%) of 213 unrelated Arabs, which was statistically significantly different (P < 0.001, Fisher's exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal-recessive with possible mild heterozygote manifestation rather than autosomal-dominant with high penetrance as usually seen in FT.
authors.affiliation: Institute of Human Genetics, Medical University of Hannover, Hannover, Germany.
authors.forename: El-Harith Abdelghaffar
authors.initials: el-HA
authors.lastname: El-Harith
authors.forename: Cornelia
authors.initials: C
authors.lastname: Roesl
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Manuela
authors.initials: M
authors.lastname: Germeshausen
authors.forename: Hildegard
authors.initials: H
authors.lastname: Frye-Boukhriss
authors.forename: Nils
authors.initials: N
authors.lastname: von Neuhoff
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Mirghani Ali Mohamed
authors.initials: MA
authors.lastname: Ahmed
authors.forename: Jeannette
authors.initials: J
authors.lastname: Hübener
authors.forename: Jörg
authors.initials: J
authors.lastname: Schmidtke
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Manfred
authors.initials: M
authors.lastname: Stuhrmann
mesh_terms: D000328:Adult; D018912:Arabs; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D018095:Germ-Line Mutation; D005858:Germany; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D010976:Platelet Count; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D013922:Thrombocytosis / Q000097:blood / Q000235:genetics*
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human