Liu Kun, Kralovics Robert, Rudzki Zbigniew, Grabowska Barbara, Buser Andreas S, Olcaydu Damla, Gisslinger Heinz, Tiedt Ralph, Frank Patricia, Okoñ Krzysztof, van der Maas Anthonie P C, Skoda Radek C
Department of Biomedicine, Experimental Hematology, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
Haematologica. 2008 May;93(5):706-14. doi: 10.3324/haematol.11801. Epub 2008 Mar 26.
Hereditary thrombocythemia is an autosomal dominant disorder with clinical features resembling sporadic essential thrombocythemia. Germline mutations in families with hereditary thrombocythemia have been identified in the gene for thrombopoietin (TPHO) and its receptor, MPL.
Here we characterized a THPO mutation in a hereditary thrombocythemia pedigree with 11 affected family members.
Affected family members carry a G --> C transversion in the splice donor of intron 3 of THPO that co-segregated with thrombocytosis within the pedigree. We previously described the identical mutation in a Dutch family with hereditary thrombocythemia. Haplotype analysis using single nucleotide polymorphisms surrounding the mutation indicated that the mutations arose independently in the two families. MPL protein levels, but not mRNA levels, were low in platelets from affected family members. Bone marrow histology showed features compatible with those of essential thrombocythemia, but the megakaryocytes were unusually compact, as assessed by planimetric analysis. Impaired microcirculation resulting in brief episodes of fainting and dizziness that responded well to aspirin were the predominant clinical features in a total of 23 affected family members studied. Disease onset is earlier in patients with hereditary thrombocythemia than in those with essential thrombocythemia, but the frequencies of thrombotic, vascular and hemorrhagic events are similar in the two groups.
A mutation in THPO occurred de novo in the same position as in a previously described family with hereditary thrombocythemia. Patients with this mutation have elevated serum levels of thrombopoietin and a phenotype that responds to aspirin and does not require cytoreductive treatment.
遗传性血小板增多症是一种常染色体显性疾病，其临床特征与散发性原发性血小板增多症相似。遗传性血小板增多症家族中的胚系突变已在血小板生成素（THPO）及其受体MPL基因中被鉴定出来。
在此，我们对一个有11名受累家庭成员的遗传性血小板增多症家系中的THPO突变进行了特征分析。
受累家庭成员在THPO第3内含子的剪接供体处发生了G→C颠换，该突变与家系中的血小板增多症共分离。我们之前在一个荷兰遗传性血小板增多症家族中描述过相同的突变。使用突变周围的单核苷酸多态性进行单倍型分析表明，这两个家族中的突变是独立发生的。受累家庭成员血小板中的MPL蛋白水平较低，但mRNA水平正常。骨髓组织学显示出与原发性血小板增多症相符的特征，但通过平面测量分析评估，巨核细胞异常紧密。在总共23名研究的受累家庭成员中，主要临床特征是微循环受损导致短暂的昏厥和头晕，阿司匹林对此反应良好。遗传性血小板增多症患者的发病年龄比原发性血小板增多症患者更早，但两组的血栓形成、血管和出血事件发生率相似。
THPO中的一个突变在与先前描述的遗传性血小板增多症家族相同的位置上从头发生。携带此突变的患者血清血小板生成素水平升高，其表型对阿司匹林有反应且不需要进行细胞减灭治疗。
