Centre for Paediatrics, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK.
Haematologica. 2012 Apr;97(4):524-8. doi: 10.3324/haematol.2011.052787. Epub 2011 Dec 16.
The primary cause of aplastic anemia remains unknown in many patients. The aim of this study was to clarify the genetic cause of familial aplastic anemia. Genomic DNA of an affected individual from a multiplex consanguineous family was hybridized to a Nimblegen exome library before being sequenced on a GAIIx genome analyzer. Once the disease causing homozygous mutation had been confirmed in the consanguineous family, this gene was then analyzed for mutation in 33 uncharacterized index cases of aplastic anemia (<13 years) using denaturing HPLC. Abnormal traces were confirmed by direct sequencing. Exome sequencing identified a novel homozygous nonsense mutation in the thrombopoietin receptor gene MPL. An additional novel homozygous MPL mutation was identified in the screen of 33 aplastic anemia patients. This study shows for the first time a link between homozygous MPL mutations and familial aplastic anemia. It also highlights the important role of MPL in trilineage hematopoiesis.
许多患者的再生障碍性贫血的主要病因仍然未知。本研究旨在阐明家族性再生障碍性贫血的遗传病因。对来自一个多源近亲家庭的受影响个体的基因组 DNA 与 Nimblegen 外显子文库杂交，然后在 GAIIx 基因组分析仪上进行测序。一旦在近亲家庭中证实了致病的纯合突变，就使用变性高效液相色谱法分析 33 例未明确特征的再生障碍性贫血（<13 岁）索引病例中的基因突变。通过直接测序证实了异常痕迹。外显子组测序鉴定出了在血小板生成素受体基因 MPL 中的一个新的纯合无义突变。在对 33 例再生障碍性贫血患者的筛查中发现了另一个新的纯合 MPL 突变。本研究首次表明 MPL 纯合突变与家族性再生障碍性贫血之间存在关联。它还强调了 MPL 在三系造血中的重要作用。
