Bonei Olam, Center for Rare Jewish Genetic Disorders, 1755 46th St., Brooklyn, NY 11204, USA.
Blood Cells Mol Dis. 2011 Jun 15;47(1):79-83. doi: 10.1016/j.bcmd.2011.03.006. Epub 2011 Apr 13.
Congenital amegakaryocytic thrombocytopenia (MIM #604498) (CAMT) is a rare inherited disease presenting as severe thrombocytopenia in infancy. Untreated, many CAMT patients develop aplastic anemia within the first decade of life; the only effective treatment of CAMT is bone marrow transplantation. CAMT is the result of the presence of homozygous or compound heterozygous mutations in the thrombopoietin receptor-encoding gene, MPL. We report here the identification and characterization of a founder mutation in MPL in the Ashkenazi Jewish (AJ) population. This mutation, termed c.79+2T>A, is a T to A transversion in the invariant second base of the intron 1 donor splice site. Analysis of a random sample of 2018 individuals of AJ descent revealed a carrier frequency of approximately 1 in 75. Genotyping of six loci adjacent to the MPL gene in the proband and in the 27 individuals identified as carriers of the c.79+2T>A mutation revealed that the presence of this mutation in the AJ population is due to a single founder. The observed carrier frequency predicts an incidence of CAMT in the AJ population of approximately 1 in 22,500 pregnancies. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation.
先天性巨核细胞血小板减少症（MIM#604498）（CAMT）是一种罕见的遗传性疾病，表现为婴儿期严重的血小板减少症。未经治疗，许多 CAMT 患者在生命的第一个十年内发展为再生障碍性贫血；CAMT 的唯一有效治疗方法是骨髓移植。CAMT 是由血小板生成素受体编码基因 MPL 中的纯合子或复合杂合突变引起的。我们在此报告在阿什肯纳兹犹太人（AJ）人群中发现和表征 MPL 中的一个启动子突变。该突变称为 c.79+2T>A，是内含子 1 供体位点不变的第二个碱基的 T 到 A 颠换。对 2018 名 AJ 血统的随机样本进行分析，发现携带者频率约为 1/75。对先证者和 27 名被确定为 c.79+2T>A 突变携带者的 MPL 基因附近的六个基因座进行基因分型表明，AJ 人群中该突变的存在是由于一个单一的启动子。观察到的携带者频率预测 AJ 人群中 CAMT 的发病率约为每 22500 例妊娠 1 例。该突变的鉴定将能够进行人群携带者检测，并有助于鉴定和治疗该突变的纯合子个体。
