Cambridge Institute for Medical Research, Cambridge, United Kingdom.
Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
Blood. 2019 Jul 18;134(3):277-290. doi: 10.1182/blood.2018893404. Epub 2019 May 31.
Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.
Shwachman-Diamond 综合征 (SDS) 是一种隐性疾病，其特征为骨髓衰竭和易患血液系统恶性肿瘤。SDS 主要由变构调节剂 Shwachman-Bodian-Diamond 综合征的缺陷引起，该调节剂与伸长因子样 GTP 酶 1 (EFL1) 合作，催化核糖体解偶联因子 eIF6 的释放并激活翻译。在这里，我们报道了 3 个无关个体中 EFL1 的双等位基因突变，这些个体具有 SDS 的临床特征。这些个体的细胞缺陷包括核糖体亚基连接受损和由于 eIF6 排出缺陷导致的全球蛋白质翻译减弱。在小鼠中，Efl1 缺陷可重现 SDS 表型的关键方面。通过鉴定 SDS 中的双等位基因突变，我们将这种白血病易感性疾病定义为一种核糖体病，其原因是基本的、保守的机制受到破坏，该机制许可大亚基进入翻译。
