Department of Haematology, University of Cambridge, Cambridge, UK.
Nat Genet. 2012 Feb 26;44(4):435-9, S1-2. doi: 10.1038/ng.1083.
The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.
外显子-连接复合物（EJC）执行重要的 RNA 处理任务。在这里，我们描述了第一个由 EJC 四个亚基之一缺失引起的人类疾病——桡骨缺如伴血小板减少症（TAR）。RBM8A（编码 EJC 的 Y14 亚基）的调控区域中罕见的无效等位基因和两个低频 SNP 的复合遗传导致了 TAR。我们发现，这种遗传机制解释了 55 例罕见先天性畸形综合征中的 53 例（P<5×10(-228))。在具有这种遗传模式的 53 例中，有 51 例携带以前与 TAR 相关的 1q21.1 亚微缺失，有 2 例携带 RBM8A 的截断或移码无效突变。我们表明，这两个调控 SNP 导致体外 RBM8A 转录减少，并且 TAR 患者的血小板中 Y14 表达减少。我们的数据表明 Y14 不足以及可能的 EJC 缺陷是 TAR 综合征的原因。
