Human Cancer Genetics Program, Ohio State University, Columbus, OH 43210, USA.
Science. 2011 Apr 8;332(6026):238-40. doi: 10.1126/science.1200587.
Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.
小核 RNA（snRNAs）是信使 RNA 剪接的重要因素。通过纯合性作图和深度测序，我们表明，编码 U4atac snRNA 的基因发生突变，U4atac snRNA 是小 U12 依赖剪接体的组成部分，该基因在小头骨发育不良性原发侏儒症 I 型（MOPD I）患者中发生突变，MOPD I 是一种严重的发育障碍，其特征为宫内生长迟缓和多种器官异常。功能分析表明，与 MOPD I 相关的突变（30G>A、51G>A、55G>A 和 111G>A）导致 U12 依赖剪接缺陷。在 MOPD I 患者成纤维细胞中发现内源性 U12 依赖但不依赖 U2 的内含子剪接不良。将野生型 U4atac snRNA 引入 MOPD I 细胞增强了 U12 依赖剪接。这些结果说明了小内含子剪接在人类发育中的关键作用。
