A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing
A missense mutation in SNRPE linked to non-syndromal microcephaly interferes with U snRNP assembly and pre-mRNA splicing
复制标题
与非综合征性小头畸形相关的 SNRPE 错义突变干扰 U snRNP 组装和前 mRNA 剪接
DOI：
10.1371/journal.pgen.1008460
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发表时间：
2019-10-01
期刊：
影响因子：
4.5
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Chen, Tao;Zhang, Bin;Chen, Wei
前mRNA加工因子的功能障碍与包括癌症和神经变性在内的几种人类疾病有关。在这里，我们报告了一个新的SNRPE基因杂合错义突变（c.65T>C（p.Phe22Ser））的非综合征原发性（先天性）小头畸形和智力残疾的患者的鉴定。SNRPE编码SmE，其是前mRNA加工U snRNP的基础组分。我们表明，microcephaly-linked SmE变体是无法与SMN复合物相互作用，因此未能组装成U snRNP。这导致来源于该患者的成纤维细胞中广泛的mRNA剪接改变。在HEK 293细胞中观察到类似的改变，SmE耗尽后，可以通过表达野生型而不是突变型SmE来挽救。重要的是，斑马鱼中SmE的缺失导致异常的mRNA剪接改变和脑大小减小，使人想起患者的小头畸形表型。我们将EMX 2 mRNA（编码大脑正常发育所需的蛋白质）确定为主要的错误拼接下游靶点。总之，我们的研究将SNRPE基因的缺陷与小头畸形联系起来，并表明特定mRNA（如EMX 2）的细胞剪接的改变导致了该疾病的神经学表型。
Malfunction of pre-mRNA processing factors are linked to several human diseases including cancer and neurodegeneration. Here we report the identification of a de novo heterozygous missense mutation in the SNRPE gene (c.65T>C (p.Phe22Ser)) in a patient with non-syndromal primary (congenital) microcephaly and intellectual disability. SNRPE encodes SmE, a basal component of pre-mRNA processing U snRNPs. We show that the microcephaly-linked SmE variant is unable to interact with the SMN complex and as a consequence fails to assemble into U snRNPs. This results in widespread mRNA splicing alterations in fibroblast cells derived from this patient. Similar alterations were observed in HEK293 cells upon SmE depletion that could be rescued by the expression of wild type but not mutant SmE. Importantly, the depletion of SmE in zebrafish causes aberrant mRNA splicing alterations and reduced brain size, reminiscent of the patient microcephaly phenotype. We identify the EMX2 mRNA, which encodes a protein required for proper brain development, as a major mis-spliced down stream target. Together, our study links defects in the SNRPE gene to microcephaly and suggests that alterations of cellular splicing of specific mRNAs such as EMX2 results in the neurological phenotype of the disease.