A missense mutation in the CSTF2 gene that impairs the function of the RNA recognition motif and causes defects in 3' end processing is associated with intellectual disability in humans.
A missense mutation in the CSTF2 gene that impairs the function of the RNA recognition motif and causes defects in 3' end processing is associated with intellectual disability in humans.
复制标题
DOI：
10.1093/nar/gkaa689
复制
发表时间：
2020-09-25
影响因子：
14.9
通讯作者：
MacDonald CC
中科院分区：
文献类型：
--
作者：
Grozdanov PN;Masoumzadeh E;Kalscheuer VM;Bienvenu T;Billuart P;Delrue MA;Latham MP;MacDonald CC
CSTF 2编码一种RNA结合蛋白，对mRNA切割和多聚腺苷酸化（C/P）至关重要。没有疾病相关的突变已被描述为该基因。在这里，我们报告了CSTF 2的RNA识别基序（RRM）中的突变，该突变将第50位的天冬氨酸变为丙氨酸（p.D50A），导致男性患者的智力残疾。在小鼠中，这种突变足以改变对大脑发育至关重要的1300多个基因中的聚腺苷酸化位点。利用报告基因分析，我们证明了CSTF 2D 50 A的C/P效率低于野生型。为了解释这一点，我们确定p.D50A改变了氨基酸侧链的位置，改变了RRM中的RNA结合位点。这些变化改变了RRM的静电势，导致对RNA的亲和力更大。这些结果强调了3′端mRNA加工在脑可塑性和神经元发育重要基因表达中的意义。
CSTF2 encodes an RNA-binding protein that is essential for mRNA cleavage and polyadenylation (C/P). No disease-associated mutations have been described for this gene. Here, we report a mutation in the RNA recognition motif (RRM) of CSTF2 that changes an aspartic acid at position 50 to alanine (p.D50A), resulting in intellectual disability in male patients. In mice, this mutation was sufficient to alter polyadenylation sites in over 1300 genes critical for brain development. Using a reporter gene assay, we demonstrated that C/P efficiency of CSTF2D50A was lower than wild type. To account for this, we determined that p.D50A changed locations of amino acid side chains altering RNA binding sites in the RRM. The changes modified the electrostatic potential of the RRM leading to a greater affinity for RNA. These results highlight the significance of 3′ end mRNA processing in expression of genes important for brain plasticity and neuronal development.
登录
查看更多内容
DOI：
10.1016/j.tig.2017.07.008
发表时间：
2017-10
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Davis JK;Broadie K
通讯作者：
Broadie K
影响因子：
5.6
作者：
Deka, P;Rajan, PK;Varani, G
通讯作者：
Varani, G
影响因子：
4.6
作者：
Fontes MM;Guvenek A;Kawaguchi R;Zheng D;Huang A;Ho VM;Chen PB;Liu X;O'Dell TJ;Coppola G;Tian B;Martin KC
通讯作者：
Martin KC
影响因子：
--
作者：
Grozdanov, Petar N.;Stocco, Douglas M.
通讯作者：
Stocco, Douglas M.
影响因子：
3.5
作者：
Shankarling GS;MacDonald CC
通讯作者：
MacDonald CC