Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome.
Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome.
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DOI：
10.1002/humu.22336
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发表时间：
2013-08
期刊：
影响因子：
3.9
通讯作者：
Crow, Yanick J.
中科院分区：
文献类型：
--
作者：
Rice, Gillian I.;Reijns, Martin A. M.;Coffin, Stephanie R.;Forte, Gabriella M. A.;Anderson, Beverley H.;Szynkiewicz, Marcin;Gornall, Hannah;Gent, David;Leitch, Andrea;Botella, Maria P.;Fazzi, Elisa;Gener, Blanca;Lagae, Lieven;Olivieri, Ivana;Orcesi, Simona;Swoboda, Kathryn J.;Perrino, Fred W.;Jackson, Andrew P.;Crow, Yanick J.
艾卡迪-古蒂埃综合征(AGS)是一种炎症性疾病，由TREX1、RNASEH2A/2B/2C、SAMHD1或ADAR1突变引起。在这里，我们提供了分子，生化和细胞证据的两个同义变异体的致病性在RNASE2A。首先，c.69G>；A(p.Val23Val)突变导致外显子1内形成剪接供体部位，导致外显子1末端框外缺失，导致RNaseH2蛋白水平降低。第二个突变是c.75C>；T(p.Arg25Arg)，它还在外显子1中引入了一个剪接供体位点，并在内部缺失了18个氨基酸。截短的蛋白质仍形成异三聚体RNaseH2复合体，但缺乏催化活性。然而，作为泄漏剪接的可能结果，显然在该突变的纯合个体中产生了少量的全长活性蛋白。识别这些变异的致病状态可以在相关家系中进行诊断性检测。
Aicardi-Goutières syndrome (AGS) is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1 or ADAR1. Here we provide molecular, biochemical and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.
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DOI：
10.1074/jbc.m110.177394
发表时间：
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期刊：
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