Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing.
Mutation of c.244G>T in NR5A1 gene causing 46, XY DSD by affecting RNA splicing.
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NR5A1 基因中 c.244G > T 突变通过影响 RNA 剪接导致 46, XY DSD
DOI：
10.1186/s13023-021-02002-0
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发表时间：
2021-08-30
影响因子：
3.7
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Yu B;Gao Y;Mao J;Wang X;Nie M;Wu X
目的探讨中国人46，XY性发育障碍（DSD）患者NR5A1基因c.244G>T突变的致病机制。受试者和方法：从中国46，XY DSD患者中提取基因组DNA。分别进行靶向下一代和桑格测序以调查和验证导致46，XY DSD的基因突变。使用计算机模拟工具预测变体的致病性。采用双荧光素酶报告基因试验和小基因剪接报告基因试验对该变异株进行致病性鉴定。在46，XY DSD患者中发现了一种新的NR5A1基因杂合突变体，即c.244G>T（p.Ala82Ser）。预测错义变异体致病性的五个计算机工具中有四个表明该变异体是致病性的。体外功能研究表明，p.Ala82Ser对NR5A1的转录活性没有影响。预测潜在剪接位点的计算机工具显示，c.244G>T导致NR5A1 RNA的异常剪接。小基因剪接报告基因分析证实c.244G>T导致外显子2缺失或外显子2 3′端19个核苷酸缺失。NR5A1中c.244G>T的突变通过诱导NR5A1 RNA的异常剪接而不是NR5A1的氨基酸取代而导致46，XY DSD。
To identify the pathogenic mechanism of the c.244G>T mutation in NR5A1 gene found in a Chinese patient with 46, XY disorders of sex development (DSD). Subjects and methods: Genomic DNA was extracted from a Chinese 46, XY DSD patient. Targeted next-generation and Sanger sequencing were performed to investigate and validate the gene mutation causing 46, XY DSD, respectively. In silico tools were used to predict the pathogenicity of the variant. Dual luciferase reporter gene assay and minigene splicing reporter assay were used to identify the pathogenicity of the variant. A novel heterozygous variant, c.244G>T (p.Ala82Ser), in NR5A1 gene was detected in the 46, XY DSD patient. Four of five silico tools predicting pathogenicity of missense variants indicated that the variant was pathogenic. However, in vitro functional study showed that p.Ala82Ser did not affect the transcriptional activity of NR5A1. In silico tools predicting the potential splicing loci revealed that c.244G>T led to aberrant splicing of NR5A1 RNA. Minigene splicing reporter assay confirmed that c.244G>T resulted in the deletion of exon2 or deletion of 19 nucleotides in 3′ end of exon2. Mutation of c.244G>T in NR5A1 results in 46, XY DSD by inducing abnormal splicing of NR5A1 RNA instead of amino acid substitution of NR5A1.
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影响因子：
14.9
作者：
SHAPIRO, MB;SENAPATHY, P
通讯作者：
SENAPATHY, P
中国 46, XY 性发育障碍患者中发现新的 NR5A1 突变
影响因子：
3.2
作者：
Yu, Bingqing;Liu, Zhaoxiang;Wu, Xueyan
通讯作者：
Wu, Xueyan
影响因子：
4.4
作者：
Gnad F;Baucom A;Mukhyala K;Manning G;Zhang Z
通讯作者：
Zhang Z
影响因子：
3.9
作者：
Krawczak, Michael;Thomas, Nick S. T.;Cooper, David N.
通讯作者：
Cooper, David N.
DOI：
10.1073/pnas.1707741114
发表时间：
2017-07-18
影响因子：
11.1
作者：
Ito, Kaoru;Patel, Parth N.;Seidman, J. G.
通讯作者：
Seidman, J. G.