外显子
错义突变
吉特尔曼综合征
外显子跳跃
小基因
遗传学
生物
RNA剪接
突变
外显子剪接增强剂
基因
选择性拼接
化学
核糖核酸
有机化学
镁
低镁血症
作者
Yoichi Takeuchi,Eikan Mishima,Hisato Shima,Yasutoshi Akiyama,Chitose Suzuki,Takehiro Suzuki,Takayasu Kobayashi,Yoichi Suzuki,Tomohiro Nakayama,Yasuhiro Takeshima,Norma Vázquez,Sadayoshi Ito,Gerardo Gamba,Takaaki Abe
出处
期刊:Journal of The American Society of Nephrology
日期:2015-02-01
卷期号:26 (2): 271-279
被引量:32
标识
DOI:10.1681/asn.2013091013
摘要
A variety of genetic backgrounds cause the loss of function of thiazide-sensitive sodium chloride cotransporter, encoded by SLC12A3, responsible for the phenotypes in Gitelman syndrome. Recently, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been associated with various diseases. Specifically, mutations in exonic splicing enhancer (ESE) sequences can promote exon skipping. Here, we used a bioinformatics program to analyze 88 missense mutations in the SLC12A3 gene and identify candidate mutations that may induce exon skipping. The three candidate mutations that reduced ESE scores the most were further investigated by minigene assay, and two (p.A356V and p.M672I) caused abnormal splicing in vitro. Furthermore, we identified the p.M672I (c.2016G>A) mutation in a patient with Gitelman syndrome and found that this single nucleotide mutation causes exclusion of exon 16 in the SLC12A3 mRNA transcript. Functional analyses revealed that the protein encoded by the aberrant SLC12A3 transcript does not transport sodium. These results suggest that aberrant exon skipping is one previously unrecognized mechanism by which missense mutations in SLC12A3 can lead to Gitelman syndrome.
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