A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia.
A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia.
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钠通道基因中一种罕见类型的内含子的突变会导致异常剪接并引起肌强直。
DOI：
10.1002/humu.21501
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发表时间：
2011-07
期刊：
影响因子：
3.9
通讯作者：
Takahashi, Masanori P.
中科院分区：
文献类型：
--
作者：
Kubota, Tomoya;Roca, Xavier;Kimura, Takashi;Kokunai, Yosuke;Nishino, Ichizo;Sakoda, Saburo;Krainer, Adrian R.;Takahashi, Masanori P.
骨骼肌钠通道基因SCN 4A的许多突变与肌强直和/或周期性麻痹有关，但到目前为止，所有这些突变都位于外显子中。我们发现了一个病人与肌强直引起的缺失/插入位于内含子21的SCN 4A，这是一个AT-AC II型内含子。这是一类罕见的内含子，尽管具有AT-AC边界，但仍由主要或U2型剪接体剪接。患者的骨骼肌表达异常剪接的SCN 4A mRNA亚型产生的激活隐蔽剪接位点。此外，使用SCN 4A小基因的遗传抑制实验表明，突变的5′剪接位点与U1和U6 snRNP的结合受损，这是识别U2型5′剪接位点的同源因子。其中一种异常剪接亚型编码一个通道，该通道在Nav1.4的结构域III和IV之间的细胞质环中插入35个氨基酸。突变通道表现出明显的快速失活破坏，计算机模拟显示通道缺陷与患者的肌强直症状一致。这是AT-AC II型内含子中的疾病相关突变的第一份报告，也是电压门控离子通道基因中第一个显示功能获得性缺陷的内含子突变。
Many mutations in the skeletal-muscle sodium-channel gene SCN4A have been associated with myotonia and/or periodic paralysis, but so far all of these mutations are located in exons. We found a patient with myotonia caused by a deletion/insertion located in intron 21 of SCN4A, which is an AT-AC type II intron. This is a rare class of introns that, despite having AT-AC boundaries, are spliced by the major or U2-type spliceosome. The patient's skeletal muscle expressed aberrantly spliced SCN4A mRNA isoforms generated by activation of cryptic splice sites. In addition, genetic suppression experiments using an SCN4A minigene showed that the mutant 5′ splice site has impaired binding to the U1 and U6 snRNPs, which are the cognate factors for recognition of U2-type 5′ splice sites. One of the aberrantly spliced isoforms encodes a channel with a 35-amino-acid insertion in the cytoplasmic loop between domains III and IV of Nav1.4. The mutant channel exhibited a marked disruption of fast inactivation, and a simulation in silico showed that the channel defect is consistent with the patient's myotonic symptoms. This is the first report of a disease-associated mutation in an AT-AC type II intron, and also the first intronic mutation in a voltage-gated ion channel gene showing a gain-of-function defect.
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影响因子：
64.8
作者：
PARKER, R;SILICIANO, PG
通讯作者：
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