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在内删除的消极蛋白前8-50 结果在DMD表型的DMD

Tatiana V Egorova^1,2, Ivan I Galkin^2,3,4, Oleg A Velyaev¹

¹Laboratory of Modeling and Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow 119334, Russia.

International journal of molecular sciences

|June 10, 2023

概括

基因组编辑旨在恢复杜恩肌肉发育不良症的双蛋白生产. 然而,在小鼠中删除8-50外显子并没有预防疾病,挑战了读取框架规则.

科学领域:

遗传学遗传学是一个
分子生物学分子生物学
生物技术是生物技术.

背景情况:

杜恩肌肉发育不良 (DMD) 是由DMD基因的突变引起的,通常是导致读取框架转移的删除.
读取框架规则表明,框架内删除会导致较轻的贝克尔肌肉发育不良症 (BMD).
基因组编辑为恢复阅读框架和在DMD中产生BMD类色素提供了潜在的潜力.

研究的目的:

调查删除DMD基因中的8-50外子的治疗潜力.
评估这种特定的删除是否恢复了双蛋白的功能,并阻止了疾病的进展.
要确定此删除是否符合已建立的读取框架规则.

主要方法:

使用CRISPR-Cas9.9创建了一种新的小鼠模型 (DMDdel8-50),使用CRISPR-Cas9.9在DMD基因中删除DMD基因8-50的外显子.
将DMDdel8-50小鼠与对照小鼠 (C57Bl6/CBA) 和先前生成的DMDdel8-34 KO小鼠进行比较.
在小鼠模型中评估蛋白质表达,定位,组织学变化和身体功能.

主要成果:

在DMDdel8-50小鼠模型中,成功地产生了缩短的dystrophin蛋白.
这种截断的双蛋白正确地定位在肉上.
尽管表达和局部化,缩短的蛋白质未能像全长的肌蛋白一样发挥作用,也没有阻止疾病的进展.

结论:

在这种情况下,删除8-50个外因子,虽然在框架内,但不会恢复素功能.
这一发现表明,异子8-50删除是读取框架规则的例外.
对每个基因组编辑变异进行仔细的体外或体内研究对于评估治疗有效性至关重要.

关键词:

这就是为什么B.M.D. BMD.贝克尔肌肉缩症贝克尔肌肉缩症克里斯普尔卡斯9 在 DMD DMD 里面,你会发现消极蛋白质是一种消极蛋白质.基因组编辑基因组编辑鼠标模型鼠标模型鼠标模型

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