Disrupted minor intron splicing is prevalent in Mendelian disorders.
Disrupted minor intron splicing is prevalent in Mendelian disorders.
复制标题
DOI：
10.1002/mgg3.1374
复制
发表时间：
2020-09
影响因子：
2
通讯作者：
Kanadia RN
中科院分区：
文献类型：
--
作者：
Olthof AM;Rasmussen JS;Campeau PM;Kanadia RN
剪接对于基因的正确表达至关重要，并且主要由主要剪接体执行。相反，699个人类含次要内含子的基因（MIGs）中的722个内含子被次要剪接体剪接。这些次要内含子的剪接在由次要剪接体中的致病性变体引起的疾病中被破坏，最终导致这些MIG的子集的异常表达。然而，微小内含子和MIGs的变异对疾病的影响仍未得到研究。使用ClinVar鉴定了MIGs的变异体和相关临床表现。然后使用HPO数据库来管理相关症状和受影响的器官系统。结果：我们在211例MIGs中发现了致病性变异，这些变异通常导致智力残疾、癫痫发作和小头畸形。这揭示了一个异常剪接可能导致轻微剪接体相关疾病发病的MIG亚组。此外，我们确定了51个致病性变异的小内含子剪接位点，减少剪接位点的强度，可以诱导选择性剪接。这些发现强调了破坏的次要内含子剪接对人类疾病的影响比以前认识到的更广泛。希望这些知识将有助于开发结合次要内含子剪接途径的治疗策略。次要剪接体组分中的致病性变体导致次要内含子的剪接破坏和影响许多器官系统的广泛症状。在这里，我们确定了一个小内含子的基因，可能在这些小剪接体相关疾病的发病机制中发挥作用的子集。此外，我们报告了51个致病性变异的存在下，在较小的内含子剪接位点，导致剪接位点强度降低。
Splicing is crucial for proper gene expression, and is predominately executed by the major spliceosome. Conversely, 722 introns in 699 human minor intron‐containing genes (MIGs) are spliced by the minor spliceosome. Splicing of these minor introns is disrupted in diseases caused by pathogenic variants in the minor spliceosome, ultimately leading to the aberrant expression of a subset of these MIGs. However, the effect of variants in minor introns and MIGs on diseases remains unexplored. Variants in MIGs and associated clinical manifestations were identified using ClinVar. The HPO database was then used to curate the related symptoms and affected organ systems. Results: We found pathogenic variants in 211 MIGs, which commonly resulted in intellectual disability, seizures and microcephaly. This revealed a subset of MIGs whose aberrant splicing may contribute to the pathogenesis of minor spliceosome‐related diseases. Moreover, we identified 51 pathogenic variants in minor intron splice sites that reduce the splice site strength and can induce alternative splicing. These findings highlight that disrupted minor intron splicing has a broader impact on human diseases than previously appreciated. The hope is that this knowledge will aid in the development of therapeutic strategies that incorporate the minor intron splicing pathway. Pathogenic variants in minor spliceosome components result in disrupted splicing of minor introns and a wide range of symptoms affecting many organ systems. Here, we identified a subset of minor intron‐containing genes that may play a role in the pathogenesis of these minor spliceosome‐related diseases. Moreover, we report the presence of 51 pathogenic variants in minor intron splice sites that result in a reduced splice site strength.
登录
查看更多内容
影响因子：
16.6
作者：
Madan, Vikas;Kanojia, Deepika;Li, Jia;Okamoto, Ryoko;Sato-Otsubo, Aiko;Kohlmann, Alexander;Sanada, Masashi;Grossmann, Vera;Sundaresan, Janani;Shiraishi, Yuichi;Miyano, Satoru;Thol, Felicitas;Ganser, Arnold;Yang, Henry;Haferlach, Torsten;Ogawa, Seishi;Koeffler, H. Phillip
通讯作者：
Koeffler, H. Phillip
影响因子：
11.1
作者：
Argente, Jesus;Flores, Raquel;Gutierrez-Arumi, Armand;Verma, Bhupendra;Martos-Moreno, Gabriel A.;Cusco, Ivon;Oghabian, Ali;Chowen, Julie A.;Frilander, Mikko J.;Perez-Jurado, Luis A. '
通讯作者：
Perez-Jurado, Luis A. '
影响因子：
7
作者：
Lord, Jenny;Gallone, Giuseppe;Hurles, Matthew E.
通讯作者：
Hurles, Matthew E.
影响因子：
9.8
作者：
Deardorff, Matthew A.;Kaur, Maninder;Krantz, Ian D.
通讯作者：
Krantz, Ian D.
影响因子：
56.9
作者：
Edery, Patrick;Marcaillou, Charles;Leutenegger, Anne-Louise
通讯作者：
Leutenegger, Anne-Louise