SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation.
SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation.
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SNUPN 缺陷会因 RNA 错误剪接和 ECM 失调而导致隐性肌营养不良症。
DOI：
10.1038/s41467-024-45933-5
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发表时间：
2024
影响因子：
16.6
通讯作者：
Richter,Manu
中科院分区：
文献类型：
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作者：
Nashabat,Marwan;Nabavizadeh,Nasrinsadat;Saraçoğlu,HilalPırıl;Sarıbaş,Burak;Avcı,Şahin;Börklü,Esra;Beillard,Emmanuel;Yılmaz,Elanur;Uygur,SeyideEcesu;Kayhan,CavitKerem;Bosco,Luca;Eren,ZeynepBengi;Steindl,Katharina;Richter,Manu
SNURPORTIN-1由SNUPN编码，在剪接体小核糖核蛋白的核输入中起核心作用。然而，它的生理功能仍未被研究。在这项研究中，我们调查了来自15个没有血缘关系的家庭的18名儿童，他们表现出非典型的肌营养不良和神经缺陷。9个亚型SNUPN双等位基因变异，主要聚集在最后一个编码外显子，被确定与该病分离。我们证明了突变的SPN1未能寡聚导致患者的原代成纤维细胞和CRISPR/Cas9介导的突变细胞系中的细胞质聚集。此外，突变的核表现出缺陷的剪接体成熟和Cajal小体的破裂。转录组分析显示剪接和mRNA表达失调，特别是在肌膜成分，导致突变细胞和患者肌肉组织中细胞骨架组织的破坏。我们的发现确定SNUPN缺乏是一种以前未被发现的肌营养不良亚型的遗传病因，并为SPN1在肌肉内稳态中的作用提供了强有力的证据。
SNURPORTIN-1, encoded bySNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphicSNUPNbiallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establishSNUPNdeficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.