RNA-seq in DMD urinary stem cells recognized muscle-related transcription signatures and addressed the identification of atypical mutations by whole-genome sequencing
| العنوان: | RNA-seq in DMD urinary stem cells recognized muscle-related transcription signatures and addressed the identification of atypical mutations by whole-genome sequencing |
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| المؤلفون: | Silvia Zia, Valeria A. Sansone, Barbara Roda, Pierluigi Reschiglian, Alessandra Ferlini, Wenyan Li, Francesca Gualandi, Andrea Barp, Andrea Grilli, Zhiyuan Lu, Silvio Bicciato, Federica Ricci, M. Fabris, Madhuri Hegde, Luca Bello, Tiziana Mongini, Paola Rimessi, Reem El Dani, Rachele Rossi, Maria Sofia Falzarano, Elena Pegoraro, Mingyan Fang, Rita Selvatici |
| المصدر: | HGG Advances, Vol 3, Iss 1, Pp 100054-(2022) Human Genetics and Genomics Advances |
| بيانات النشر: | Elsevier, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Antisense therapy, musculoskeletal diseases, Mutation, congenital, hereditary, and neonatal diseases and abnormalities, Duchenne muscular dystrophy, government.form_of_government, Socio-culturale, RNA-Seq, Computational biology, Biology, QH426-470, medicine.disease_cause, medicine.disease, Article, Gene expression profiling, Transcription (biology), RNA splicing, medicine, government, biology.protein, Genetics, Molecular Medicine, Dystrophin, Genetics (clinical) |
| الوصف: | Summary Urinary stem cells (USCs) are a non-invasive, simple, and affordable cell source to study human diseases. Here we show that USCs are a versatile tool for studying Duchenne muscular dystrophy (DMD), since they are able to address RNA signatures and atypical mutation identification. Gene expression profiling of DMD individuals’ USCs revealed a profound deregulation of inflammation, muscle development, and metabolic pathways that mirrors the known transcriptional landscape of DMD muscle and worsens following USCs’ myogenic transformation. This pathogenic transcription signature was reverted by an exon-skipping corrective approach, suggesting the utility of USCs in monitoring DMD antisense therapy. The full DMD transcript profile performed in USCs from three undiagnosed DMD individuals addressed three splicing abnormalities, which were decrypted and confirmed as pathogenic variations by whole-genome sequencing (WGS). This combined genomic approach allowed the identification of three atypical and complex DMD mutations due to a deep intronic variation and two large inversions, respectively. All three mutations affect DMD gene splicing and cause a lack of dystrophin protein production, and one of these also generates unique fusion genes and transcripts. Further characterization of USCs using a novel cell-sorting technology (Celector) highlighted cell-type variability and the representation of cell-specific DMD isoforms. Our comprehensive approach to USCs unraveled RNA, DNA, and cell-specific features and demonstrated that USCs are a robust tool for studying and diagnosing DMD. We defined urinary stem cell (USC) RNA-seq signatures and provided evidence that they are a non-invasive, affordable cell source to study Duchenne muscular dystrophy (DMD), an X-linked disease, due to dystrophin gene mutations. Based on USCs’ RNA profiling and whole-genome sequencing (WGS), we identified three undetected atypical DMD mutations. |
| اللغة: | English |
| تدمد: | 2666-2477 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8e477b56a8959acf282748c98930674aTest http://www.sciencedirect.com/science/article/pii/S266624772100035XTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8e477b56a8959acf282748c98930674a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26662477 |
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