Jackson JaNise J, Mao Yiyang, White Tyshawn R, Foye Catherine, Oliver Kathryn E
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States.
Center for Cystic Fibrosis and Airways Disease Research, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, United States.
Front Genet. 2023 Apr 24;14:1166529. doi: 10.3389/fgene.2023.1166529. eCollection 2023.
Cystic fibrosis (CF) is an autosomal recessive disease impacting ∼100,000 people worldwide. This lethal disorder is caused by mutation of the gene, which encodes an ATP-binding cassette-class C protein. More than 2,100 variants have been identified throughout the length of . These defects confer differing levels of severity in mRNA and/or protein synthesis, folding, gating, and turnover. Drug discovery efforts have resulted in recent development of modulator therapies that improve clinical outcomes for people living with CF. However, a significant portion of the CF population has demonstrated either no response and/or adverse reactions to small molecules. Additional therapeutic options are needed to restore underlying genetic defects for all patients, particularly individuals carrying rare or refractory variants. Concerted focus has been placed on rescuing variants that encode truncated CFTR protein, which also harbor abnormalities in mRNA synthesis and stability. The current mini-review provides an overview of CFTR mRNA features known to elicit functional consequences on final protein conformation and function, including considerations for RNA-directed therapies under investigation. Alternative exon usage in the 5'-untranslated region, polypyrimidine tracts, and other sequence elements that influence splicing are discussed. Additionally, we describe mechanisms of CFTR mRNA decay and post-transcriptional regulation mediated through interactions with the 3'-untranslated region (e.g. poly-uracil sequences, microRNAs). Contributions of synonymous single nucleotide polymorphisms to CFTR transcript utilization are also examined. Comprehensive understanding of CFTR RNA biology will be imperative for optimizing future therapeutic endeavors intended to address presently untreatable forms of CF.
囊性纤维化（CF）是一种常染色体隐性疾病，全球约有10万人受其影响。这种致命疾病是由 基因的突变引起的，该基因编码一种ATP结合盒C类蛋白。在 基因全长范围内已鉴定出2100多种变体。这些缺陷在mRNA和/或蛋白质合成、折叠、门控和周转方面造成不同程度的严重程度。药物研发工作导致了调节剂疗法的近期发展，改善了CF患者的临床结局。然而，很大一部分CF患者对小分子药物无反应和/或出现不良反应。需要更多的治疗选择来修复所有患者的潜在基因缺陷，特别是携带罕见或难治性 变体的个体。人们一致将重点放在挽救编码截短CFTR蛋白的变体上，这些变体在mRNA合成和稳定性方面也存在异常。本综述概述了已知会对最终蛋白质构象和功能产生功能影响的CFTR mRNA特征，包括对正在研究的RNA导向疗法的考虑。讨论了5'-非翻译区的可变外显子使用、多嘧啶序列以及其他影响剪接的序列元件。此外，我们描述了CFTR mRNA衰变的机制以及通过与3'-非翻译区（如聚尿嘧啶序列、微小RNA）相互作用介导的转录后调控。还研究了同义单核苷酸多态性对CFTR转录本利用的影响。全面了解CFTR RNA生物学对于优化未来旨在治疗目前无法治疗的CF形式的治疗努力至关重要。
