BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
Sorbonne Université, Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, 75005 Paris, France.
Biosci Rep. 2022 Jul 29;42(7). doi: 10.1042/BSR20212006.
Cystic fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. Although all mutations lead to the lack or reduction in channel function, the mechanisms through which this occurs are diverse - ranging from lack of full-length mRNA, reduced mRNA levels, impaired folding and trafficking, targeting to degradation, decreased gating or conductance, and reduced protein levels to decreased half-life at the plasma membrane. Here, we review the different molecular mechanisms that cause cystic fibrosis and detail how these differences identify theratypes that can inform the use of directed therapies aiming at correcting the basic defect. In summary, we travel through CFTR life cycle from the gene to function, identifying what can go wrong and what can be targeted in terms of the different types of therapeutic approaches.
囊性纤维化是白种人中最常见的常染色体隐性遗传病，由囊性纤维化跨膜电导调节因子（CFTR）基因突变引起，该基因编码一种 cAMP 激活的氯离子和碳酸氢根通道，调节分泌上皮中的离子和水转运。虽然所有突变都会导致通道功能丧失或减少，但发生这种情况的机制是多种多样的——从缺乏全长 mRNA、降低的 mRNA 水平、受损的折叠和运输、靶向降解、门控或电导降低以及蛋白质水平降低到质膜半衰期缩短。在这里，我们回顾了导致囊性纤维化的不同分子机制，并详细说明了这些差异如何确定可用于指导旨在纠正基本缺陷的靶向治疗的治疗类型。总之，我们从基因到功能描述了 CFTR 的生命周期，确定了可能出错的地方以及可以针对不同类型的治疗方法进行靶向治疗的地方。
