Evolution of the delta F508 CFTR mutation.
Evolution of the delta F508 CFTR mutation.
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Delta F508 CFTR 突变的进化。
DOI：
10.1016/s0966-842x(98)01442-5
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发表时间：
1999
影响因子：
15.9
通讯作者：
Guggino,SE
中科院分区：
文献类型：
--
作者：
Guggino,SE
CF具有ΔF508 CFTR突变纯合子的CF个体存在许多上皮组织功能缺陷，导致男性无法分泌胰腺酶、咸汗、气道疾病和不育。直到最近几年，该疾病最严重的表现出现在胰腺，甚至在出生前胰腺就变得囊性和纤维化，导致无法分泌消化酶。在20世纪50年代末酶替代疗法开始之前，CF患者在10岁之前死于营养不良。然而，如果今天出生，患有ΔF508 CFTR突变的CF个体预计寿命约为40年。这些人抵御肺部感染的能力受损，尤其是由铜绿假单胞菌引起的肺部感染，从而导致进行性肺功能障碍。CF患者肺部存在细菌感染，这是由于黏液粘度增加和黏液纤毛跳动减少的共同作用，从而减缓了肺部所有颗粒物的清除。患者对上皮来源的抗菌肽提供的感染保护也可能受损13。铜绿假单胞菌通过菌毛或菌毛与上皮asialoGM1片段相互作用粘附在气道上皮细胞上；在CF患者中，asialoGM1片段增加14。先前，Pier等15报道铜绿假单胞菌也被抑制通过CFTR进入气道上皮，类似于伤寒沙门氏菌进入肠上皮。Pier等人15认为，铜绿假单胞菌进入气道上皮细胞是杀死和清除肺部铜绿假单胞菌的最后步骤，而铜绿假单胞菌进入ΔF508患者上皮的能力受损会导致抵御局部肺部感染的能力下降。因此，根据Pier等人的研究1，抑制伤寒沙门氏菌通过ΔF508 CFTR进入肠道为杂合子提供了一个选择优势，因为它不会通过肠上皮将细菌运送到体内。我们不知道杂合子是否在胰腺酶分泌或肺部定殖细菌杀灭减少方面同时具有选择性劣势。无论Pier et al. 1的假设是否正确，杂合子可能会牺牲一些肺和胰腺功能来抵御肠道感染。显然，肠道作为细菌感染的入口，可能导致疾病，特别是婴儿疾病，仍然是世界卫生关注的一个主要问题。无论它是否起到预防腹泻病或伤寒的作用，目前的假设都支持肠杆菌作为维持ΔF508 CFTR突变的主要选择压力，其在基因库中的高丰度为1:25。
CF has many symptoms Individuals with CF that are homozygous for the ΔF508 CFTR mutation present with defects in the function of many epithelial tissues, resulting in inability to secrete pancreatic enzymes, salty sweat, airway disease and infertility in males. Until recent years, the most serious manifestation of the disease occurred in the pancreas, which became cystic and fibrotic even before birth, resulting in the inability to secrete digestive enzymes. Until enzyme replacement regimens began in the late 1950s, individuals with CF died before the age of ten from malnutrition. However, if born today, CF individuals homozygous for the ΔF508 CFTR mutation have a predicted life span of~ 40 years. Such individuals have an impaired ability to ward off lung infections, in particular those caused by Pseudomonas aeruginosa, which results in progressive lung dysfunction12. Bacterial infections are harbored in the lung of CF patients because of a combination of increased mucus viscosity and decreased mucociliary beating, which slows clearance of all particulate matter from the lung. Patients might also have impaired protection from infection provided by epithelialderived antimicrobial peptides13. P. aeruginosa adheres to airway epithelial cells by way of interaction between bacterial fimbriae or pili and epithelial asialoGM1 moieties; the asialoGM1 moieties are increased in CF patients14. Previously, Pier et al. 15 reported that P. aeruginosa is also inhibited from entering airway epithelia via CFTR, analogous to S. typhi entry into intestinal epithelia. Pier et al. 15 suggest that entry of P. aeruginosa into airway epithelial cells is needed for the final steps in killing and clearing of P. aeruginosa in the lung and that impaired entry of P. aeruginosa into the epithelium of ΔF508 patients results in a reduced ability to ward off local lung infections. Thus, according to Pier et al. 1, inhibition of entry of S. typhi via ΔF508 CFTR in the gut provides a selective advantage to the heterozygote by not transporting bacteria into the body across the intestinal epithelium. We do not know if the heterozygote has a concomitant selective disadvantage in either pancreatic enzyme secretion or decreased killing of colonizing bacteria in the lung. Whether the hypothesis of Pier et al. 1 is correct or not, it might be that the heterozygote can sacrifice some lung and pancreatic function to withstand intestinal infection. Clearly, the intestine as an entry point for bacterial infections likely to result in morbidity, especially in infants, remains a major cause of concern to world health16. Whether or not it acts to ward off diarrheal disease or typhoid fever, current hypotheses favor enterobacteria as the major selective pressure for maintenance of the ΔF508 CFTR mutation at the high abundance of 1: 25 in the gene pool.