The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs.
The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs.
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ΔF508突变会导致CFTR错误处理和猪的囊性纤维化样疾病。
DOI：
10.1126/scitranslmed.3001868
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发表时间：
2011-03-16
影响因子：
17.1
通讯作者：
Stoltz DA
中科院分区：
文献类型：
--
作者：
Ostedgaard LS;Meyerholz DK;Chen JH;Pezzulo AA;Karp PH;Rokhlina T;Ernst SE;Hanfland RA;Reznikov LR;Ludwig PS;Rogan MP;Davis GJ;Dohrn CL;Wohlford-Lenane C;Taft PJ;Rector MV;Hornick E;Nassar BS;Samuel M;Zhang Y;Richter SS;Uc A;Shilyansky J;Prather RS;McCray PB Jr;Zabner J;Welsh MJ;Stoltz DA
编码囊性纤维化跨膜电导调节因子 (CFTR) 阴离子通道的基因突变会导致常染色体隐性遗传疾病，囊性纤维化 (CF)。最常见的突变是 ΔF508，它删除了苯丙氨酸 508。体外研究表明 CFTR-ΔF508 被错误处理，但该突变的体内后果尚不确定。为了更好地了解 ΔF508 突变的影响，我们培育了 CFTRΔF508/ΔF508 猪。我们对新生猪 CFTR-ΔF508 的生化、免疫细胞化学和电生理学数据与体外结果相似。他们还指出，CFTRΔF508/ΔF508气道上皮保留了少量残留的CFTR电导；最大刺激产生约 6% 的野生型功能。有趣的是，cAMP 激动剂在 CFTRΔF508/ΔF508 上皮细胞中刺激电流的效力较差，这表明最大阴离子电流的定量测试可能高估了生理条件下的转运。尽管有残余的 CFTR 功能，四头老年 CFTRΔF508/ΔF508 猪却出现了与人类 CF 惊人相似的肺部疾病。这些结果表明，这种有限的 CFTR 活性不足以预防 CF 猪的肺部或胃肠道疾病。这些数据还表明，重组 CFTR-ΔF508 错误加工的研究可以预测体内行为，这验证了其在生化和药物发现实验中的用途。这些发现有助于阐明常见 CF 突变的分子发病机制，并将指导开发新疗法的策略。
Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel cause the autosomal recessive disease, cystic fibrosis (CF). The most common mutation is ΔF508, which deletes phenylalanine508. In vitro studies indicate that CFTR-ΔF508 is misprocessed, though in vivo consequences of the mutation are uncertain. To better understand effects of the ΔF508 mutation, we produced CFTRΔF508/ΔF508 pigs. Our biochemical, immunocytochemical and electrophysiological data on CFTR-ΔF508 in newborn pigs paralleled in vitro results. They also indicated that CFTRΔF508/ΔF508 airway epithelia retain a small residual CFTR conductance; maximal stimulation produced ~6% of wild-type function. Interestingly, cAMP agonists were less potent at stimulating current in CFTRΔF508/ΔF508 epithelia, suggesting that quantitative tests of maximal anion current may overestimate transport under physiological conditions. Despite residual CFTR function, four older CFTRΔF508/ΔF508 pigs developed lung disease strikingly similar to human CF. These results suggest that this limited CFTR activity is insufficient to prevent lung or gastrointestinal disease in CF pigs. These data also suggest that studies of recombinant CFTR-ΔF508 misprocessing predict in vivo behavior, which validates its use in biochemical and drug discovery experiments. These findings help elucidate the molecular pathogenesis of the common CF mutation and will guide strategies for developing new therapeutics.
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DOI：
10.1085/jgp.200409059
发表时间：
2004-08
期刊：
The Journal of general physiology
影响因子：
--
作者：
Muanprasat C;Sonawane ND;Salinas D;Taddei A;Galietta LJ;Verkman AS
通讯作者：
Verkman AS
DOI：
10.1126/science.1191542
发表时间：
2010-08-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Okiyoneda T;Barrière H;Bagdány M;Rabeh WM;Du K;Höhfeld J;Young JC;Lukacs GL
通讯作者：
Lukacs GL
影响因子：
24.3
作者：
Ho, LP;Samways, JM;Innes, JA
通讯作者：
Innes, JA
DOI：
10.1124/jpet.109.162032
发表时间：
2010-04-01
影响因子：
3.5
作者：
Kelly, Mairead;Trudel, Stephanie;Fritsch, Janine
通讯作者：
Fritsch, Janine
DOI：
10.1165/rcmb.2008-0434oc
发表时间：
2010-03-01
影响因子：
6.4
作者：
Jurkuvenaite, Asta;Chen, Lan;Collawn, James F.
通讯作者：
Collawn, James F.