Kubesch P, Dörk T, Wulbrand U, Kälin N, Neumann T, Wulf B, Geerlings H, Weissbrodt H, von der Hardt H, Tümmler B
Department of Biophysical Chemistry, Medizinische Hochschule Hannover, Germany.
Lancet. 1993 Jan 23;341(8839):189-93. doi: 10.1016/0140-6736(93)90062-l.
Exocrine pancreatic insufficiency and lung infection with Pseudomonas aeruginosa are major features of cystic fibrosis (CF). This monogenic disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. 267 children and adolescents with CF who were regularly seen at the same centre were assessed for an association of the CFTR mutation genotype with exocrine pancreatic function and the age of onset of chronic colonisation with P aeruginosa. The major mutation delta F508 accounted for 74% of CF alleles; 33 further CFTR mutations had been detected on the CF chromosomes of the study population by June, 1992. With the exception of delta F508/R347P compound heterozygotes, patients of the same mutation genotype were either pancreas insufficient (PI) or pancreas sufficient (PS). The age-specific colonisation rates with P aeruginosa were significantly lower in PS than in PI patients. The missense and splice site mutations that are "mild" CF alleles with respect to exocrine pancreatic function were also "low risk" alleles for the acquisition of P aeruginosa. On the other hand, the proportion of P aeruginosa-positive patients increased most rapidly in the PI delta F508 compound heterozygotes who were carrying a termination mutation in the nucleotide binding fold-encoding exons. Pancreatic status and the risk of chronic airways' colonisation with P aeruginosa are predisposed by the CFTR mutation genotype and can be differentiated by the type and location of the mutations in the CFTR gene.
外分泌性胰腺功能不全和铜绿假单胞菌肺部感染是囊性纤维化（CF）的主要特征。这种单基因疾病由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起。对在同一中心定期就诊的267名CF儿童和青少年进行评估，以确定CFTR突变基因型与外分泌胰腺功能以及铜绿假单胞菌慢性定植发病年龄之间的关联。主要突变ΔF508占CF等位基因的74%；到1992年6月，在研究人群的CF染色体上又检测到33种CFTR突变。除了ΔF508/R347P复合杂合子外，相同突变基因型的患者要么胰腺功能不全（PI），要么胰腺功能正常（PS）。PS患者铜绿假单胞菌的年龄特异性定植率显著低于PI患者。就外分泌胰腺功能而言，那些“轻度”CF等位基因的错义突变和剪接位点突变也是获得铜绿假单胞菌的“低风险”等位基因。另一方面，在核苷酸结合折叠编码外显子中携带终止突变的PI ΔF508复合杂合子中，铜绿假单胞菌阳性患者的比例上升最快。胰腺状态和铜绿假单胞菌慢性气道定植的风险由CFTR突变基因型决定，并且可以通过CFTR基因中突变的类型和位置来区分。
