Coutelle C, Grade K
Max-Delbrück-Centrum für Molekulare Medizin, Max-Delbrück-Haus, Berlin-Buch, Germany.
Padiatr Grenzgeb. 1992;31(2):73-95.
The elucidation of the basic defect causing cystic fibrosis (CF) is a paradigm for the application of "reverse genetics" to the analysis of human genetic disease. Following this strategy, linkage analysis localized the responsible gene for CF on chromosome 7. Chromosome mediated gene transfer and chromosome walking and jumping led to the isolation of the CFTR-gene and its cDNA. A major 3 bp deletion mutation (DeltaF508) and more than 100 other mutations of this gene have been identified as molecular basis of cystic fibrosis. The CFTR-amino acid sequence, obtained by conversion of the cDNA-sequence, indicates that CFTR belongs to a group of integral membrane transport proteins (ABC-proteins). The normal cAMP-stimulated chloride-transport, lacking in CF-cells is restored by transfer and expression of CFTR-cDNA-recombinants in these cells. CFTR is most likely itself a chloride channel. The molecular identification of this gene has already led to substantial advances in diagnosis and prevention of this disease. New therapeutic approaches by pharmacological means or gene therapy are expected from the further molecular and functional analysis of the CFTR-gene.
对导致囊性纤维化（CF）的基本缺陷的阐明，是“反向遗传学”应用于人类遗传疾病分析的一个范例。按照这一策略，连锁分析将CF的致病基因定位到了7号染色体上。染色体介导的基因转移以及染色体步移和跳查，导致了CFTR基因及其cDNA的分离。该基因上一个主要的3bp缺失突变（ΔF508）以及其他100多种突变，已被确定为囊性纤维化的分子基础。通过cDNA序列转化得到的CFTR氨基酸序列表明，CFTR属于一类整合膜转运蛋白（ABC蛋白）。CF细胞中缺乏的正常cAMP刺激的氯离子转运，通过在这些细胞中转移和表达CFTR-cDNA重组体得以恢复。CFTR很可能本身就是一个氯离子通道。该基因的分子鉴定已经在这种疾病的诊断和预防方面取得了重大进展。通过对CFTR基因的进一步分子和功能分析，有望采用药理学方法或基因治疗开发新的治疗方法。
