Casals T, Bassas L, Ruiz-Romero J, Chillón M, Giménez J, Ramos M D, Tapia G, Narváez H, Nunes V, Estivill X
Molecular Genetics Department, Hospital Duran i Reynals, Barcelona, Catalonia, Spain.
Hum Genet. 1995 Feb;95(2):205-11. doi: 10.1007/BF00209403.
Mutations in the cystic fibrosis (CF) conductance transmembrane regulator (CFTR) gene have been detected in patients with CF and in males with infertility attributable to congenital bilateral absence of the vas deferens (CBAVD). Thirty individuals with CBAVD and 10 with congenital unilateral absence of the vas deferens (CUAVD) were analyzed by single-strand conformation analysis and denaturing gradient gel electrophoresis for mutations in most of the CFTR gene. All 40 individuals were pancreatic sufficient, but twenty patients had recurrent or sporadic respiratory infections, asthma/asthmatic bronchitis, and/or rhino-sinusitis. Agenesia or displasia of one or both seminal vesicles was detected in 30 men and other urogenital malformations were present in six subjects. Among the 40 samples, we identified 13 different CFTR mutations, two of which were previously unknown. One new mutation in exon 4 was the deletion of glutamic acid at codon 115 (delta E115). A second new mutation was found in exon 17b, viz., an A --> C substitution at position 3311, changing lysine to threonine at codon 1060 (K1060T). CFTR mutations were detected in 22 out of 30 (73.3%) CBAVD patients and in one out of 10 (10%) CUAVD individuals, showing a significantly lower incidence of CFTR mutations in CBAVD/CUAVD patients (P << 0.0001), compared with that found in the CF patient population. Only three CBAVD patients were found with more than one CFTR mutation (delta F508/L206W, delta F508/R74W + D1270N, R117H/712-1G --> T), highlighting L206W, R74W/D1270N, and R117H as benign CF mutations. Sweat electrolyte values were increased in 76.6% of CBAVD patients, but three individuals without CFTR mutations had normal sweat electrolyte levels (10% of the total CBAVD patients), suggesting that factors other than CFTR mutations are involved in CBAVD. The failure to identify a second mutation in exons and their flanking regions of the CFTR gene suggests that these mutations could be located in introns or in the promoter region of CFTR. Such mutations could result in CFTR levels below the minimum 6%-10% necessary for normal protein function.
在囊性纤维化（CF）患者以及因先天性双侧输精管缺如（CBAVD）导致不育的男性中，已检测到囊性纤维化跨膜传导调节因子（CFTR）基因的突变。通过单链构象分析和变性梯度凝胶电泳对30例CBAVD患者和10例先天性单侧输精管缺如（CUAVD）患者进行分析，以检测CFTR基因大部分区域的突变。所有40例个体胰腺功能均正常，但有20例患者有反复或散发性呼吸道感染、哮喘/喘息性支气管炎和/或鼻-鼻窦炎。在30名男性中检测到一个或两个精囊发育不全或发育异常，6名受试者存在其他泌尿生殖系统畸形。在这40个样本中，我们鉴定出13种不同的CFTR突变，其中两种是以前未知的。外显子4中的一个新突变是第115密码子谷氨酸的缺失（ΔE115）。在17b外显子中发现了第二个新突变，即第3311位的A→C替换，使第1060密码子的赖氨酸变为苏氨酸（K1060T）。30例CBAVD患者中有22例（73.3%）检测到CFTR突变，10例CUAVD个体中有1例（10%）检测到CFTR突变，与CF患者群体相比，CBAVD/CUAVD患者中CFTR突变的发生率显著较低（P << 0.0001）。仅发现3例CBAVD患者有不止一种CFTR突变（ΔF508/L206W、ΔF508/R74W + D1270N、R117H/712-1G→T），突出显示L206W、R74W/D1270N和R117H为良性CF突变。76.6%的CBAVD患者汗液电解质值升高，但3例无CFTR突变的个体汗液电解质水平正常（占CBAVD患者总数的10%），这表明除CFTR突变外，其他因素也参与了CBAVD的发生。在CFTR基因的外显子及其侧翼区域未能鉴定出第二种突变，这表明这些突变可能位于内含子或CFTR的启动子区域。此类突变可能导致CFTR水平低于正常蛋白质功能所需的最低6%-10%。
