Cuppens H, Lin W, Jaspers M, Costes B, Teng H, Vankeerberghen A, Jorissen M, Droogmans G, Reynaert I, Goossens M, Nilius B, Cassiman J J
Center for Human Genetics, KULeuven, B-3000 Leuven, Belgium.
J Clin Invest. 1998 Jan 15;101(2):487-96. doi: 10.1172/JCI639.
In congenital bilateral absence of the vas deferens patients, the T5 allele at the polymorphic Tn locus in the CFTR (cystic fibrosis transmembrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportion of CFTR transcripts that lack exon 9, whose translation products will not contribute to apical chloride channel activity. Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. We hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins was affected by two other polymorphic loci: (TG)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a sixfold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.
在先天性双侧输精管缺如患者中，囊性纤维化跨膜传导调节因子（CFTR）基因多态性Tn位点的T5等位基因是一种常见的具有不完全外显率的疾病突变。该T5等位基因会导致高比例的CFTR转录本缺失外显子9，其翻译产物对顶端氯离子通道活性无贡献。除了多态性Tn位点外，CFTR基因中已描述了120多种多态性。我们推测，几个多态性位点特定等位基因的组合可能导致CFTR蛋白功能降低甚至不足。对一般人群中常见等位基因的三个多态性位点进行分析发现，除了Tn位点的已知作用外，CFTR转录本和/或蛋白的数量和质量还受另外两个多态性位点（TG）m和M470V的影响。在T7背景下，与（TG）10等位基因相比，（TG）11等位基因使缺失外显子9的CFTR转录本比例增加了2.8倍，（TG）12等位基因则使其增加了6倍。发现来自患者的T5 CFTR基因携带大量TG重复序列，而来自健康CF父亲的T5 CFTR基因携带少量TG重复序列。此外，还发现M470 CFTR蛋白成熟较慢，与V470 CFTR蛋白相比，其内在氯离子通道活性增加了1.7倍，这表明M470V位点可能也在T5作为疾病突变的部分外显中起作用。这种多变异突变基因可以解释为什么看似正常的CFTR基因会导致疾病。此外，它们可能是CFTR突变表型表达变异的原因，并且与其他遗传疾病相关。
