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首页> 美国卫生研究院文献>The Journal of Clinical Investigation >A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis.
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A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis.

机译：无意义突变E92X激活的囊性纤维化患者气道上皮细胞中的一个新的外显子。

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摘要

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We report on a novel nonsense mutation that leads to exon skipping and the activation of a cryptic exon. Screening of genomic DNA from 700 German patients with CF uncovered four cases with the nonsense mutation E92X, a G-->T transversion that creates a termination codon and affects the first base of exon 4 of the CFTR gene. Lymphocyte RNA of two CF patients heterozygous for E92X was found to contain the wild type sequence and a differentially spliced isoform lacking exon 4. In RNA derived from nasal epithelial cells of E92X patients, a third fragment of longer size was observed. Sequencing revealed the presence of E92X and an additional 183-bp fragment, inserted between exons 3 and 4. The 183-bp sequence was mapped to intron 3 of the CFTR gene. It is flanked by acceptor and donor splice sites. We conclude that the 183-bp fragment in intron 3 is a cryptic CFTR exon that can be activated in epithelial cells by the presence of the E92X mutation. E92X abolishes correctly spliced CFTR mRNA and leads to severe cystic fibrosis.
机译：囊性纤维化（CF）是由囊性纤维化跨膜电导调节剂（CFTR）基因突变引起的。我们报告了一种新型的无意义突变，该突变导致外显子跳跃和隐性外显子的激活。从700名德国CF患者中筛选基因组DNA时发现了4例无意义突变E92X，这是一种由G-> T颠倒的基因，产生终止密码子并影响CFTR基因第4外显子的第一个碱基。发现两名E92X杂合的CF患者的淋巴细胞RNA包含野生型序列和缺少外显子4的差异剪接同工型。在E92X患者鼻上皮细胞衍生的RNA中，观察到第三个更长的片段。测序显示存在E92X和一个外显子3和4之间插入的另一个183bp片段。该183bp序列被定位到CFTR基因的内含子3。它的侧面是受体和供体剪接位点。我们得出的结论是，内含子3中的183bp片段是一个隐秘的CFTR外显子，可以通过存在E92X突变而在上皮细胞中被激活。 E92X消除正确剪接的CFTR mRNA，并导致严重的囊性纤维化。

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