A NOVEL MUTATION IN THE CYSTIC-FIBROSIS GENE IN PATIENTS WITH PULMONARY-DISEASE BUT NORMAL SWEAT CHLORIDE CONCENTRATIONS
A NOVEL MUTATION IN THE CYSTIC-FIBROSIS GENE IN PATIENTS WITH PULMONARY-DISEASE BUT NORMAL SWEAT CHLORIDE CONCENTRATIONS
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DOI：
10.1056/nejm199410133311503
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发表时间：
1994-10-13
影响因子：
158.5
通讯作者：
KNOWLES, MR
中科院分区：
文献类型：
--
作者：
HIGHSMITH, WE;BURCH, LH;KNOWLES, MR
背景许多患有类似囊性纤维化的慢性肺部疾病的患者的汗液氯化物值正常（或非诊断性）。在这些患者中很难诊断囊性纤维化，因为囊性纤维化跨膜传导调节因子（CFTR）基因中没有相关突变。我们评估了23例具有囊性纤维化特征的肺部疾病患者，但汗液氯化物浓度在正常范围内。通过聚合酶链反应扩增鼻上皮信使RNA的直接测序和检测受影响上皮的功能来寻找CFTR基因的突变。在来自8个无关家族的13名患者中鉴定出CFTR基因内含子19中的胞苷磷酸鸟苷二核苷酸C至T点突变，称为3849+10 kb C至TI。这种突变在来自三个不同种族的患者中发现，具有三种不同的扩展单倍型。该突变导致在内含子19中产生部分活性剪接位点，并在外显子19和20之间插入新的84碱基对“外显子”，其含有框内终止密码子。正常剪接的转录本也被检测到，其水平约为正常受试者的8%。该突变与鼻上皮和汗液腺泡上皮功能异常有关。我们已经确定了CFTR内含子19的点突变和患有囊性纤维化样肺病但汗液氯化物值正常的患者的上皮功能异常。这种突变的鉴定表明这种综合征是囊性纤维化的一种形式。突变筛查应该证明在这一人群的患者诊断有用。
Background. Many patients with chronic pulmonary disease similar to that seen in cystic fibrosis have normal (or nondiagnostic) sweat chloride values. It has been difficult to make the diagnosis of cystic fibrosis in these patients because no associated mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been identified.Methods. We evaluated 23 patients with pulmonary disease characteristic of cystic fibrosis but with sweat chloride concentrations in the normal range. Mutations in the CFTR gene were sought by direct sequencing of polymerase chain reaction-amplified nasal epithelial messenger RNA and by testing the functioning of affected epithelium.Results. A cytidine phosphate guanosine dinucleotide C-to-T point mutation in intron 19 of the CFTR gene, termed 3849+10 kb C to TI was identified in 13 patients from eight unrelated families. This mutation was found in patients from three different ethnic groups with three different extended haplotypes. The mutation leads to the creation of a partially active splice site in intron 19 and to the insertion into most CFTR transcripts of a new 84-base-pair ''exon,'' containing an in-frame stop codon, between exons 19 and 20. Normally spliced transcripts were also detected at a level approximately 8 percent of that found in normal subjects. This mutation is associated with abnormal nasal epithelial and sweat acinar epithelial function.Conclusions. We have identified a point mutation in intron 19 of CFTR and abnormal epithelial function in patients who have cystic fibrosis-like lung disease but normal sweat chloride values. The identification of this mutation indicates that this syndrome is a form of cystic fibrosis. Screening for the mutation should prove diagnostically useful in this population of patients.