Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene:: a cystic fibrosis mutation of Slavic origin common in Central and East Europe
Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene:: a cystic fibrosis mutation of Slavic origin common in Central and East Europe
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DOI：
10.1007/s004390000246
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发表时间：
2000-03-01
期刊：
影响因子：
5.3
通讯作者：
Zielenski, J
中科院分区：
文献类型：
--
作者：
Dörk, T;Macek, M;Zielenski, J
我们报告了囊性纤维化跨膜传导调节（CFTR）基因的大基因组缺失，即。这种缺失在中欧和东欧经常观察到。该突变被称为CFTRdele2.3(21 kb)，删除了21,080 bp，跨越CFTR基因的内含子1-3。转录分析显示，这种缺失导致上皮CFTR mRNA外显子2和3的丢失，从而在外显子4内产生过早终止信号。为了开发一种简单的聚合酶链反应测定该等位基因，我们在DNA序列水平上定义了缺失的终点。接下来，我们在一组具有代表性的欧洲人和欧洲血统人群中筛选这种突变。在我们的研究过程中，大约有197名CF患者，包括7名纯合子，携带这种突变。CFTRdele2.3（21 kb）纯合子的临床评估，以及Delta F508/ cftrdele2,3 （21 kb）的复合杂合子与两两匹配的Delta F508纯合子的比较表明，这种缺失代表了与胰腺功能不全和早期诊断相关的严重突变。目前的数据显示，这种突变在捷克人（占所有CF染色体的6.4%）、俄罗斯人（5.2%）和白俄罗斯人（3.3%）中尤为常见。奥地利（2.6%）、德国（1.5%）、波兰（1.5%）、斯洛文尼亚（1.5%）、乌克兰（1.2%）和斯洛伐克（1.1%）患者。在立陶宛、拉脱维亚、马其顿和希腊也有发现，在加拿大、美国、法国、西班牙、土耳其和英国也有零星发现，但在保加利亚、克罗地亚、罗马尼亚和塞尔维亚的CF患者中没有发现。单倍型分析鉴定出相同的基因外cf单倍型：XV-2c/KM。在所有检测的cftrdele2,3 （21 kb）染色体上都有19“A”和相同的罕见的基因内微卫星单倍型16-33-13 (IVS8CA-IVS17bTA-IVSI7bCA)，表明这种缺失有共同的起源。我们得出结论，在东斯拉夫和西斯拉夫血统人群中，21 kb的缺失是一种频繁和严重的CF突变。
We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz.. a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2.3(21 kb), deletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2.3(21 kb) homozygotes and a comparison of compound heterozygotes for Delta F508/CFTRdele2,3(21 kb) with pairwise-matched Delta F508 homozygotes indicate that this deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%). Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype: XV-2c/KM. 19 "A" and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVSI7bCA) in all examined CFTRdele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.