Background

The Mutation I1234V is a CF causing mutation; however the mechanisms leading to loss of function are not fully understood. In this study, we aimed to characterize phenotypically individuals with the I1234V variant, and to gain a structural point of view of the mutant CFTR using computational studies.

Methods

We conducted a retrospective descriptive study, reviewing the clinical records of 9 Israeli patients. The study was designed to include patients either homozygous or compound heterozygous for the I1234V mutation. For a comparison we analyzed clinical data of 12 patients homozygous for the F508del mutation. Computer models were constructed for I1234V, 1234-1239del and wild type CFTR.

Results

Mean FEV1 was 73.8 ± 21% predicted with an average annual rate of decline of 1%. When compared to patients homozygous for F508del the mean annual values of FEV1% predicted during the 6 years of data collection ranged from 51 to 58 ± 22–30 in the F508del group versus 76–82 ± 14–19 in the I1234V group (p < 0.05). Structural models did not demonstrate noticeable differences between the three simulated constructs. Although the mutation resides in the NBD2, no interference with ATP binding was detected.

Discussion

This study describes phenotypically patients carrying the I1234V mutation. Compared to patients homozygous for F508del, these patients present with more favorable outcome. Structural models show high similarity between the static and dynamics pictures obtained for both the mutated and the WT-CFTR; however this model does not explore the folding process and therefore may strengthen the notion of a misfolding mutation.

中文翻译：

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携带I1234V突变的CF患者的表型和分子特征。

背景

I1234V突变是CF引起的突变；然而，导致功能丧失的机制尚不完全清楚。在这项研究中，我们旨在表征具有I1234V变异的表型个体，并使用计算研究获得突变体CFTR的结构性观点。

方法

我们进行了回顾性描述性研究，回顾了9名以色列患者的临床记录。该研究被设计为包括I1234V突变的纯合或复合杂合患者。为了进行比较，我们分析了12名F508del突变纯合患者的临床数据。针对I1234V，1234-1239del和野生型CFTR构建了计算机模型。

结果

预测的平均FEV1为73.8±21％，年平均下降速度为1％。与纯合子F508del的患者相比，F508del组在6年的数据收集期间预测的FEV1％的年平均值在51至58±22–30之间，而I1234V组在76–82±14–19之间（p < 0.05）。结构模型没有显示出三种模拟结构之间的明显差异。尽管突变位于NBD2中，但未检测到对ATP结合的干扰。

讨论区

这项研究从表型上描述了携带I1234V突变的患者。与纯合子F508del的患者相比，这些患者的预后更好。结构模型显示了针对变异和WT-CFTR获得的静态图片和动态图片之间的高度相似性；但是，此模型没有探讨折叠过程，因此可能会增强错误折叠突变的概念。