Zhang Xiaoying, Hothi Jaspal S, Zhang Yanhui H, Ren Aixia, Rock Michael J, Srinivasan Saumini, Stokes Dennis C, Naren Anjaparavanda P, Zhang Weiqiang
Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
University of Tennessee Cystic Fibrosis Care and Research Center at Le Bonheur Children's Hospital-Methodist University Hospital, Memphis, TN 38103, USA.
Life (Basel). 2021 Feb 8;11(2):131. doi: 10.3390/life11020131.
(1) Background: many rare (CFTR) mutations remain poorly characterized with regard to functional consequences of the mutation. We present the clinical features of two pediatric cystic fibrosis (CF) subjects who are heterozygous for F1099L (c.3297C>G), one with G551D (a class III mutation) and one with 3849 + 10kbC->T (a class V mutation). We also identified the molecular defect(s) that are associated with F1099L mutation to correlate with the clinical features that we observed; (2) Methods: clinical findings and history were extracted from the electronic medical record and de-identified. F1099L-CFTR protein expression level and maturation status, channel function, and the effects of CFTR modulation on these characteristics were investigated using western blotting and iodide efflux assay; (3) Results: these two subjects have mild CF phenotypes when F1099L is combined with two known disease-causing mutations. F1099L-CFTR has a moderate defect in processing and maturation, causing fewer CFTR channels at the cell surface and, therefore, impaired channel activities. These defects could be effectively corrected using VX-809 (lumacaftor); and, (4) Conclusions: our biochemical data correlate with the disease manifestations and suggest that F1099L is potentially a CF-causing mutation. The study expands our knowledge of rare CFTR mutations and may help in developing effective therapies for subjects with F1099L mutation.
(1) 背景：许多罕见的囊性纤维化跨膜传导调节因子（CFTR）突变在突变的功能后果方面仍未得到充分表征。我们报告了两名患有F1099L（c.3297C>G）杂合子的小儿囊性纤维化（CF）患者的临床特征，其中一名患者还伴有G551D（III类突变），另一名伴有3849 + 10kbC->T（V类突变）。我们还确定了与F1099L突变相关的分子缺陷，以使其与我们观察到的临床特征相关联；(2) 方法：从电子病历中提取临床发现和病史并进行去识别处理。使用蛋白质免疫印迹法和碘外流试验研究F1099L-CFTR蛋白的表达水平、成熟状态、通道功能以及CFTR调节剂对这些特征的影响；(3) 结果：当F1099L与两个已知的致病突变结合时，这两名患者具有轻度CF表型。F1099L-CFTR在加工和成熟过程中存在中度缺陷，导致细胞表面的CFTR通道减少，从而损害通道活性。使用VX-809（鲁马卡托）可以有效纠正这些缺陷；(4) 结论：我们的生化数据与疾病表现相关，表明F1099L可能是一种导致CF的突变。该研究扩展了我们对罕见CFTR突变的认识，并可能有助于开发针对F1099L突变患者的有效治疗方法。
