Diana Anna, Polizzi Angela Maria, Santostasi Teresa, Ratclif Luigi, Pantaleo Maria Giuseppina, Leonetti Giuseppina, Iusco Danila Rosa, Gallo Crescenzio, Conese Massimo, Manca Antonio
Cystic Fibrosis Regional Puglia Center, Department of Pediatric Surgery and Sciences - Operational Unit B. Trambusti, University Hospital Policlinico, Bari, Italy.
Cystic Fibrosis Support Center, Pediatrics Section, Hospital of Cerignola, Cerignola, Italy.
J Hum Genet. 2016 Jun;61(6):473-81. doi: 10.1038/jhg.2016.15. Epub 2016 Feb 25.
Few mutations in cis have been annotated for F508del homozygous patients. Southern Italy patients who at a first analysis appeared homozygous for the F508del mutation (n=63) or compound heterozygous for the F508del and another mutation in the cystic fibrosis transmembrane conductance regulator gene (n=155) were searched for the A238V mutation in exon 6. The allelic frequency of the complex allele [A238V;F508del] was 0.04. When the whole data set was used (comprised also of 56 F508del/F508del and 34 F508del/other mutation controls), no differences reached the statistical significance in the clinical parameters, except chloride concentrations which were lower in [A238V;F508del]/other mutation compared with F508del/other mutation (P=0.03). The two study groups presented less complications than the control groups. Within the minimal data set (34 F508del/F508del, 27 F508del/other mutation, 4 [A238V;F508del]/F508del cases and 5 [A238V;F508del]/other mutation cases); that is, presenting all the variables in each patient, forced expiratory volume in 1 s and forced vital capacity presented a trend to lower levels in the study groups in comparison with the F508del/F508del group, and C-reactive protein approximated statistically significant higher levels in the [A238V;F508del]/other mutation as compared with F508del/F508del patients (P=0.09). The analysis of statistical dependence among the variables showed a significant anticorrelation between chloride and body mass index in the [A238V;F508del]/other mutation group. In conclusion, the complex allele [A238V;F508del] seems to be associated with less general complications than in the control groups, on the other hand possibly giving a worse pulmonary phenotype and higher systemic/local inflammatory response. These findings have implications for the correct recruitment and clinical response of F508del patients in the clinical trials testing the new etiological drugs for cystic fibrosis.
针对F508del纯合患者，顺式突变的注释较少。对意大利南部最初分析显示为F508del突变纯合子（n = 63）或F508del与囊性纤维化跨膜传导调节因子基因中的另一种突变的复合杂合子（n = 155）的患者，检测其第6外显子中的A238V突变。复合等位基因[A238V;F508del]的等位基因频率为0.04。当使用整个数据集时（还包括56例F508del/F508del和34例F508del/其他突变对照），除了[A238V;F508del]/其他突变组的氯浓度低于F508del/其他突变组（P = 0.03）外，临床参数方面的差异均未达到统计学显著性。两个研究组的并发症均少于对照组。在最小数据集中（34例F508del/F508del、27例F�08del/其他突变、4例[A238V;F508del]/F508del病例和5例[A238V;F508del]/其他突变病例）；即呈现每位患者的所有变量，与F508del/F508del组相比，研究组的1秒用力呼气量和用力肺活量呈现出降低的趋势，并且与F508del/F508del患者相比，[A238V;F508del]/其他突变组的C反应蛋白在统计学上接近显著更高水平（P = 0.09）。变量之间的统计依赖性分析显示，在[A238V;F508del]/其他突变组中，氯与体重指数之间存在显著的负相关。总之，复合等位基因[A238V;F508del]似乎比对照组的总体并发症更少，另一方面可能导致更差的肺部表型和更高的全身/局部炎症反应。这些发现对在测试囊性纤维化新病因药物的临床试验中F508del患者的正确招募和临床反应具有重要意义。
