Noone P G, Pue C A, Zhou Z, Friedman K J, Wakeling E L, Ganeshananthan M, Simon R H, Silverman L M, Knowles M R
Cystic Fibrosis/Pulmonary Research and Treatment Center, Departments of Medicine, and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Am J Respir Crit Care Med. 2000 Nov;162(5):1919-24. doi: 10.1164/ajrccm.162.5.2003160.
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The 5T allele in intron 8 (IVS8) causes abnormal splicing in the CFTR gene, and is associated with lung disease when it occurs in cis with a missense mutation in the CFTR gene, R117H. However, the 5T variant alone has not been reported to cause lung disease. We describe two adult female patients with CF-like lung disease associated with the 5T allele. One patient's genotype is 5T-TG12-M470V/5T-TG12-M470V, and the other is DeltaF508/5T-TG12-M470V; full sequencing of the CFTR gene revealed no other mutation on the same allele as the 5T variant. The levels of full-length CFTR mRNA in respiratory epithelia were very low in these patients (11 and 6%, respectively, of total CFTR mRNA expression). Both patients had defective CFTR-mediated chloride conductance in the sweat ductal and/or acinar epithelia (sweat chloride, mmol/L, mean +/- SEM: 40.0 +/- 5.0 [n = 8 samples] and 80. 0 +/- 3.5 [n = 6 samples]) and airway epithelia (mV, mean +/- SEM CFTR-mediated Cl(-) conductance of 1.2 +/- 2.2 [n = 5 studies] and -6.75 +/- 8.1 [n = 4 studies]). These data suggest that the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12 and M470V) may cause a low level of full-length functional CFTR protein and CF-like lung disease.
囊性纤维化由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起。内含子8（IVS8）中的5T等位基因导致CFTR基因异常剪接，当它与CFTR基因中的错义突变R117H顺式发生时，与肺部疾病相关。然而，单独的5T变异体尚未被报道可导致肺部疾病。我们描述了两名患有与5T等位基因相关的类似CF肺部疾病的成年女性患者。一名患者的基因型为5T-TG12-M470V/5T-TG12-M470V，另一名为DeltaF508/5T-TG12-M470V；CFTR基因的全序列分析显示，与5T变异体相同的等位基因上没有其他突变。这些患者呼吸道上皮中全长CFTR mRNA水平非常低（分别占总CFTR mRNA表达的11%和6%）。两名患者在汗腺导管和/或腺泡上皮（汗液氯化物，mmol/L，平均值±标准误：40.0±5.0 [n = 8个样本]和80.0±3.5 [n = 6个样本]）以及气道上皮（mV，CFTR介导的Cl(-)电导平均值±标准误为1.2±2.2 [n = 5项研究]和-6.75±8.1 [n = 4项研究]）中CFTR介导的氯化物传导均存在缺陷。这些数据表明，特定单倍型背景（TG12和M470V）上的5T多聚胸腺嘧啶序列可能导致全长功能性CFTR蛋白水平降低以及类似CF的肺部疾病。
