INSERM UMR 938, UPMC, Université Paris 6, France.
Hum Mutat. 2010 Feb;31(2):E1146-62. doi: 10.1002/humu.21183.
NKX2-1 (NK2 homeobox 1) is a critical regulator of transcription for the surfactant protein (SP)-B and -C genes (SFTPB and SFTPC, respectively). We identified and functionally characterized two new de novo NKX2-1 mutations c.493C>T (p.R165W) and c.786_787del2 (p.L263fs) in infants with closely similar severe interstitial lung disease (ILD), hypotonia, and congenital hypothyroidism. Functional analyses using A549 and HeLa cells revealed that NKX2-1-p.L263fs induced neither SFTPB nor SFTPC promoter activation and had a dominant negative effect on wild-type (WT) NKX2-1. In contrast,NKX2-1-p.R165W activated SFTPC, to a significantly greater extent than did WTNKX2-1, while SFTPB activation was only significantly reduced in HeLa cells. In accordance with our in vitro data, we found decreased amounts of SP-B and SP-C by western blot in bronchoalveolar lavage fluid (patient with p.L263fs) and features of altered surfactant protein metabolism on lung histology (patient with NKX2-1-p.R165W). In conclusion, ILD in patients with NKX2-1 mutations was associated with altered surfactant protein metabolism, and both gain and loss of function of the mutated NKX2-1 genes on surfactant protein promoters were associated with ILD in "Brain-Lung-Thyroid syndrome".
NKX2-1（NK2 同源盒 1）是肺表面活性蛋白（SP）-B 和 -C 基因（SFTPB 和 SFTPC）转录的关键调节因子。我们在患有严重间质性肺病（ILD）、肌张力低下和先天性甲状腺功能减退症的婴儿中鉴定并功能表征了两种新的从头 NKX2-1 突变 c.493C>T（p.R165W）和 c.786_787del2（p.L263fs）。使用 A549 和 HeLa 细胞进行的功能分析表明，NKX2-1-p.L263fs 既不能诱导 SFTPB 也不能诱导 SFTPC 启动子激活，并且对野生型（WT）NKX2-1 具有显性负效应。相比之下，NKX2-1-p.R165W 激活了 SFTPC，其程度明显大于 WTNKX2-1，而 SFTPB 激活仅在 HeLa 细胞中显著降低。与我们的体外数据一致，我们通过免疫印迹在支气管肺泡灌洗液中发现了 SP-B 和 SP-C 的量减少（p.L263fs 患者），并且在肺组织学上发现了表面活性蛋白代谢改变的特征（NKX2-1-p.R165W 患者）。总之，NKX2-1 突变患者的 ILD 与表面活性蛋白代谢改变有关，突变 NKX2-1 基因对表面活性蛋白启动子的功能获得和丧失均与“脑-肺-甲状腺综合征”中的 ILD 有关。
