Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred
Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred
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DOI：
10.1164/rccm.200112-123oc
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发表时间：
2002-05-01
影响因子：
24.7
通讯作者：
Loyd, JE
中科院分区：
文献类型：
--
作者：
Thomas, AQ;Lane, K;Loyd, JE
家族性肺纤维化是一组病因不明的异质性间质性肺疾病，与多种病理亚型相关。表面活性蛋白C（SP-C）基因（SFTPC）突变与家族性脱屑性和非特异性间质性肺炎相关。家族性普通型间质性肺炎的遗传学研究尚无定论。采用候选基因方法，我们在一个大型家族性肺纤维化家系中发现了一个SFTPC的杂合外显子5 + 128 T-->A颠换，包括患有普通型间质性肺炎的成人和患有细胞非特异性间质性肺炎的儿童。该突变被预测为谷氨酰胺取代保守的亮氨酸残基，并可能阻碍SP-C前体蛋白的加工。SP-C前体蛋白显示异常的亚细胞定位的免疫染色。受累肺的电子显微镜检查显示肺泡II型细胞增生，伴有大量异常板层小体。值得注意的是，转染SFTPC突变的小鼠肺上皮细胞具有相似的电子显微镜检查结果和夸大的细胞毒性。我们发现，SFTPC突变分离与肺纤维化表型在这个家族，并可能导致II型细胞损伤。在受影响的亲属共享这种突变的两种不同的病理诊断的存在表明，在这个家族中，这些疾病可能代表相同的中央发病机制的多效性表现。
Familial pulmonary fibrosis is a heterogeneous group of interstitial lung diseases of unknown cause that is associated with multiple pathologic subsets. Mutations in the surfactant protein C (SP-C) gene (SFTPC) are associated with familial desquamative and nonspecific interstitial pneumonitis. Genetic studies in familial usual interstitial pneumonitis have been inconclusive. Using a candidate gene approach, we found a heterozygous exon 5 + 128 T-->A transversion of SFTPC in a large familial pulmonary fibrosis kindred, including adults with usual interstitial pneumonitis and children with cellular nonspecific interstitial pneumonitis. The mutation is predicted to substitute a glutamine for a conserved leucine residue and may hinder processing of SP-C precursor protein. SP-C precursor protein displayed aberrant subcellular localization by immunostaining. Electron microscopy of affected lung revealed alveolar type II cell atypia, with numerous abnormal lamellar bodies. Mouse lung epithelial cells transfected with the SFTPC mutation were notable for similar electron microscopy findings and for exaggerated cellular toxicity. We show that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred and may cause type II cellular injury. The presence of two different pathologic diagnoses in affected relatives sharing this mutation indicates that in this kindred, these diseases may represent pleiotropic manifestations of the same central pathogenesis.