Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred

被引:464
作者
Thomas, AQ
Lane, K
Phillips, J
Prince, M
Markin, C
Speer, M
Schwartz, DA
Gaddipati, R
Marney, A
Johnson, J
Roberts, R
Haines, J
Stahlman, M
Loyd, JE
机构
[1] Vanderbilt Univ, Med Ctr, Ctr Lung Res, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Div Med Genet, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Med Ctr, Program Human Genet, Nashville, TN 37232 USA
[5] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA
[6] Duke Univ, Med Ctr, Div Pulm & Crit Care Med, Durham, NC 27710 USA
关键词
pulmonary fibrosis; familial; surfactant protein C; interstitial lung disease; genetics;
D O I
10.1164/rccm.200112-123OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
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.
引用
收藏
页码:1322 / 1328
页数:7
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