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Genetic Defects in Surfactant Protein A2 Are Associated with Pulmonary Fibrosis and Lung Cancer |
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| Authors: | Yongyu Wang Phillip J. Kuan Chao Xing Jennifer T. Cronkhite Fernando Torres Randall L. Rosenblatt J. Michael DiMaio Lisa N. Kinch Nick V. Grishin Christine Kim Garcia |
| Affiliation: | 1 Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA 2 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA 3 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA 5 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA |
| Abstract: | Idiopathic pulmonary fibrosis (IPF) is a lethal scarring lung disease that affects older adults. Heterozygous rare mutations in the genes encoding telomerase are found in ~15% of familial cases. We have used linkage to map another disease-causing gene in a large family with IPF and adenocarcinoma of the lung to a 15.7 Mb region on chromosome 10. We identified a rare missense mutation in a candidate gene, SFTPA2, within the interval encoding surfactant protein A2 (SP-A2). Another rare mutation in SFTPA2 was identified in another family with IPF and lung cancer. Both mutations involve invariant residues in the highly conserved carbohydrate-recognition domain of the protein and are predicted to disrupt protein structure. Recombinant proteins carrying these mutations are retained in the endoplasmic reticulum and are not secreted. These data are consistent with SFTPA2 germline mutations that interfere with protein trafficking and cause familial IPF and lung cancer. |
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