SFTPA1, encoding pulmonary surfactant protein A1, is a member of the C-type lectin subfamily. It plays a critical role in maintaining lung tissue homeostasis and the innate immune response, being involved in the toll-like receptor signaling pathway [2]. The protein is crucial for several processes of innate immunity as well as surfactant-related functions [1].

A homozygous missense mutation in SFTPA1 was found to cause idiopathic pulmonary fibrosis (IPF) in a consanguineous Japanese family. Sftpa1 knock-in (Sftpa1-KI) mice with the same mutation spontaneously developed pulmonary fibrosis, which was accelerated by influenza virus infection. The mutation disturbed the secretion of SFTPA1 protein, increased necroptosis of alveolar epithelial type II (AEII) cells through JNK-mediated up-regulation of Ripk3 [3]. In a multigenerational family, a heterozygous missense mutation in SFTPA1 was associated with either isolated IIP/IPF or IPF associated with lung adenocarcinoma, and this mutation impaired SP-A1 secretion [4]. Pathogenic SFTPA1 mutations also led to abolished secretion of the corresponding mutated proteins both in vitro and ex vivo in patients with interstitial lung diseases and lung cancer [5].

In conclusion, SFTPA1 is essential for lung tissue homeostasis and innate immunity. Studies using Sftpa1-KI mouse models have revealed its role in diseases like IPF, highlighting the importance of this gene in understanding the pathogenesis of chronic respiratory diseases, including the association between lung fibrosis and cancer [3,4].

References:

1. Floros, Joanna, Tsotakos, Nikolaos. 2021. Differential Regulation of Human Surfactant Protein A Genes, SFTPA1 and SFTPA2, and Their Corresponding Variants. In Frontiers in immunology, 12, 766719. doi:10.3389/fimmu.2021.766719. https://pubmed.ncbi.nlm.nih.gov/34917085/

2. Yuan, Lu, Wu, Xixi, Zhang, Longshan, Guan, Jian, Liu, Laiyu. 2021. SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma. In Cancer immunology, immunotherapy : CII, 71, 399-415. doi:10.1007/s00262-021-02995-4. https://pubmed.ncbi.nlm.nih.gov/34181042/

3. Takezaki, Akio, Tsukumo, Shin-Ichi, Setoguchi, Yasuhiro, Nishioka, Yasuhiko, Yasutomo, Koji. 2019. A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis. In The Journal of experimental medicine, 216, 2724-2735. doi:10.1084/jem.20182351. https://pubmed.ncbi.nlm.nih.gov/31601679/

4. Nathan, Nadia, Giraud, Violaine, Picard, Clément, Amselem, Serge, Clement, Annick. 2016. Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer. In Human molecular genetics, 25, 1457-67. doi:10.1093/hmg/ddw014. https://pubmed.ncbi.nlm.nih.gov/26792177/

5. Legendre, Marie, Butt, Afifaa, Borie, Raphaël, Amselem, Serge, Nathan, Nadia. 2020. Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer. In The European respiratory journal, 56, . doi:10.1183/13993003.02806-2020. https://pubmed.ncbi.nlm.nih.gov/32855221/