Germline<i>SFTPA1</i>mutation in familial idiopathic interstitial pneumonia and lung cancer

Nathan, Nadia; Giraud, Violaine; Picard, C.; Nunès, Hilario; Moal, Florence Dastot-Le; Copin, Bruno; Galeron, Laurie; Ligniville, Alice De; Kuziner, Nathalie; Reynaud‐Gaubert, Martine; Valeyre, Dominique; Couderc, Louis‐Jean; Chinet, Thierry; Borie, Raphaël; Crestani, Bruno; Simansour, Maud; Nau, Valérie; Tissier, S.; Duquesnoy, Philippe; Mansour‐Hendili, Lamisse; Legendre, M.; Kannengiesser, Caroline; Coulomb-L’Herminé, Aurore; Gouya, Laurent; Amselem, Serge; Clément, Annick

doi:10.1093/hmg/ddw014

Cited by 121 publications

(78 citation statements)

References 43 publications

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“…TABLE IV shows top ten results with the significant pearson score. Among the genes, the expression of SFTPA1 was associated with an increased frequency of lung cancer [36].…”

Section: The Filtered Relationship By Mirna Target Databasesmentioning

confidence: 99%

Integrated Analysis of miRNA and Gene Networks on Cancer Expression Data

Li¹,

Du²,

He³

et al. 2017

Proceedings of the 2016 International Conference on Biological Engineering and Pharmacy (BEP 2016)

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Abstract-MircroRNAs (miRNAs) are one type of small noncoding RNAs and play important roles in regulating wide range of biological processes, such as stem cell maintenance, tissue development and cell metabolism. By modulating these key cellular processes, miRNAs can simultaneously regulate both oncogenes and tumor suppressor genes in cancer. With the development of high-throughput RNASeq technology, aberrant miRNA profiles and gene profiles have been detected in many cancers. And numerous studies indicate that vast miRNAs are involved in tumorigenesis and development of many cancers. They may act as either oncogenes or tumor suppressor genes in cancer and can be used as potential biomarkers for diagnosis, therapy and prognosis. To explore carcinogenic mechanism, it is critical to discover the aberrantly expressed miRNAs and their target genes. In this article, we propose an improved multiply-step approach to identify the target relationship between miRNA and gene pairs. An improved minimum redundancy maximum relevance (mRMR) feature selection method is used to get the differentially expressed miRNAs and genes. Then, we determine the significantly negative correlation between miRNA and gene pairs based on the expression level of selected miRNAs and genes in tumor and their corresponding adjacent normal tissues. To reduce the false positive rate of our approach, we check the relationship between miRNAs and their target genes by multiple miRNA target prediction databases.

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“…TABLE IV shows top ten results with the significant pearson score. Among the genes, the expression of SFTPA1 was associated with an increased frequency of lung cancer [36].…”

Section: The Filtered Relationship By Mirna Target Databasesmentioning

confidence: 99%

Integrated Analysis of miRNA and Gene Networks on Cancer Expression Data

Li¹,

Du²,

He³

et al. 2017

Proceedings of the 2016 International Conference on Biological Engineering and Pharmacy (BEP 2016)

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“…All pathogenic heterozygous rare variants in the SFTPA1 and SFTPA2 genes encode missense mutations located within the carbohydrate recognition domain of the protein 36 86 87. These mutations result in reduced secretion of mature protein and increased ER stress,36 86 88 markers of which have been found in alveolar epithelial cells of sporadic IPF patients adjacent to regions of lung fibrosis,89 90 suggesting that increased ER stress may lead to a cellular substrate with increased vulnerability to fibrosis after injury. Thus, the pathway identified by studying rare patients and families with surfactant mutations is relevant to a broader IPF patient population.…”

Section: Rare Variants In Genes Involved With Surfactant Metabolismmentioning

confidence: 99%

Pulmonary fibrosis in the era of stratified medicine

Mathai

Newton

Schwartz

et al. 2016

Thorax

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Both common and rare variants contribute to the genetic architecture of pulmonary fibrosis. Genome-wide association studies have identified common variants, or those with a minor allele frequency of >5%, that are linked to pulmonary fibrosis. The most widely replicated variant (rs35705950) is located in the promoter region of the MUC5B gene and has been strongly associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) across multiple different cohorts. However, many more common variants have been identified with disease risk and in aggregate account for approximately one-third of the risk of IPF. Moreover, several of these common variants appear to have prognostic potential. Next generation sequencing technologies have facilitated the identification of rare variants. Recent whole exome sequencing studies have linked pathogenic rare variants in multiple new genes to FIP. Compared with common variants, rare variants have lower population allele frequencies and higher effect sizes. Pulmonary fibrosis rare variants genes can be subdivided into two pathways: telomere maintenance and surfactant metabolism. Heterozygous rare variants in telomere-related genes co-segregate with adult-onset pulmonary fibrosis with incomplete penetrance, lead to reduced protein function, and are associated with short telomere lengths. Despite poor genotype-phenotype correlations, lung fibrosis associated with pathogenic rare variants in different telomere genes is progressive and displays similar survival characteristics. In contrast, many of the heterozygous rare variants in the surfactant genes predict a gain of toxic function from protein misfolding and increased endoplasmic reticulum (ER) stress. Evidence of both telomere shortening and increased ER stress have been found in sporadic IPF patients, suggesting that the mechanisms identified from rare variant genetic studies in unique individuals and families are applicable to a wider spectrum of patients. The ability to sequence large cohorts of individuals rapidly has the potential to further our understanding of the relative contributions of common and rare variants in the pathogenesis of pulmonary fibrosis. The UK 100,000 Genomes Project will provide opportunities to interrogate both common and rare variants and to investigate how these biological signals provide diagnostic and prognostic information in the era of stratified medicine.

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“…SFTPA2 forms a complex with SFTPA1, which is secreted into the alveolar space as SP-A (Maitra et al, 2010). A heterozygous missense mutation in SFTPA1 was also found in IPF patients (Nathan et al, 2016). However, it remains unclear how the mutations in SFTPA1 or SFTPA2 are associated with the pathogenesis of IPF.…”

Section: Introductionmentioning

confidence: 99%

A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis

Takezaki

Tsukumo

Setoguchi

et al. 2019

Journal of Experimental Medicine

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Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in SFTPA1 promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.

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GermlineSFTPA1mutation in familial idiopathic interstitial pneumonia and lung cancer

Cited by 121 publications

References 43 publications

Integrated Analysis of miRNA and Gene Networks on Cancer Expression Data

Integrated Analysis of miRNA and Gene Networks on Cancer Expression Data

Pulmonary fibrosis in the era of stratified medicine

A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis

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