<i>SFTPA2</i> Mutations in Familial and Sporadic Idiopathic Interstitial Pneumonia

Moorsel, Coline H.M. van; Klooster, Liesbeth ten; Oosterhout, Matthijs F.M. van; Jong, Pim A. de; Adams, Human; Es, Hendrik W. van; Ruven, Henk J.T.; Vis, Joanne J. van der; Grutters, Jan C.

doi:10.1164/rccm.201504-0675le

Cited by 73 publications

(54 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Approximately 5% of patients with FIP have mutations in genes encoding surfactant proteins, mainly pulmonary surfactant-associated protein C (SFTPC) and, less frequently, SFTPA2 (REFS 18–22). Mutations in the genes encoding these proteins result in the misfolding, misrouting and/or misprocessing of the protein, which provokes either toxicity and possible cell death, or cell activation and epithelial–mesenchymal transition (EMT) in alveolar epithelial type 2 cells (AEC2s), which leads to a fibrotic response.…”

Section: Genetic Susceptibilitymentioning

confidence: 99%

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora¹,

Rojas²,

Pardo³

et al. 2017

Nat Rev Drug Discov

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches.

show abstract

Section: Genetic Susceptibilitymentioning

confidence: 99%

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Mora¹,

Rojas²,

Pardo³

et al. 2017

Nat Rev Drug Discov

View full text Add to dashboard Cite

show abstract

“…Mutations in both genes have been associated with FIP and lung adenocarcinoma. 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.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Very recently, three new SFTPA2 mutations were found in FIP, again with localization in exon 6: N210T, G231R and N171Y [109]. All three missense mutations were predicted to have deleterious consequences by in silico studies, and caused UIP (with features of DIP) and concomitant adenocarcinoma in heterozygous mutation carriers.…”

Section: Er Stress In Familial Interstitial Pneumonia Due To Sftpa2 Mmentioning

confidence: 99%

“…All three missense mutations were predicted to have deleterious consequences by in silico studies, and caused UIP (with features of DIP) and concomitant adenocarcinoma in heterozygous mutation carriers. However, the new mutations have yet not been experimentally tested [109].…”

Section: Er Stress In Familial Interstitial Pneumonia Due To Sftpa2 Mmentioning

confidence: 99%

“…In general, future research should comprise a detailed in vivo-analysis of ER stress-protein markers in AECII and adenocarcinoma cells, as well as of accumulated SP-A2 in non-native aggregates in lung tissue of patients with SFTPA2 mutations by means of immunohistochemistry or immuno-EM, and should also include the quantitative analysis of SP-A in BALF of affected patients -because such studies have not been performed so far [99,102,109].…”

Section: Er Stress In Familial Interstitial Pneumonia Due To Sftpa2 Mmentioning

confidence: 99%

See 1 more Smart Citation

The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

Korfei

Ruppert

Loeh

et al. 2016

Endoplasmic Reticulum Stress in Diseases

View full text Add to dashboard Cite

The activation of Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) was first observed in patients with familial interstitial pneumonia (FIP) carrying mutations in the C-terminal BRICHOS domain of surfactant protein C (SFTPC). Here, aggresome formation and severe ER stress was demonstrated in type-II alveolar epithelial cells (AECII), which specifically express this very hydrophobic surfactant protein. In subsequent studies, FIP-patients with mutations in the gene encoding surfactant protein A2 (SFTPA2) were discovered, whose overexpression in epithelial cells in vitro also resulted in significant induction of ER stress. Moreover, prominent ER stress in AECII was also observed in FIP-patients not carrying the SFTPC/SFTPA2 mutations, as well as in patients with the more common sporadic forms of IP. Additionally, cases of adult-onset FIP with mutations in Telomerase genes and other telomereassociated components were reported. These mutations were associated with telomere shortening, which is a potential cause for triggering a persistent DNA damage response and replicative senescence in affected cells. Moreover, shortened telomeres were observed directly in the AECII of FIP-patients, and even sporadic IP cases, in the absence of any gene mutations. Here, we try to figure out the possible origins of ER stress in sporadic IP cases and non-SFTPC/SFTPA2-associated FIP.

show abstract

SFTPA2 Mutations in Familial and Sporadic Idiopathic Interstitial Pneumonia

Cited by 73 publications

References 12 publications

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

Pulmonary fibrosis in the era of stratified medicine

The role of Endoplasmic Reticulum (ER) stress in pulmonary fibrosis

Contact Info

Product

Resources

About