FAM13A is a modifier gene of cystic fibrosis lung phenotype regulating rhoa activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition

Corvol, Harriet; Rousselet, Nathalie; Thompson, Kristin; Berdah, Laura; Cottin, Guillaume; Foussignière, Tobias; Longchampt, Élisabeth; Fiette, Laurence; Sage, Édouard; Prunier, Céline; Drumm, Mitchell L.; Hodges, Craig A.; Boëlle, Piérre Yves

doi:10.1016/j.jcf.2017.11.003

Cited by 40 publications

(48 citation statements)

References 47 publications

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“…Fam13a expression was remarkably reduced in the lungs of wild-type (WT) mice exposed to chronic hypoxia comparing to that in the lungs of control mice (Figs 1A and B). It has been reported that FAM13A is expressed in airway cells including mucosal cells, Club cells, and alveolar cells [8, 10]; however it remained unknown whether FAM13A is expressed in the lung vasculature as well. We have generated mice with target deletion of FAM13A ( Fam13a -/- ) in which LacZ cassette was inserted into the intron of the Fam13a gene locus.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, FAM13A has been involved in multiple biological processes such as epithelial cell regeneration, tumor cell proliferation and survival, and insulin signaling. FAM13A is known to harbor a Ras-homologous GTPase-activating protein (RhoGAP) domain that is important for proliferation and survival in lung adenocarcinoma cell A549 [24], and this domain could activates RhoA which can affect actin cytoskeleton and promotes epithelial-to-mesenchymal transition in cystic fibrosis lung [8]. FAM13A also has two coiled-coil domains that often play a role in the protein-protein interaction.…”

Section: Discussionmentioning

confidence: 99%

“…FAM13A has been reported to regulate the β-catenin signaling in airway epithelial cells [10, 25], and we found that FAM13A negatively regulates β-catenin activity in endothelial cell as well. β-catenin signaling has been involved in epithelial-to-mesenchymal transition in pulmonary disease and cancer [8,12,26]. Also, β-catenin has been reported to promote EndMT through nuclear accumulation and subsequent activation of TCF/Lef transcription factors [13, 14].…”

Section: Discussionmentioning

confidence: 99%

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Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

Rinastiti

Ikeda

Rahardini

et al. 2019

Preprint

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1819 Pulmonary hypertension is a progressive lung disease with poor prognosis due to the 20 consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction 21 are culprits for pathologically increased pulmonary arterial pressure, but their 22 underlying molecular mechanisms remain to be elucidated. Previous genome-wide 23 association studies revealed a significant correlation between the genetic locus of family 24 with sequence similarity 13, member A (FAM13A) and various lung diseases such as 25 chronic obstructive pulmonary disease and pulmonary fibrosis; however whether 26 FAM13A is also involved in the pathogenesis of pulmonary hypertension remained 27 unknown. Here, we identified a significant role of FAM13A in the development of 28 pulmonary hypertension. FAM13A expression was reduced in mouse lungs of 29 hypoxia-induced pulmonary hypertension model. We identified that FAM13A was 30 expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A 31 exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association 32 with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated 3 33 endothelial-to-mesenchymal transition potentially by inhibiting -catenin signaling in 34 pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in 35 the development of pulmonary hypertension, and therefore increasing and/or preserving 36 FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic 37 strategy for the treatment of pulmonary hypertension. 38 39 Introduction 40 41 Pulmonary hypertension is a progressive and fatal lung disease diagnosed by a 42 sustained elevation of pulmonary arterial pressure more than 20 mmHg [1]. Pulmonary 43 arterial hypertension including idiopathic pulmonary arterial hypertension and 44 pulmonary hypertension related with collagen disease is characterized by pathological 45 pulmonary artery remodeling such as intimal and medial thickening of muscular arteries, 46 vaso-occlusive lesions, and fully muscularized small diameter vessels that are normally 47 non-muscular peripheral vessels. These vascular remodeling is a result from endothelial 48 cell dysfunction, smooth muscle cell and endothelial cell proliferation, and also cellular 4 49 transdifferentiation [2]. Although detailed molecular mechanisms remain to be 50 elucidated, many pathogenic pathways in pulmonary arterial hypertension have been 51 revealed. These include TGF- signaling, inflammation, pericyte-mediated vascular 52 remodeling, iron homeostasis, and endothelial-to-mesenchymal transition (EndMT) [3]. 53 Recent genome-wide association studies identified family with sequence similarity 54 13, member A (FAM13A) gene as a genetic locus associated with pulmonary function 55 [4], and it is known to be associated with lung diseases including chronic obstructive 56 pulmonary disease (COPD) [5], asthma [6] and pulmonary fibrosis [7-9]. Moreover, 57 causative role of FAM13A in the development of COPD...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

Rinastiti

Ikeda

Rahardini

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Fam13a expression was remarkably reduced in the lungs of wild-type (WT) mice exposed to chronic hypoxia comparing to that in the lungs of control mice under normoxic condition (Fig 1A and 1B). It has been reported that FAM13A is expressed in airway cells including mucosal cells, Club cells, and alveolar cells [8,10]; however it remained unknown whether FAM13A is expressed in the lung vasculature as well. We have generated mice with target deletion of FAM13A (Fam13a -/-) in which LacZ cassette was inserted into the intron of the Fam13a gene locus.…”

Section: Fam13a Is Expressed In Lung Vasculaturesmentioning

confidence: 99%

“…Recent genome-wide association studies identified family with sequence similarity 13, member A (FAM13A) gene as a genetic locus associated with pulmonary function [4], and it is known to be associated with lung diseases including chronic obstructive pulmonary disease (COPD) [5], asthma [6] and pulmonary fibrosis [7][8][9]. Moreover, causative role of FAM13A in the development of COPD has been revealed.…”

Section: Introductionmentioning

confidence: 99%

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

et al. 2020

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Pulmonary hypertension is a progressive lung disease with poor prognosis due to the consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction are culprits for pathologically increased pulmonary arterial pressure, but their underlying molecular mechanisms remain to be elucidated. Previous genome-wide association studies revealed a significant correlation between the genetic locus of family with sequence similarity 13, member A (FAM13A) and various lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis; however whether FAM13A is also involved in the pathogenesis of pulmonary hypertension remained unknown. Here, we identified a significant role of FAM13A in the development of pulmonary hypertension. FAM13A expression was reduced in the lungs of mice with hypoxia-induced pulmonary hypertension. We identified that FAM13A was expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated endothelial-to-mesenchymal transition potentially by inhibiting β-catenin signaling in pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in the development of pulmonary hypertension, and therefore increasing and/or preserving FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic strategy for the treatment of pulmonary hypertension.

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Association of family sequence similarity gene 13A gene polymorphism and interstitial lung disease susceptibility: A systematic review and meta‐analysis

Hu,

Li,

Ren

et al. 2023

Molec Gen & Gen Med

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BackgroundAmong present reports, the T/G allelic variation at the rs2609255 locus of the family sequence similarity gene 13A (FAM13A) was considerable associated with susceptibility to interstitial lung diseases (ILDs). In this study, we summarized relevant studies and applied a meta‐analysis to explore whether the polymorphism of rs2609255 site of the FAM13A gene can be utilized to predict susceptibility to idiopathic pulmonary fibrosis (IPF) patients or rheumatoid arthritis‐associated interstitial lung disease (RA‐ILD) or silicosis patients in different populations for the first time.MethodsWe compared the frequency of G allele on rs2609255 site of FAM13A between the control subjects and IPF or RA‐ILD or silicosis patients from different races by using meta‐analysis. Nine studies were involved in this meta‐analysis, including five IPF studies, two RA‐ILD studies, and two silicosis studies, and containing 14 subgroups. We conducted separate meta‐analyses for different races.ResultsIn all individuals, a substantial link between the G allele of the FAM13A rs2609255 polymorphism and IPF (OR: 1.47, 95% CI: 1.33–1.63, p < 0.00001) was indicated. After dividing by ethnicity, the G allele was illustrated to be considerable correlation with IPF in Asian (OR: 2.63, 95% CI: 1.81–3.81, p < 0.00001) and with RA‐ILD individuals (OR: 3.27, 95% CI: 1.26–8.49, p = 0.01). Conversely, there was no correlation with the G allele and IPF in European individuals (OR: 1.27, 95% CI: 0.89–1.83, p = 0.13) or silicosis in Chinese individuals (OR: 1.20, 95% CI: 0.99–1.46, p = 0.07).ConclusionThis is the first meta‐analysis that provides evidence that the rs2609255 of FAM13A might increase susceptibility to RA‐ILD, and IPF especially in Asian but not in European individuals, and not be correlated with silicosis in Chinese individuals, which indicated the differences in susceptibility to disease by race were noteworthy.

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FAM13A is a modifier gene of cystic fibrosis lung phenotype regulating rhoa activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition

Abstract: Our data show that FAM13A is a modifier gene of CF lung phenotype regulating RhoA activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition.

Cited by 40 publications

References 47 publications

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

Loss of family with sequence similarity 13, member A exacerbates pulmonary hypertension through accelerating endothelial-to-mesenchymal transition

Association of family sequence similarity gene 13A gene polymorphism and interstitial lung disease susceptibility: A systematic review and meta‐analysis

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