Equipe Corvol - Corvol et al. JCF. 2017.

05 - Décembre - 2017

Corvol et al. FAM13A is a modifier gene of cystic fibrosis lung phenotype regulating rhoa activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition. Journal of Cystic Fibrosis. 2017.

AbstractBackground:Cysticfibrosis (CF) lung disease severity is highly variable and dependent on several factors including genetic modifiers. Family withsequence similarity 13 member A (FAM13A) has been previously associated with lung function in the general population as well as in several chroniclung diseases, such as chronic obstructive pulmonary disease (COPD), we examined whetherFAM13Ais a modifier gene of CF lung phenotype. Wealso studied howFAM13Amay contribute to the physiopathological mechanisms associated with CF.Methods:We investigated the association ofFAM13Awith lung function in CF French patients (n = 1222) by SNP-wise analysis and Versatile GeneBased Association Study. We also analyzed the consequences of FAM13A knockdown in A549 cells and primary bronchial epithelial cells from CFpatients.Results:We found thatFAM13Ais associated with lung function in CF patients. Utilizing lung epithelial A549 cells and primary human bronchialepithelial cells from CF patients we observed that IL-1βand TGFβreduced FAM13A expression. Knockdown of FAM13A was associated withincreased RhoA activity, induction of F-actin stressfibers and regulation of epithelial-mesenchymal transition markers such as E-cadherin,α-smoothmuscle actin and vimentin.Conclusion:Our data show that FAM13A is a modifier gene of CF lung phenotype regulating RhoA activity, actin cytoskeleton dynamics andepithelial-mesenchymal transition.© 2017 The Author(s). Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under theCC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).


Cystic fibrosis (CF) is a monogenic disease caused bymutations in the CF transmembrane conductance regulator(CFTR) gene. However, lung disease severity is highly variableand dependent of several factors including genetic modifiers[1,2]. The modifier genes are indeed thought to contributeto approximately 50% of the lung phenotype in CF patientsharboring the commonCFTRF508del mutation[3]. Familywith sequence similarity 13 member A (FAM13A) has beenpreviously shown to be associated with the lung function inthe general population[4] as well as in patients with asthma,COPD, idiopathic pulmonary fibrosis and lung cancer[5–10].The protein sequence of FAM13A contains a rho GTPaseactivating protein (GAP) domain. GAPs inactivate GTPases bythe conversion of GTP to GDP. GTPases are known to play arole in the actin cytoskeleton and remodeling as they regulateassembly of focal adhesions and F-actin stress fibers[11].Therefore, variants affecting the on/off switch of this GTPasefeedback loop via the FAM13A-GAP domain may modifydisease progression possibly by dysregulating Rho signaling anddisrupting the cytoskeleton. The most common rho GTPasesinclude RhoA, RhoB, RhoC, Rac1 and Cdc42. Perturbed rhoGTPase signaling is associated with several lung diseases,including asthma, pulmonary hypertension, chronic obstructivepulmonary disease (COPD), and lung cancer[12] .Inchroniclung diseases, RhoA is the most commonly associated GTPasefor changes in the barrier function and actin cytoskeleton.Interestingly, RhoA has been reported to be upregulated in CFcells[13] .To date, no study has explored the role ofFAM13Aasa potential candidate for modifying the CF lung phenotype.In this study, we investigated whetherFAM13Avariantsassociated with CF lung phenotype. Considering the numerouspublications involvingFAM13Ain lung disease progression,susceptibility and severity, and the potential role of therhoGAP domain, we also examined the function of FAM13Ain the lung and how it could participate in the CF lungphysiopathology.

Abbreviations : CF, Cystic fibrosis; FAM13A, Family with sequence similarity 13 member A; COPD, Chronic obstructive pulmonary diseases; CFTR, CFtransmembrane conductance regulator; GAP, GTPase activating protein; VEGAS, Versatile Gene Based Association Study; EMT, epithelial to mesenchymaltransition; KNoRMA, Kulich normalized mortality adjusted CF-specific lung phenotype; hAECBs, human airway epithelial cells from bronchi; MAF, minor allelefrequency; FEV1, forced expiratory volume in 1 s; siFAM13, siRNA for FAM13A; siCTRL, siRNA negative control.

⁎ Corresponding author at: Inserm UMR_S 938, CRSA, Inserm, Bât. Kourilsky 6èmeÉtage, 34 Rue Crozatier, 75012 Paris, France.E-mail address:loic.guillot@inserm.fr(L. Guillot).

1 - Co-first authors.

1569-1993/© 2017 The Author(s). Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/

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