Genetic and cellular bases of CF and surfactant disorders
Research focus :
Our team is involved in understanding the mechanisms that control the phenotypic variability of cystic fibrosis and in studying the molecular basis of surfactant diseases. Our translational research is at the interface of basic and applied research. We have been contributing to research in the field of cystic fibrosis for the past 20 years, and we have expanded our research into surfactant diseases in the past 7 years. Our main objectives are to identify new genes involved in these pathologies, whether they are directly responsible or only modulators of phenotypic expression, to understand the molecular mechanisms leading to the expression of pathological phenotypes and to find new therapeutic targets to move towards personalized therapy.
Analyses of the consequences of mutations in genes known to be involved in the pathology (CFTR for CF; ABCA3, SFTPB, SFTPC and NKX2-1 for surfactant pathologies) are carried out using functional tests that we are constantly developing. The search for new genes is based on Whole Exome Sequencing (WES) and RNAseq approaches associated with their bioinformatic analyses. Concerning the NKX2-1 gene, which encodes a master-key transcription factor for lung development and alveolar cell function, we are initiating new projects aimed on the one hand at evaluating whether the regulation of the gene depends on non-coding RNAs, and on the other hand at finely analyzing with proteomic tools what are the structural and functional consequences in the cell of the expression of mutant forms of the NKX2-1 protein.
Main results :
Implementation of a new strategy, which combines in silico and in vitro analyses to anticipate the occurrence of “splicing-causing” mutations in CFTR exons;
First description of the molecular mechanism of an exonic SFTPC mutation, which unmasked a splicing defect;
Expansion of the phenotypic spectrum of interstitial lung disease i.e. due to NKX2-1 mutations;
New use for an old drug: COX-independent anti-inﬂammatory effects of Sulindac in models of CF;
First evidence of anti-inflammatory effect of COMMD1 in bronchial cells.
Nattes E, Lejeune S, Carsin A, Borie R, Gibertini I, Balinotti J, Nathan N, Marchand-Adam S, Thumerelle C, Fauroux B, et al. Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.Respir Med 2017; 129:16–23.
Delestrain C, Simon S, Aissat A, Medina R, Decrouy X, Nattes E, Tarze A, Costes B, Fanen P, Epaud R. Deciphering the mechanism of Q145H SFTPC mutation unmasks a splicing defect and explains the severity of the phenotype.Eur J Hum Genet 2017; 25:779–82.
Rocca J, Manin S, Hulin A, Aissat A, Verbecq-Morlot W, Pruliere-Escabasse V, Wohlhuter-Haddad A, Epaud R, Fanen P, Tarze A. New use for an old drug: COX-independent anti-inflammatory effects of sulindac in models of cystic fibrosis.Br J Pharmacol 2016; 173:1728–41.
Epaud R, Delestrain C, Louha M, Simon S, Fanen P, Tazi A. Combined pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations.Eur Respir J 2014; 43:638–41.
Aissat A, de Becdelièvre A, Golmard L, Vasseur C, Costa C, Chaoui A, Martin N, Costes B, Goossens M, Girodon E, Fanen P, Hinzpeter A. Combined Computational-Experimental Analyses of CFTR Exon Strength Uncover Predictability of Exon-Skipping Level.Hum Mutat. 2013 Jun;34(6):873-81.
de Becdelièvre A, Rocca J, Aissat A, Drévillon L, Moutereau S, Le Gouvello S, Hinzpeter A, Tarze A, Fanen P. COMMD1 modulates noxious inflammation in cystic fibrosis.Int J Biochem Cell Biol. 2013 Nov;45(11):2402-9.
IMRB – Inserm U955
GEIC2O: Genetic and Environmental interactions in COPD, Cystic Fibrosis and Other (rare) respiratory diseases
Creteil’s health faculty – 5th floor
8, rue du Général Sarrail
Administrative assistant – Contact
Tél. : +33-1 49 81 36 56
Adenosine-to-inosine (A-to-I) RNA editing, mediated by enzymes of the ADAR family, is a well-known contributor of transcriptomic and, to a lesser extent, proteomic diversity.Read more
Ciliary dyskinesia are a group of heterogeneous diseases characterized by an alteration of the respiratory ciliary beating that may induce a degradation of the mucociliary clearance which is the first line of defense of the respiratory system..Read more
The molecular cause of sickle cell disease is the polymerization of mutant hemoglobin S during deoxygenation, which is the cause of the multiple attacks of the disease. The amount of fibres in equilibrium and the kinetics of fibre formation both depend on the concentration of haemoglobin S and the partial pressure of oxygen. Pablo […]Read more