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Molecular and Genetic Bases of CFTR Anomalies and Surfactant Metabolism

Contacts

Pascale Fanen Head Pascale Fanen

Tél.: +33-(0)1 49 81 48 22
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Our team develops research projects focused on mechanisms controlling phenotypic variability of cystic fibrosis and the molecular basis of diseases surfactant. Our research is translational, at the interface between basic and applied research.

 

Our goal is to identify the responsible genes and / or modulating the phenotypic expression of these diseases, and understand, by functional studies, the pathophysiological consequences of molecular anomalies detected in patients, at the cellular level or at the scale of a whole organism by studying animal models.

 

Our main results of the 2008-2014 period were
– Identification of splicing defects CFTR as modifier phenotype of cystic fibrosis by in vitro and ex vivo analysis of transcripts,
– Characterization of proteins capable of modulating partners addressing CFTR to the membrane,
– Identification of active anti-inflammatory targets in cystic fibrosis,
– Study of SFTPC mutational spectrum, ABCA3 and NKX2-1 in patients with diffuse lung disease.

 

We pursue three main objectives:
(1) Improving the understanding of the molecular and genetic basis of cystic fibrosis, nasal polyposis and diseases associated with metabolic dysfunction of the surfactant. For this we will use the expertise gained by the study of CFTR especially at the mRNA level to apply to mRNA SFTPC.
(2) Further study of the CFTR protein partners involved in inflammation and improve knowledge of the cellular bases of surfactant in pathologies characterized isoforms SP-C and their partners involved in the pathway of autophagy.
(3) Define the mechanisms involved in the exacerbated inflammatory response observed in both CF patients and in hereditary diseases linked to abnormalities of surfactant. Indeed, the knowledge of these mechanisms will allow to propose new types of anti-inflammatory treatments.

 

Patents:

-Tarze A, Fanen P. “Methods and pharmaceutical compositions for treatment of cystic fibrosis.” European Patent EP12305999, 13/08/2012 in the name of INSERM.
-Prulière-Escabasse V. “Diagnosis of cystic fibrosis.” EB12140, 13/11/2012 in the name of INSERM.

Selected publications

Rocca J, Manin S, Hulin A, Aissat A, Verbecq-Morlot W, Prulière-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 Jun;173(11):1728-41.

Bush A, Cunningham S, de Blic J, Barbato A, Clement A, Epaud R, Hengst M, Kiper N, Nicholson AG, Wetzke M, Snijders D, Schwerk N, Griese M; chILD-EU Collaboration. European protocols for the diagnosis and initial treatment of interstitial lung disease in children.

Thorax. 2015 Nov;70(11):1078-84. Review.

Hinzpeter A, de Becdelièvre A, Bieth E, Gameiro C, Brémont F, Martin N, Costes B, Costa C, Aissat A, Lorot A, Prulière-Escabasse V, Goossens M, Fanen P, Girodon E. Identification of a novel 5' alternative CFTR mRNA isoform in a patient with nasal polyposis and CFTR mutations.

Hum Mutat. 2014 Jul;35(7):805-8.

Fanen P, Wohlhuter-Haddad A, Hinzpeter A. Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies.

Int J Biochem Cell Biol. 2014 Jul;52:94-102. Review.

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 Feb;43(2):638-41.

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.

Delestrain C, Flamein F, Jonard L, Couderc R, Guillot L, Fanen P, Epaud R. Lung diseases in children associated with inherited disorders of surfactant metabolism.

Rev Pneumol Clin. 2013 Aug;69(4):183-9. Review.

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.

Hinzpeter A, Aissat A, de Becdelièvre A, Bieth E, Sondo E, Martin N, Costes B, Costa C, Goossens M, Galietta LJ, Girodon E, Fanen P. Alternative splicing of in-frame exon associated with premature termination codons: implications for readthrough therapies.

Hum Mutat. 2013 Feb;34(2):287-91.

El-Seedy A, Girodon E, Norez C, Pajaud J, Pasquet MC, de Becdelièvre A, Bienvenu T, des Georges M, Cabet F, Lalau G, Bieth E, Blayau M, Becq F, Kitzis A, Fanen P, Ladeveze V. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes.

Hum Mutat. 2012 Nov;33(11):1557-65.

Epaud R, Jonard L, Ducou-le-Pointe H, Delestrain C, Fanen P, Guillot L, Flamein F. Genetic disorders of surfactant.

Arch Pediatr. 2012 Feb;19(2):212-9. Review.

Costa C, Pruliere-Escabasse V, de Becdelievre A, Gameiro C, Golmard L, Guittard C, Bassinet L, Bienvenu T, Georges MD, Epaud R, Bieth E, Giurgea I, Aissat A, Hinzpeter A, Costes B, Fanen P, Goossens M, Claustres M, Coste A, Girodon E. A recurrent deep-intronic splicing CF mutation emphasizes the importance of mRNA studies in clinical practice.

J Cyst Fibros. 2011 Dec;10(6):479-82.

Drévillon L, Tanguy G, Hinzpeter A, Arous N, de Becdelièvre A, Aissat A, Tarze A, Goossens M, Fanen P. COMMD1-mediated ubiquitination regulates CFTR trafficking.

PLoS One. 2011 Mar 31;6(3):e18334.

Hinzpeter A, Aissat A, Sondo E, Costa C, Arous N, Gameiro C, Martin N, Tarze A, Weiss L, de Becdelièvre A, Costes B, Goossens M, Galietta LJ, Girodon E, Fanen P. Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier.

PLoS Genet. 2010 Oct 7;6(10). pii: e1001153.

Caputo A, Hinzpeter A, Caci E, Pedemonte N, Arous N, Di Duca M, Zegarra-Moran O, Fanen P, Galietta LJ. Mutation-specific potency and efficacy of cystic fibrosis transmembrane conductance regulator chloride channel potentiators.

J Pharmacol Exp Ther. 2009 Sep;330(3):783-91.

Tanguy G, Drévillon L, Arous N, Hasnain A, Hinzpeter A, Fritsch J, Goossens M, Fanen P. CSN5 binds to misfolded CFTR and promotes its degradation.

Biochim Biophys Acta. 2008 Jun;1783(6):1189-99.

Prulière-Escabasse V, Planès C, Escudier E, Fanen P, Coste A, Clerici C. Modulation of epithelial sodium channel trafficking and function by sodium 4-phenylbutyrate in human nasal epithelial cells.

J Biol Chem. 2007 Nov 23;282(47):34048-57.