Genetic analyses and pathophysiology of inflammatory diseases
Auto-inflammatory and chronic osteoarticular disorders represent an enormous socio-economic burden for our society. Systemic auto-inflammatory disorders (SAID) are defined as illnesses caused by primary dysfunction of the innate immune system. These diseases encompass a wide spectrum of disorders characterised by recurrent attacks of fever, abdominal pain, arthritis and cutaneous signs, which sometimes overlap obscuring the diagnosis. Rheumatoid arthritis (RA) and JIA (juvenile idiopathic arthritis) are systemic and chronic inflammatory diseases, which manifest in multiple joints. Although very different in their manifestations, most of these diseases are considered to result upon a failure of the immune system’s auto-regulatory mechanisms. The aetiology of disease remains a matter of debate in many instances.
Our project is divided into 2 main objectives:
1) Identification of new genes by exome sequencing
The development of next-generation sequencing (NGS) has transformed the study of genetic and diagnosis of human diseases by making possible the study of the genome at the individual level by sequencing all exons.
* RA and JIA are considered to be complex multifactorial genetic diseases. We hypothesize that some rare RA and JIA patients from the same family with symptoms occuring in an early-onset manner would present with autosomal Mendelian condition. In 2012, our group initiated a NGS project on multiplex families presenting with at least one member suffering from JIA, to identify potential genes.
* Some patients with SAID referred to our genetic diagnosis and clinical departments at the CHU of Montpellier (http://umai-montpellier.fr/) are genetically orphans. We propose to identify the causative genes in these families by NGS.
Based on genetic models of defined SAID or new candidate genes responsible for JIA, we propose using functional studies to determine the pathogenic effect of the mutations found in order to clarify the role of these genes in the development of autoinflammation and autoimmunity.
* The TRAPS syndrome
The TNFRSF1A gene responsible for the dominantly inherited auto-inflammatory disease TRAPS (TNFR-Associated Periodic Syndrome) encodes the TNF receptor 1 (TNFR1). We have identified a novel exon 2-spliced transcript of this gene, named TNFR1-d2, that is translated by an internal initial codon leading to expression of protein lacking the N-terminal part of TNFR1. Our project aims at identifying the molecular function of TNFR1-d2 in TNF-signalling pathways and at elucidating its possible implication in TRAPS pathophysiology, in particularl in patients carrying the T50M mutation.
* A new AJI gene FR+, CCP+
We identified a new stop codon variant in exon 1 of a candidate gene associated with JIA. This gene encodes a protein of the endoplasmic reticulum in B-lymphocyte cells. By evaluating the endoplasmic reticulum stress, we propose to study the functional consequences of the variant identified to clarify the pathophysiological pathways that play a key role in JIA.
* A new systemic JIA gene
In two independent families with a new syndrome combining arthritis, autoinflammation and autoimmunity, we identified mutations in an inflammasome gene. We develop in vitro and ex vivo functional tests to evaluate the formation and activity of the inflammasome in order to define the pathogenic effect of these mutations on the secretion of pro-inflammatory cytokines, IL-1β and IL -18.
More informations: https://umai-montpellier.fr/
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- Sarrabay G et al. The auto-inflammatory diseases: a fashion with blurred boundaries! Semin Immunopathol. 2015 May 22. [Epub ahead of print]
- Sarrabay G et al. Diagnosis of cryopyrin associated periodic syndrome: Challenges, recommendations and emerging concepts. Expert Rev Clin Immunol. 2015 May 15;:1-9. [Epub ahead of print]
- Arnaud M et al. Kabuki syndrome: Update and review. Arch Pediatr. 2015 Apr 28. pii: S0929-693X(15)00111-6. doi: 10.1016/j.arcped.2015.03.020. [Epub ahead of print]
- Ciucci T et al. Bone marrow Th17 TNFα cells induce osteoclast differentiation, and link bone destruction to IBD. Gut. 2015 Jul;64(7):1072-81. doi: 10.1136/gutjnl-2014-306947. Epub 2014 Oct 8.
- Duroux-Richard I. et al. Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis. Mediators Inflamm. 2014;2014:342524.
- Rittore C et al. Identification of a novel exon 2-skipped TNFR1 transcript: regulation by three functional polymorphisms of the TNFR-Associated Periodic Syndrome (TRAPS) gene. Ann Rheum Dis. 2013 Mar 16. [Epub ahead of print]
- Présumey J. et al. Nicotinamide phosphoribosyltransferase/visfatin expression by inflammatory monocytes mediates arthritis pathogenesis. Ann Rheum Dis. 2013 Oct;72(10):1717-24. doi: 10.1136/annrheumdis-2012-202403. Epub 2013 Jan 12.
More references, click on PubMed:
*Coordonnatrice du Département de génétique médicale, maladies rares et médecine personnalisée
adress: Unité médicale des maladies auto-inflammatoires (centre de référence)
Pôle de biologie-pathologie
Hôpital Arnaud de Villeneuve
34295, Montpellier Cedex 5
Tel: 04 67 33 58 57 (secrétariat)
04 67 33 58 59 (direct)
Fax: 04 67 33 58 67
*Responsable du service de Génétique Clinique
Département de génétique médicale, maladies rares et médecine personnalisée
filière ANDDI http://www.anddi-rares.org/
Centre de référence DGOS http://www.feclad.org/montpellier.html
CHRU Montpellier http://www.chu-montpellier.fr/fr/a-propos-du-chru/offre-de-soins/departement/detail/Genetique-Medicale/?no_cache=1
adress: 371, Avenue du Doyen G Giraud
34295 Montpellier Cedex 5 - France
Tel secrétariat: +33 04 67 33 65 64
Tel poste direct: +33 04 67 33 61 04
Fax: +33 04 67 33 60 52
TOUITOU Isabelle (PU-PH/CHU)
GENEVIEVE David (PU-PH/CHU)
TRAN Tu-Anh (PU-PH/CHU Nimes)
FILLERON Anne (CCA/CHU Nimes)
GRANDEMANGE Sylvie (IH, PhD/CHU)
SARRABAY Guillaume (PH/CHU, PhD student)
SANCHEZ Elodie (TSH/CHU)
MECHIN Déborah (TH/CHU)
CEZAR Renaud (IR)
Molecular genetic: sequencing, next generation sequencing
Molecular and cell biology: RNA and protein biology, cell culture and transfection, in vitro and ex vivo functionnal tests
Immunology: human T and B cells purification and differentiation purification, flux cytometry