Étude génétique et fonctionnelle des gènes de la région 14q31 associée aux maladies inflammatoires de l’intestin

Les maladies inflammatoires de l’intestin (MIIs) comprennent la colite ulcéreuse (CU) et la maladie de Crohn (MC). Elles résultent en l’inflammation chronique du tractus gastro-intestinal. Des études d’association pan-génomiques ont associé le locus 14q31, incluant les gènes galactosylceramidase (GALC) et G protein-coupled receptor 65 (GPR65), à ces pathologies. Nous avons déterminé que le variant le plus associé aux MIIs de cette région (rs8005161; p=2,35x10-14) est parfaitement corrélé (r2=1) à un variant codant dans le gène GPR65 (rs3742704: Ile231Leu). GPR65 code pour un récepteur couplé à des protéines G (RCPG) senseur de pH. Nous avons observé que GPR65 est exprimé dans les tissus lymphoïdes et mucoïdes en plus des lignées cellulaires immunitaires et des cellules immunes primaires humaines. Son expression augmente significativement dans les biopsies inflammées de patients atteints de la CU comparativement à des biopsies non-inflammées ou à des biopsies d’individus sains. GPR65, lorsqu’activée par un pH acide, stimule l’accumulation d’AMPc, la formation de fibres de stress et l’activation de la voie RhoA. GPR65 semble donc être un bon candidat pour l’étude de l’étiologie des MIIs. Nos objectifs étaient donc de définir les voies découlant de l’activation de GPR65 et d’évaluer l’impact de GPR65*231Leu sur ces voies. Nous avons utilisé des HEK293 exprimant de façon stable l’une ou l’autre des deux allèles de GPR65 et déficientes pour Gαs/olf, Gαq/11 ou Gα12/13 puisqu’il est connu que Gαs/olf activent l’adénylate cyclase, Gαq/11 mènent au relâchement de Ca2+ intracellulaire et peuvent activer certaines isoformes de l’adénylate cyclase et Gα12/13 régulent le remodelage du cytosquelette d’actine. Nous avons démontré que l’accumulation d’AMPc dépendante de l’activation de GPR65 par un pH acide est causée, au moins en partie, aux voies Gαs/olf et peu ou pas aux voies Gαq/11. Il ne semble pas y avoir un effet du variant GPR65*231Leu sur ces voies. Cependant, nous avons observé que le variant GPR65*231Leu réduit la formation de fibres de stress et inhibe l’accumulation d’actine filamenteuse (F-actine) dépendantes de l’activation de GPR65 par un pH acide. Des données préliminaires nous montrent que la formation de fibres de stress est causée, au moins en partie, aux voies G12/13. En conclusion, nous avons démontré que GPR65 active les voies Gαs/olf et Gα12/13 et que le variant codant associé aux MIIs altère le remodelage de l’actine. GPR65 pourrait donc potentiellement avoir un rôle dans la pathologie des MIIs.Inflammatory bowel diseases, mainly comprising of ulcerative colitis (UC) and Crohn’s disease (CD), result in the chronic inflammation of the gastrointestinal tract. Genome-wide association studies have associated the 14q31 locus, including the genes galactosylceramidase (GALC) and G protein-coupled receptor 65 (GPR65), to those phenotypes. The most associated variant in this region for IBD (rs8005161; p=2,35x10-14) is correlated (r2=1) to a missense coding variant of GPR65 (rs3742704: Ile231Leu). GPR65 encodes a pH-sensing G protein-coupled receptor (GPCR). We observed that GPR65 is expressed in lymphoid and mucosal tissues as well as in immune cell lines and human primary immune cells. We also found that its expression is significantly increased in inflamed biopsies from UC patients compared to non-inflamed biopsies and biopsies from healthy controls. Upon activation by low pH, GPR65 stimulates accumulation of cAMP, formation of stress fibers and activation of the RhoA pathway. Thus GPR65 is a good candidate causal gene for the IBD pathology. Our objective, therefore, was to define pathways downstream of activation of GPR65 and to evaluate the impact GPR65*231Leu on these pathways. We used HEK 293 cells stably expressing one or the other allele of GPR65 and deficient for either Gαs/olf, Gαq/11 or Gα12/13 as it is known that Gαs/olf activates adenylyl cyclase, Gαq/11 leads to the release of intracellular Ca2+, which can also activate certain isoforms of adenylyl cyclase, and that Gα12/13 regulates actin cytoskeletal remodeling. We demonstrated that cAMP accumulation upon activation of GPR65 is, at least partly, due to the Gαs/olf pathway and only slightly or not at all to the Gαq/11 pathway. The coding variant, however, does not appear to have an effect on that pathway. In contrast, we observed that GPR65*231Leu variant reduces the GPR65-dependent stress fiber formation and inhibits the increase of filamentous actin (F-actin) content versus free globular-actin (G-actin) upon activation by low pH. Also, preliminary data showed that the stress fiber formation in HEK293 cells is due to the G12/13 pathways. In conclusion, we demonstrate that GPR65 activates both Gαs and Gα12/13, the coding variant alters the actin remodeling pathway and that GPR65 potentially has a causal role in IBD

Introduction

Ce dossier présente un corpus original de travaux menés par des chercheurs, principa­lement mexicains, portant sur les enjeux et les évolutions contemporaines des migrations internationales au Mexique et, pour la plupart, jamais encore traduits en langue française. L’emblématique couple migratoire Mexique/États-Unis traverse l’une des frontières les plus convoitées et les plus sécurisées du monde contemporain. Plus de 10 % de la population mexicaine vit aux États-Unis (soit 17 % de la populat..

Le Mexique dans les migrations internationales : Introduction

Cet article est une introduction au dossier de la revue qui présente un corpus original de travaux menés par des chercheurs, principalement mexicains, portant sur les enjeux et les évolutions contemporaines des migrations internationales au Mexique et, pour la plupart, jamais encore traduits en langue française

Structure and evolution of the Demerara Plateau, offshore French Guiana : rifting, tectonic inversion and post-rift tilting at transform-divergent margins intersection

International audienceWe present the structure and evolution of the eastern part of the Demerara plateau, offshore French Guiana, from the analysis of geophysical data collected during GUYAPLAC cruise. This area is located at the intersection of a transform segment and a divergent segment of a continental margin related to the Early Cretaceous opening of the Equatorial Atlantic. The main structures are NNE-SSW to NNW-SSE trending normal faults on the eastern edge of the plateau, and WNW-ESE to NW-SE trending acoustic basement ridges on its northern edge. When replaced in their Albian position, these structures appear to be parallel to the coeval oceanic accretion axis and transform faults, respectively. The most striking structures are related to a post-rift but syn-transform tectonic inversion, producing E-W to WNW-ESE trending folds, sealed by a regional unconformity. This shortening can not be related to ridge push, but is probably related to a plate kinematic change 105 My ago, that modified the deformation in the vicinity of the transform fault. Late post-rift evolution also includes a significant Tertiary oceanward tilt of the edge of the Demerara plateau. The driving mechanism of this late tilt is unclear, but may be related to a lithospheric flexure resulting from the loading of the abyssal plain by the Orinoco and Amazon deep-sea fans

HFE-Related Hemochromatosis: The Haptoglobin 2-2 Type Has a Significant but Limited Influence on Phenotypic Expression of the Predominant p.C282Y Homozygous Genotype

Phenotypic expression of the common p.C282Y/p.C282Y HFE-related hemochromatosis genotype is heterogeneous and depends on a complex interplay of genetic and non-genetic factors. Haptoglobin has a crucial role in free hemoglobin iron recovery, and exists as three major types: Hp1-1, Hp2-1 and Hp2-2. Hp2-2 favors endocytosis of hemoglobin iron in monocytes/macrophages, resulting in partial iron retention and increased intracellular ferritin levels. This situation is generally not expected to severely affect iron homeostasis, but was found to correlate with elevated serum iron indices in healthy men. Whether the Hp2-2 genotype acts as a modifier in HFE-related hemochromatosis is unclear. In this study we investigated influence of Hp2-2 and of potential confounders on the iron indices of 351 p.C282Y homozygous patients. We conclude that there is a cause-and-effect relationship between the Hp2-2 genotype and increased iron indices in p.C282Y homozygous patients. The Hp2-2 effect is, however, limited and only apparent in males

Recent and active deformation pattern off the easternmost Algerian margin, Western Mediterranean Sea: New evidence for contractional tectonic reactivation

International audienceWe describe for the first time a set of large active thrusts and folds near the foot of the easternmost Algerian margin, Western Mediterranean, from swath bathymetry and high-resolution seismic data acquired in 2005 during the Maradja2/Samra cruise. This active system resumes a previous passive margin and creates growth strata deposition on the limbs of large folds, resulting in the development of perched basins at the foot of the margin since less than ~ 1 Ma. They form a set of overlapping fault segments verging toward the Algerian basin, in a way similar to what has been observed off eastern Algiers on the rupture zone of the 2003 Mw 6.8 Boumerdes earthquake. The horizontal shortening rate across large folds is estimated to be of the order of 1 mm/yr. Although no historical earthquakes are reported here, these fault segments could have been responsible for large (M ~ 7.5) events in the past. This young tectonic system further supports the hypothesis of subduction inception of the Neogene oceanic lithosphere in the context of the Africa–Eurasia convergence

Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data

BACKGROUND: Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE), and of its main mutation (C282Y), has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH. METHODS: We studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France. RESULTS: In this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p < 10(-5)), meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p < 0.001) and hepatomegaly (11.0 vs. 22.7%, OR = 0.42, p = 0.006). In contrast, fatigue became a more common symptom at diagnosis (68.0 vs. 51.2%, OR = 2.03, p = 0.004). CONCLUSION: This study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients

Searching for the Africa-eurasia Miocene Boundary offshore western algeria (Maradja'03 cruise)

International audienceWe present new results from the MARADJA'03 cruise depicting the geological structures offshore central and western Algeria. Using swath bathymetry and seismic reflection data, we map and discuss the offshore limits of the Internal Zones corresponding to relics of the AlKaPeCa domain that drifted and collided the African plate during the Miocene. We identify large reverse faults and folds that reactivate part of these limits and are still active today. The morphology of the westernmost NE–SW margin suggests a former strike-slip activity accommodating a westward block translation responsible for the shift of the Internal Zones towards the Moroccan Rif. To cite this article: A. Domzig et al., C. R. Geoscience 338 (2006). Nous présentons les résultats récents de la campagne MARADJA'03, qui visent à mettre en évidence les structures géologiques dans le domaine marin au nord-ouest de l'Algérie. Grâce aux données de bathymétrie multifaisceau et de sismique réflexion, nous cartographions et discutons les limites en mer des Zones internes correspondant aux reliques du domaine AlKaPeCa qui a dérivé, puis est entré en collision avec la plaque africaine au Miocène. De grandes failles inverses et plis, actifs dans le champ de contrainte actuel, réactivent certaines de ces limites. La marge ouest-algérienne, orientée NE–SW, indique la présence d'une ancienne activité en décrochement ayant accommodé la translation des Zones internes vers l'ouest