Retards mentaux liés à l’X

Les retards mentaux liés au chromosome X (RMLX), qui touchent 1,8 garçons pour 1 000 naissances masculines, sont classiquement divisés en formes syndromiques et formes non spécifiques, selon la présence ou non de signes particuliers associés au retard mental. L’extrême hétérogénéité phénotypique et allélique, parfois visible au sein d’une même famille, complique toutefois cette classification. L’évaluation rétrospective appronfondie des familles atteintes, une fois la mutation identifiée dans un gène, devrait aider à clarifier la situation et faciliter la prise en charge du diagnostic moléculaire de ces retards mentaux. L’analyse des protéines produites par les 60 gènes de RMLX actuellement identifiés montre une grande diversité des fonctions biologiques affectées dans le retard mental. Dans cette revue, nous présenterons les données récentes concernant trois gènes, FMR1, ARX et le gène de l’oligophrénine 1, qui non seulement illustrent la complexité des RMLX, mais soulignent aussi l’importance des voies de signalisation impliquées dans la régulation de l’expression génique, ainsi que celles relayées pas les GTPases Rho dans la maturation et la plasticité neuronale.X-linked mental retardation (XLMR) affects 1.8 ‰ male births and is usually categorized as “syndromic” (MRXS) or “non-specific” (MRX) forms according to the presence or absence of specific signs in addition to the MR. Up to 60 genes have been implicated in XLMR and certain mutations can alternatively lead to MRXS or MRX. Indeed the extreme phenotypic and allelic heterogeneity of XLMR makes the classification of most genes difficult. Therefore, following identification of new genes, accurate retrospective clinical evaluation of patients and their families is necessary to aid the molecular diagnosis and the classification of this heterogeneous group of disorders. Analyses of the protein products corresponding to XLMR genes show a great diversity of cellular pathways involved in MR. Common mechanisms are beginning to emerge : a first group of proteins belongs to the Rho and Rab GTPase signaling pathways involved in neuronal differentiation and synaptic plasticity and a second group is related to the regulation of gene expression. In this review, we illustrate the complexity of XLMR conditions and present recent data about the FMR1, ARX and Oligophrenin 1 genes

Robustness and Reproducibility of a Glenoid-Centered Scapular Coordinate System Derived From Low-Dose Stereoradiography Analysis

A robust and reproducible scapular coordinate system is necessary to study scapulo-thoracic kinematics. The coordinate system recommended by the ISB (International Society of Biomechanics) is difficult to apply in studies using medical imaging, which mostly use a glenoid-centered coordinate system. The aim of this study was to assess the robustness of a glenoid-centered coordinate system compared to the ISB coordinate system, and to study the reproducibility of this coordinate system measure during abduction. A Monte-Carlo analysis was performed to test the robustness of the two coordinate systems. This method enabled the variability of the orientation of the coordinate system to be assessed in laboratory setting. A reproducibility study of the glenoid-centered coordinate system in the thorax reference frame was performed during abduction in the scapular plane using a low-dose stereoradiography system. We showed that the glenoid-centered coordinate system was slightly more robust than the ISB-recommended coordinate system. Most reproducible rotation was upward/downward rotation (x axis) and most reproducible translation was along the Y axis (superior-inferior translation). In conclusion, the glenoid-centered coordinate system can be used with confidence for scapular kinematics analysis. The uncertainty of the measures derived from our technique is acceptable compared to that reported in the literature. Functional quantitative analysis of the scapular-thoracic joint is possible with this method.We would like to thank Guillaume Simer and Benjamin Aubert for their technical support. Funding: IRSST, ParisTech BiomecAM Chair, Société Générale and Covea

IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from γδ T Cells

Summary: Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease. : Han et al. report that genetic depletion of IL-38 in mice delays the resolution of imiquimod-induced psoriasis by increasing the production of the inflammatory cytokine IL-17A by skin-infiltrating T cells. Depleting these T cells or the receptor that is targeted by IL-38 reduces psoriatic skin inflammation. Keywords: IL-38, IL1RAPL1, IL-17, γδ T cells, psoriasis, inflammatio

Investigation of 3D glenohumeral displacements from 3D reconstruction using biplane X-ray images: Accuracy and reproducibility of the technique and preliminary analysis in rotator cuff tear patients

Rotator cuff (RC) tears may be associated with increased glenohumeral instability; however, this instability is difficult to quantify using currently available diagnostic tools. Recently, the three-dimensional (3D) reconstruction and registration method of the scapula and humeral head, based on sequences of low-dose biplane X-ray images, has been proposed for glenohumeral displacement assessment. This research aimed to evaluate the accuracy and reproducibility of this technique and to investigate its potential with a preliminary application comparing RC tear patients and asymptomatic volunteers. Accuracy was assessed using CT scan model registration on biplane X-ray images for five cadaveric shoulder specimens and showed differences ranging from 0.6 to 1.4 mm depending on the direction of interest. Intra- and interobserver reproducibility was assessed through two operators who repeated the reconstruction of five subjects three times, allowing defining 95% confidence interval ranging from ±1.8 to ±3.6 mm. Intraclass correlation coefficient varied between 0.84 and 0.98. Comparison between RC tear patients and asymptomatic volunteers showed differences of glenohumeral displacements, especially in the superoinferior direction when shoulder was abducted at 20 and 45 . This study thus assessed the accuracy of the low-dose 3D biplane X-ray reconstruction technique for glenohumeral displacement assessment and showed potential in biomechanical and clinical research.Fondation Paris-Tech Programme BIOMECAM Chaire ParisTech Institut de Recherche Robert-Sauvé en Santé et Sécurité du Travail du Québec Natural Science and Engineering Research Council of Canada Fonds de Recherche sur la Nature et les Technologies du Québec Fonds de Recherche en Santé du Québec, EOS Imaging, and French pôle de compétitivité MEDICEN (STEREOS + program)

Reduced Gamma Oscillations in a Mouse Model of Intellectual Disability: A Role for Impaired Repetitive Neurotransmission?

Intellectual disability affects 2-3% of the population; mutations of the X-chromosome are a major cause of moderate to severe cases. The link between the molecular consequences of the mutation and impaired cognitive function remains unclear. Loss of function mutations of oligophrenin-1 (OPHN1) disrupt Rho-GTPase signalling. Here we demonstrate abnormal neurotransmission at CA3 synapses in hippocampal slices from Ophn1-/y mice, resulting from a substantial decrease in the readily releasable pool of vesicles. As a result, synaptic transmission fails at high frequencies required for oscillations associated with cognitive functions. Both spontaneous and KA-induced gamma oscillations were reduced in Ophn1-/y hippocampal slices. Spontaneous oscillations were rapidly rescued by inhibition of the downstream signalling pathway of oligophrenin-1. These findings suggest that the intellectual disability due to mutations of oligophrenin-1 results from a synaptopathy and consequent network malfunction, providing a plausible mechanism for the learning disabilities. Furthermore, they raise the prospect of drug treatments for affected individuals

Mécanismes physiopathologiques du déficit cognitif associé aux mutations du gène IL-1 receptor accesory protein like-1

Les mutations du gène IL1-Receptor Accessory Protein Like 1 (IL1RAPL1) sont associées à un déficit cognitif isolé ou associé à l autisme. Cette protéine transmembranaire appartient à une nouvelle famille de récepteurs à l IL-1. Sa structure est similaire à celles de ces récepteurs mais elle possède en plus un domaine cytoplasmique spécifique à son extrémité carboxy-terminale. IL1RAPL1 interagit via cette région avec NCS-1, senseur calcique neuronal impliqué dans la régulation de l exocytose. En utilisant une lignée de cellules neuroendocrines, nous avons montré que la surexpression d IL1RAPL1 a un effet inhibiteur sur l exocytose et sur les courants calciques de type N. Cette inhibition est dépendante de l'interaction d'IL1RAPL1 avec NCS-1. La région C-terminale d IL1RAPL1 contient également un motif d interaction avec PSD-95, molécule d échafaudage de la synapse excitatrice. La caractérisation du modèle murin montre le rôle d IL1RAPL1 dans la régulation de la localisation synaptique de PSD-95 en contrôlant la voie des kinases JNK et la phosphorylation de PSD-95. Le déficit en IL1RAPL1 aboutit in vivo à une diminution du nombre de synapses excitatrices dans l hippocampe et une altération de la plasticité synaptique. Dans le cervelet, l inactivation d IL1RAPL1 induit un déséquilibre de la balance inhibition/excitation au cours du développement post-natal. L ensemble de ces résultats montre qu IL1RAPL1 est impliquée dans le fonctionnement de la synapse et la maturation des réseaux neuronaux. De plus, la régulation de la voie de signalisation JNK par IL1RAPL1 ouvre des perspectives de correction du déficit synaptique présent chez la souris et peut-être, chez l homme.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Un rôle pour les astrocytes dans les déficiences intellectuelles ?

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Do Astrocytes Play a Role in Intellectual Disabilities?

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Hippocampal Excitatory Synaptic Transmission and Plasticity Are Differentially Altered during Postnatal Development by Loss of the X-Linked Intellectual Disability Protein Oligophrenin-1

International audienceOligophrenin-1 (OPHN1) is a Rho-GTPase-activating protein (RhoGAP), whose mutations are associated with X-linked intellectual disability (XLID). OPHN1 is enriched at the synapse in both pre- and postsynaptic compartments, where it regulates the RhoA/ROCK/MLC2 signaling pathway, playing a critical role in cytoskeleton remodeling and vesicle recycling. Ophn1 knockout (KO) adult mice display some behavioral deficits in multiple tasks, reminiscent of some symptoms in the human pathology. We also previously reported a reduction in dendritic spine density in the adult hippocampus of KO mice. Yet the nature of the deficits occurring in these mice during postnatal development remains elusive. Here, we show that juvenile KO mice present normal basal synaptic transmission, but altered synaptic plasticity, with a selective impairment in long-term depression, but no change in long-term potentiation. This contrasts with the functional deficits that these mice display at the adult stage, as we found that both basal synaptic transmission and long-term potentiation are reduced at later stages, due to presynaptic alterations. In addition, the number of excitatory synapses in adult is increased, suggesting some unsuccessful compensation. Altogether, these results suggest that OPHN1 function at synapses is differentially affected during maturation of the brain, which provides some therapeutic opportunities for early intervention

Crystallization of Nanodomains in Polyethylene Latexes

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