Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice

Monocouches auto-assemblées d’organothiols mono- et bipodes sur le cuivre

The present work is included in the framework of molecular assemblies on oxidizable metals surface and globally intends to create different functional coatings with specific properties. The general methodology involves the formation of Self-Assembled Monolayers (SAMs) of mono- or bipodal organothiols on copper substrates. The first part of this thesis highlights the feasibility of the grafting on polycrystalline and electroreduced copper substrate of alcanethiol molecules with a single (thiol, RSH) or a double anchoring group (dithiol R(SH)2 and dithiocarboxylic RS2H). It comes out that the nature of the anchoring group has a strong impact on the structural properties of the monolayer, but also on its electrochemical and chemical (after immersion in another organothiol solution) stabilities. The dithiol SAMs lead to a significant increase of electrochemical stability and surface coverage by comparison with thiol and dithiocarboxylic SAMs; meanwhile, the dithiocarboxylic monolayers lead to the less stable coatings. The second part of the study is devoted to the elaboration of amine terminated monolayers (NH2RSH or NH2R(SH)2) as promotor of adhesion between copper substrate and a polymer (epoxy resin or polyimide). In order to counter the reactivity of the amine function (oxidation and multilayers formation) and to obtain densely packed amine terminated SAMs, several optimisations of the processes are first investigated. A polymeric film (epoxy or polyimide) is then deposited on those monolayers: the presence of amine terminated SAMs on copper affords a significant increase of the copper-epoxy adhesion. However, this coating doesn’t show any improvement on the copper-polyimide adhesion. Finally, a bilayer film formed by an adsorbed first part (CF3O(CF2)2RSH or CF3O(CF2)2R(SH)2 SAM) and a second mobile part (perfluoropolyether lubricant) is achieved. The perfluoroether-alcanethiol and dithiol SAMs own high blocking and insulating properties, even if they are loosely packed. The spreading of a thin lubricant film on their surface then permits the formation of a homogeneous bilayer film with high wettability. Furthermore, the presence of a monolayer leads to a decrease of the lubricant mobility, and therefore an improvement of its retention on the copper surface. This lower mobility is more pronounced for monolayers with large interchain spacing.Cette thèse s'inscrit dans la thématique des assemblages moléculaires sur des surfaces de métaux oxydables, en vue de former des revêtements fonctionnels avec des propriétés spécifiques. La méthodologie employée dans le cadre de cette thèse consiste à former des monocouches auto-assemblées d’organothiols mono- ou bipodes sur des substrats de cuivre. La première partie de cette thèse a mis en évidence la faisabilité du greffage d’alcanethiol possédant un pied d’ancrage simple (thiol, RSH) ou double (dithiol (R(SH)2) et dithiocarboxylique (RS2H)) sur un substrat de cuivre polycristallin électroréduit. La nature du groupement ancreur s’est révélée être déterminante au niveau des propriétés structurelles de la monocouche résultante mais également du point de vue de sa stabilité électrochimique et en solution. La monocouche de dithiols offre une stabilité électrochimique ainsi qu’une capacité couvrante accrue comparativement au thiol et au dithiocarboxylique. Le dithiocarboxylique forme, quant à lui, le revêtement le moins stable. La deuxième partie de ce manuscrit est dédiée à la formation de monocouche aminée alkylthiols (NH2RSH) et dithiols (NH2R(SH)2) en tant que promoteur d’adhésion entre le substrat de cuivre et un polymère (résine époxy ou polyimide). La complexité apportée par la fonction amine terminale a nécessité l’optimisation des conditions expérimentales afin d’aboutir à des monocouches organisées et de bonne qualité. Un film polymère (résine époxy ou polyimide) a ensuite été déposé sur le substrat de cuivre modifié par les monocouches aminées. La présence de la monocouche aminée (NH2RSH et NH2R(SH)2) sur le substrat de cuivre a apporté un gain substantiel en terme d’adhésion entre le cuivre et la résine époxy. Ce traitement de surface n’a, par contre, pas permis d’améliorer l’adhésion du film polyimide sur le cuivre. Pour terminer, un système de bicouches moléculaires formé d’une partie fixe (SAM de type CF3O(CF2)2RSH ou CF3O(CF2)2R(SH)2) et d’une partie mobile (lubrifiant perfluoro polyéther) a été réalisé. Les monocouches de perfluoro-éther alcanethiols et dithiols, bien qu’elles possèdent une organisation moindre, ont montré des propriétés bloquante et isolante accrues. L’étalement du film lubrifiant à leur surface a abouti un système de bicouches homogène, mouillant parfaitement la surface. De plus, la présence d’une monocouche a permis d’améliorer la retenue du film lubrifiant en surface en atténuant sa mobilité. Cette retenue en surface est d’autant plus prononcée lorsque l’espace interchaîne au sein de la monocouche est important.(DOCSC02) -- FUNDP, 201

Aminealkylthiol and dithiol self-assembly as adhesion promoter between copper substrate and epoxy resin

To improve adhesion between copper and epoxy resin in printed circuit board, a roughness treatment of copper has been widely used. Nevertheless, new adhesion promoters have to be developed to face the miniaturization and sophistication of the electronic device. Self-assembled monolayers have met increasing interest in this field by using them as coupling agent between copper and the epoxy resin. This paper presents the deposition of an epoxy resin on copper modified by amine alkylthiol and dithiol monolayers and highlights the benefit brought by the monolayer in terms of adhesion. The chemical linkage between the amine SAMs and the epoxy function has been proved by the deposition on a short epoxy fragment, the 2-(4-fluorophenoxy-methyl)oxirane. The deposition of an epoxy resin mixed with amine curing agent has then been successfully achieved on amine terminated SAMs. The resulting polymer is homogeneous and well adherent on their surface, while the adhesion is lower on bare copper and not existing on methyl terminated SAMs. The formation of chemical bond Cu-S and N-epoxy is thus essential to increase the adhesion strength between copper and the polymer. © 2011 Elsevier B.V. All rights reserved

Self-assembly of amine terminated alkylthiol and alkyldithiol films on a polycrystalline copper substrate

Amine terminated self-assembled monolayers on gold are widely used as adhesion promoter agent to immobilize nanostructure such as fullerene, proteins and biological cells. The reactivity of the amine function makes difficult the formation of high quality SAMs. Most studies report disordered structure with the presence of oxidized sulphur on the surface. In this work, SAMs of 11-aminoundecyl-1-thiol (NH 2-(CH 2) 11-SH) and 2-aminoundecylpropane-1,3-dithiol (NH 2-(CH 2) 11-CH-(CH 2SH) 2) have been elaborated on copper substrates, following different protocols (alkalinization during or after the self-assembly). The modification of copper by amine terminated SAMs of thiol and dithiol has been successfully achieved. The best quality of SAMs are obtained when the alkalinization to free amine is carried on after the self-assembly process. Characterizaton of the SAMs are carried out using contact angle goniometry, PM-IRRAS, XPS and CV. © 2011 The Electrochemical Society

Stability of self-assembled monolayers of organothiol mono and bipode on copper in presence of another organothiol solution

The stability of alkanethiol self-assembled monolayers (SAMs) on metallic substrates is an important aspect for further application. Some studies point out the poor stability of this coating and the displacement of alkanethiol from the monolayer by immersion in another alkanethiol solution. The aim of this work consists in a comparative investigation of self-exchange of three organothiols: 11-perfluorobutyl-1-thiol-undecane (or R fSH), 2-dodecylpropane-1,3- dithiol (or R(SH) 2) and n-decanedithiocarboxylic (or RS 2H). The immersion of RS 2H monolayer into R fSH solution (first approach) leads to the incorporation of thiol molecules into the defects of the initial SAMs followed by the displacement of RS 2H molecules by R fSH. While for R fSH SAM in presence of R(SH) 2 solution (second approach), longer time of immersion is required to observe the incorporation of dithiol molecules into the coating as well as the displacement of thiol molecules. © 2011 Elsevier B.V. All rights reserved

Surface modification of copper with 2-dodecylpropane-1,3-dithiol: The key effect of the solvent

Self-assembly of alkanethiol on gold in various solvents (alkane, alcohol, etc) leads to monolayers with similar properties. However when the self-assembly is performed on copper substrates, the nature of the solvent has an effect on the properties of the monolayer. This phenomenon arises from the chemical interaction of copper with the solvent, which is not the case of gold. Ethanol is a solvent widely used for self-assembly, however some studies pointed out its negative effect due to its significant chemical reactivity towards copper and its ability to chemisorb on the surface. The aim of this work consists in a comparative investigation of 2-dodecylpropane-1,3-dithiol (or R(SH)2) in various solvents and its ability to form stable SAMs, densely packed and well ordered. Characterizations of the SAMs are carried out using X-ray photoelectron spectroscopy (XPS), polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS) and cyclic voltammetry (CV). © 2009 Elsevier B.V. All rights reserved