Purpose
Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. Up to now, four genome-wide ...association studies of AN have been conducted to date and identified only few significant loci. However, both previous studies focused on common variation and on rare exonic variants. Currently, de novo variants are one of the most significant risk factors for neurodevelopmental disorders and psychiatric disorders.
Methods
We analyzed by whole exome sequencing a cohort of nine female AN individuals and their parents (mother and father), and focused our analysis on de novo variants.
Results
Here, we found seven de novo missense variants in potential genes in nine studied AN patients. Four of these genes (
CSMD1, CREB3, PTPRD
and
GAB1
) belong to a same signaling pathway involving neuron differentiation and dopamine pathway.
Conclusions
This study provides a list of interesting genes such as
CSDM1
and
CREB3
that are candidates to be involved in the etiology of anorexia nervosa.
Level of Evidence
basic research.
Il est courant d’envisager le rôle du patrimoine dans le déploiement d’une thématique fonctionnelle (la qualité patrimoniale comme élément facilitant de la mise en tourisme, par exemple) ou, à ...l’inverse, le rôle d’une fonction urbaine dans la mise en patrimoine (le commerce comme fonction qui réinvestit certaines des friches industrielles par exemple). L’idée de rapprocher, dans un même numéro de revue, la question des fonctions urbaines et la question patrimoniale, peut dès lors apparaître c...
Spondyloarthritis is a group of articular disorders sharing a genetic background. Polymorphisms in the IL-1 gene cluster have previously been associated with ankylosing spondylitis (AS), a subset of ...spondyloarthritis. This study examined the association between several of these polymorphisms and the whole spondyloarthritis. Particular attention was devoted to genotype-phenotype correlations.
Seven single-nucleotide polymorphisms (SNP) and a variable number tandem repeat located in the IL-1 gene cluster were genotyped in 185 independent spondyloarthritis trios. Family-based association test (FBAT) was computed using the FBAT software. Analysis was carried in spondyloarthritis as a whole and also in AS. A case-control replication study was performed for four of the SNP, in an independent sample of 414 spondyloarthritis and 264 controls. A combined analysis of both studies was performed.
The SNP rs2856836 in IL1A was significantly associated with spondyloarthritis (p=0.009) and AS (p=0.010) in the family study. The case-control study revealed an association between another IL1A variant (rs1894399) and AS (p=0.035), and between IL1F10.3 (rs3811058) and spondyloarthritis (p=0.041). By combining family and case-control studies an association between AS and IL1A was confirmed (rs1894399, p=0.024), whereas non-AS was more significantly associated with IL1F10.3 (p=0.0043). Family-based and case-control studies revealed significant association between the two most frequent haplotypes combining the four SNP of the replication study and both spondyloarthritis (p=0.0054 and p=0.038) and AS phenotypes (p=0.018 and 0.0036).
This study is the first to demonstrate an association between several polymorphisms located in the IL-1 gene cluster and spondyloarthritis as a whole. The IL1A locus was strongly associated with AS phenotype, whereas IL1F10 was associated with non-AS.
Anorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration ...after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches. We describe preliminary data about the effect of weight gain on the symptomatology of patients suffering from acute AN (n = 225) and partially recovered (n = 41). We measured more precisely physical activity with continuous cardiac monitoring in a sub-group (n = 68). Using a mouse model, we investigated whether a long-term food restriction followed by nutritional recovery associated or not with physical activity may differentially impact peripheral and central homeostatic regulation. We assessed the plasma concentration of acyl ghrelin, desacyl ghrelin and leptin and the mRNA expression of hypothalamic neuropeptides and their receptors. Our data show an effect of undernutrition history on the level of physical activity in AN. The preclinical model supports an important role of physical activity in the recovery process and points out the leptin system as one factor that can drive a reliable restoration of metabolic variables through the hypothalamic regulation of neuropeptides involved in feeding behavior.
Over the last years, the critical role of cytoskeletal proteins in cortical development including neuronal migration as well as in neuronal morphology has been well established. Inputs from genetic ...studies were provided through the identification of several mutated genes encoding either proteins associated with microtubules (DCX, LIS1, KIF2A, KIF5C, DYNC1H1) or tubulin subunits (TUBA1A, TUBB2B, TUBB5 and TUBG1), in malformations of cortical development (MCD). We also reported the identification of missense mutations in TUBB3, the postmitotic neuronal specific tubulin, in six different families presenting either polymicrogyria or gyral disorganization in combination with cerebellar and basal ganglial abnormalities. Here, we investigate further the association between TUBB3 mutations and MCDs by analyzing the consequences of Tubb3 knockdown on cortical development in mice. Using the in utero-electroporation approach, we demonstrate that Tubb3 knockdown leads to delayed bipolar morphology and radial migration with evidence, suggesting that the neuronal arrest is a transient phenomenon overcome after birth. Silenced blocked cells display a round-shape and decreased number of processes and a delay in the acquisition of the bipolar morphology. Also, more Tbr2 positive cells are observed, although less cells express the proliferation marker Ki67, suggesting that Tubb3 inactivation might have an indirect effect on intermediate progenitor proliferation. Furthermore, we show by rescue experiments the non-interchangeability of other beta-tubulins which are unable to rescue the phenotype. Our study highlights the critical and specific role of Tubb3 on the stereotyped morphological changes and polarization processes that are required for initiating radial migration to the cortical plate.
A growing number of histone modifiers are involved in human neurodevelopmental disorders, suggesting that proper regulation of chromatin state is essential for the development of the central nervous ...system. Among them, heterozygous de novo variants in
KMT2A
, a gene coding for histone methyltransferase, have been associated with Wiedemann–Steiner syndrome (WSS), a rare developmental disorder mainly characterized by intellectual disability (ID) and hypertrichosis. As KMT2A is known to regulate the expression of multiple target genes through methylation of lysine 4 of histone 3 (H3K4me), we sought to investigate the transcriptomic consequences of
KMT2A
variants involved in WSS. Using fibroblasts from four WSS patients harboring loss-of-function
KMT2A
variants, we performed RNA sequencing and identified a number of genes for which transcription was altered in
KMT2A
-mutated cells compared to the control ones. Strikingly, analysis of the pathways and biological functions significantly deregulated between patients with WSS and healthy individuals revealed a number of processes predicted to be altered that are relevant for hypertrichosis and intellectual disability, the cardinal signs of this disease.
Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts ...with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients.
To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of ...cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.
La crise du Covid-19 a forgé un paysage urbain et marchand inédit, des stratégies et des adaptations diverses, à la fois du côté des commerçants et des clients, et a pu reconfigurer ou réaffirmer le ...lien profond entre la ville et le commerce. Ce numéro thématique, initié quelques mois seulement après l’annonce par le gouvernement français de nouvelles mesures de restriction (avril 2021), propose d’examiner la déstabilisation et les réaménagements provoqués par la crise sanitaire dans le secteur du commerce de détail et d’étudier les conséquences provisoires ou durables de celle-ci sur l’espace urbain. Qu’est-ce qu’une ville marchande quand elle ne peut plus l’être, quand la plupart de ses commerces sont fermés ou font l’objet de contraintes et de nouvelles réglementations ? Et comment l’analyser ? Réunissant sociologues, anthropologues, géographes, urbanistes, le dossier expose des analyses menées en Chine, en Afrique du Sud, aux États-Unis et en France sur une diversité d’espaces et de situations d’échange marchand, qui d’ordinaire ne sont pas pensés ensemble (boutiques, restaurants, marchés de gros et de détail, commerce en ligne). Ces dernières se voient ici rassemblées dans une interrogation commune – ce que la pandémie du Covid-19 a fait à la ville et aux commerces – tout en pensant plus globalement les réalités urbaines et leur avenir. This issue, initiated just a few months after the French government's announcement of new restrictive measures (April 2021), proposes to examine the destabilization and redevelopment caused by the pandemic is in the retail sector, and to study its temporary or lasting consequences on urban space. What is a market town when it can no longer be one, when most of its shops are closed or subject to constraints and new regulations? Bringing together sociologists, anthropologists, geographers and urban planners, the dossier presents analyses carried out in China, South Africa, the United States and France on a diversity of spaces and situations of commercial exchange, which are not usually thought of together (stores, restaurants, wholesale and retail markets, online commerce). These are brought together here in a common interrogation –what the Covid-19 pandemic has done to the city and to commerce– while thinking more globally about urban realities and their future.
PDF
