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Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.

This study aims to decipher the role of short tandem repeats (STRs) in epilepsy patients. Whole genome short-read sequencing data of 734 epileptic patients was used to look for known STR expansions associated with increased risk of neurodevelopmental diseases or epilepsy using three different software. Results show one hit of particular interest onARXgene associated with Early Infantile Encephalopathic Epilepsy that could be causal for one patient with developmental and epileptic encephalopathy. However, we show that the different software do not agree on most of the calls above the threshold and that experimental validation is still needed for diagnostic, although these algorithms could prove useful for pre-selection of samples to be validated.

Although impairment in sensory integration is suggested in the autism spectrum (AS), empirical evidences remain equivocal. We assessed the integration of low-level visual and tactile information within and across modalities in AS and typically developing (TD) individuals. TD individuals demonstrated increased redundancy gain for cross-modal relative to double tactile or visual stimulation, while AS individuals showed similar redundancy gain between cross-modal and double tactile conditions. We further observed that violation of the race model inequality for cross-modal conditions was observed over a wider proportion of the reaction times distribution in TD than AS individuals. Importantly, the reduced cross-modal integration in AS individuals was not related to atypical attentional shift between modalities. We conclude that AS individuals displays selective decrease of cross-modal integration of low-level information.

Germline copy number variants (CNVs) are known to affect a large portion of the human genome and have been implicated in many diseases. Although whole-genome sequencing can help identify CNVs, existing analytical methods suffer from limited sensitivity and specificity. Here we show that this is in large part due to the non-uniformity of read coverage, even after intra-sample normalization, and that this is exacerbated in regions of low-mappability. To improve on this, we propose PopSV, an analytical method that uses multiple samples to control for technical variation and enables the robust detection of CNVs. We show that PopSV is able to detect up to 2.7 times more variants compared to previous methods, with an accuracy of about 90%. Applying PopSV to 640 normal and cancer whole-genome datasets, we demonstrate that CNVs affect on average 7.4 million DNA bases in each individual, a 23% increase versus previous estimates. Notably, we find that regions of low-mappability, which were often concealed in previous analyses, harbor approximately 10 times more CNVs than the rest of the genome and that this contrasts with somatic CNVs (sCNVs) that are nearly uniformly distributed. We also observe that CNVs are found more than expected near centromeres and telomeres, in segmental duplications, in specific types of satellite repeats and in some of the most recent families of transposable elements. Although CNVs are found to be depleted in protein-coding genes, we identify 7206 genes with at least one exonic CNV, 324 of which harbored CNVs that would have been missed if low-mappability regions had been excluded. Similarly, 2253 trait- and disease-associated loci are observed to overlap at least one CNV. Our results provide the most comprehensive map of CNVs across the human genome to date and demonstrate the broad functional impact of this type of genetic variation including in regions of low-mappability.

Supercritical carbon dioxide (CO2) is an established medium for synthesizing molecular compounds and activation of microporous solids, but is much less explored for transformations of high-melting ionic reactants, such as metal oxides. We show that supercritical CO2 enables direct, clean, and rapid transformation of zinc oxide into zeolitic imidazolate frameworks (ZIFs), without requiring toxic or corrosive metal nitrate or chloride precursors, organic or aqueous solvents, additives, or auxiliaries. While recent syntheses of coordination polymers and metal–organic frameworks from supercritical CO2 highlighted the need for specialized metal reagents designed for solubility, we unexpectedly find that ZnO is quantitatively converted into grams of diverse ZIFs in minutes, with hundred grams of popular ZIF-8 accessible within an hour.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through treatment with dexamethasone, cAMP elevating agents or NFkB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.

Autism spectrum disorder (ASD) is a highly heterogeneous genetic disorder with strong evidence of ASD-association currently available only for a small number of genes. This makes it challenging to identify the underlying genetic cause in many cases of ASD, and there is a continuing need for further discovery efforts. We sequenced whole genomes of 119 deeply phenotyped ASD probands in order to identify likely pathogenic variants. We prioritized variants found in each subject by predicted damage, population frequency, literature evidence, and phenotype concordance. We used Sanger sequencing to determine the inheritance status of high-priority variants where possible. We report five novel de novo damaging variants as well as several likely damaging variants of unknown inheritance; these include two novel de novo variants in the well-established ASD gene SCN2A. The availability of rich phenotypic information and its concordance with the literature allowed us to increase our confidence in pathogenicity of discovered variants, especially in probands without parental DNA. Our results contribute to the documentation of potential pathogenic variants and their associated phenotypes in individuals with ASD.

Inhibition of oxidative phosphorylation (OXPHOS) is a promising therapeutic strategy in Acute Myeloid Leukemia (AML), but patients respond heterogeneously. Through chemically interrogation of 200 sequenced specimens, we identified Mubritinib as a strongin vitroandin vivoanti-leukemic compound, acting through ubiquinone-dependent inhibition of Electron Transport Chain complex I (ETC1). ETC1 targeting showed selective toxicity against a subgroup of chemotherapy-resistant leukemias exhibiting OXPHOS hyperactivity, high expression of mitochondrial activity-related genes, and mutations affectingNPM1, FLT3andDNMT3A. Altogether, our work thus identifies a novel ETC1 inhibitor with high clinical potential and reveals the landscape of OXPHOS dependency in AML.

Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB-CD86 activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through either CD86 suppression, treatment with dexamethasone, cAMP elevating agents or NFKB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.

BACKGROUND The effect of maternal age at conception on various aspects of offspring health is well documented and often discussed. We seldom hear about the paternal age effect on offspring health, although the link is now almost as solid as with maternal age. The causes behind this, however, are drastically different between males and females. CONTENT In this review article, we will first examine documented physiological changes linked to paternal age effect. We will start with all morphological aspects of the testis that have been shown to be altered with aging. We will then move on to all the parameters of spermatogenesis that are linked with paternal age at conception. The biggest part of this review will focus on genetic changes associated with paternal age effects. Several studies that have established a strong link between paternal age at conception and the rate of de novo mutations will be reviewed. We will next discuss paternal age effects associated with telomere length and try to better understand the seemingly contradictory results. Finally, severe diseases that affect brain functions and normal development have been associated with older paternal age at conception. In this context, we will discuss the cases of autism spectrum disorder and schizophrenia, as well as several childhood cancers. SUMMARY In many Western civilizations, the age at which parents have their first child has increased substantially in recent decades. It is important to summarize major health issues associated with an increased paternal age at conception to better model public health systems.

Summary Human hematopoietic stem cells (HSCs) exhibit attrition of their self-renewal capacity when cultured ex vivo, a process that is partially reversed upon treatment with epigenetic modifiers, most notably inhibitors of histone deacetylases (HDACs) or lysine-specific demethylase LSD1. A recent study showed that the human HSC self-renewal agonist UM171 modulates the CoREST complex, leading to LSD1 degradation, whose inhibition mimics the activity of UM171. The mechanism underlying the UM171-mediated loss of CoREST function remains undetermined. We now report that UM171 potentiates the activity of a CULLIN3-E3 ubiquitin ligase (CRL3) complex whose target specificity is dictated by the poorly characterized Kelch/BTB domain protein KBTBD4. CRL3KBTBD4 targets components of the LSD1/RCOR1 corepressor complex for proteasomal degradation, hence re-establishing H3K4me2 and H3K27ac epigenetic marks, which are rapidly decreased upon ex vivo culture of human HSCs.

Identification of MYC mutations in acute myeloid leukemias with NUP98 – NSD1 translocations

Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

International audience; The ubiquitin-associated protein 2-like (UBAP2L) gene remains poorly studied in human and mouse development. UBAP2L interacts with the Polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and determines the activity of mouse hematopoietic stem cells in vivo Here we show that loss of Ubap2l leads to disorganized respiratory epithelium of mutant neonates, which die of respiratory failure. We also show that UBAP2L overexpression leads to epithelial-mesenchymal transition-like phenotype in a non-small cell lung carcinoma (NSCLC) cell line. UBAP2L is amplified in 15% of human primary lung adenocarcinoma specimens. Such patients express higher levels of UBAP2L and show a reduction in survival when compared with those who do not have this gene amplification. Supporting a possible role for UBAP2L in lung tumor progression, NSCLC cells engineered to express low levels of this gene produce much smaller tumors in vivo than wild-type control cells. Together, these results suggest that UBAP2L contributes to epithelial lung cell identity in mice and that it plays an important role in human lung adenocarcinoma.-Aucagne, R., Girard, S., Mayotte, N., Lehnertz, B., Lopes-Paciencia, S., Gendron, P., Boucher, G., Chagraoui, J., Sauvageau, G. UBAP2L is amplified in a large subset of human lung adenocarcinoma and is critical for epithelial lung cell identity and tumor metastasis.

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. For both large and small variants, we found an enrichment of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive sequence-based profiling of CNVs could help explain a larger fraction of epilepsy cases., Author summary Epilepsy is a common neurological disorder affecting around 3% of the population. In some cases, epilepsy is caused by brain trauma or other brain anomalies but there are often no clear causes. Genetic factors have been associated with epilepsy in the past such as rare genetic variations found by linkage studies as well as common genetic variations found by genome-wide association studies and large copy-number variants. We sequenced the genome of ∼200 epilepsy patients and ∼300 healthy controls and compared the distribution of deletion (loss of a copy) and duplication (additional copy) of genomic regions. Thanks to the sequencing technology and a new method that takes advantage of the large sample size, we could compare the distribution of small copy-number variants between epilepsy patients and controls. Overall, we found that small variants are also associated with epilepsy. Indeed, the genome of epilepsy patients had more exonic copy-number variants, especially when rare or affecting genes with predicted loss-of-function intolerance. Focusing on regions around genes that have been previously associated with epilepsy, we also found more non-coding variants in epilepsy patients, especially deletions or variants in regulatory regions. Finally, we provide a list of 21 regions in which we found likely pathogenic variants.

International audience; Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.

Idiopathic scoliosis (IS) is a spine deformity that affects approximately 3% of the population. The underlying causes of IS are not well understood, although there is clear evidence that there is a genetic component to the disease. Genetic mapping studies suggest high genetic heterogeneity, but no IS disease-causing gene has yet been identified. Here, genetic linkage analyses combined with exome sequencing identified a rare missense variant (p.A446T) in the centriolar protein gene POC5 that cosegregated with the disease in a large family with multiple members affected with IS. Subsequently, the p.A446T variant was found in an additional set of families with IS and in an additional 3 cases of IS. Moreover, POC5 variant p.A455P was present and linked to IS in one family and another rare POC5 variant (p.A429V) was identified in an additional 5 cases of IS. In a zebrafish model, expression of any of the 3 human IS-associated POC5 variant mRNAs resulted in spine deformity, without affecting other skeletal structures. Together, these findings indicate that mutations in the POC5 gene contribute to the occurrence of IS.

Multipotent long-term repopulating hematopoietic stem cells (LT-HSCs) can self-renew or differentiate into the less primitive short-term repopulating stem cells (ST-HSCs), which themselves produce progenitors that ensure the daily supply of all essential blood components. The Polycomb group (PcG) protein BMI1 is essential for the activity of both HSCs and progenitor cells. Although BMI1 operates by suppressing the Ink4a/Arf locus in progenitors and ST-HSCs, the mechanisms through which this gene regulates the activity of LT-HSCs remain poorly understood. Toward this goal, we isolated BMI1-containing protein complexes and identified UBAP2L as a novel BMI1-interacting protein. We also showed that UBAP2L is preferentially expressed in mouse and human HSC-enriched populations when compared with more mature cell types, and that this gene is essential for the activity of LT-HSCs. In contrast to what is observed for Bmi1 knockdown, we found that UBAP2L depletion does not affect the Ink4a/Arf locus. Given that we demonstrated that BMI1 overexpression is able to rescue the deleterious effects of Ubap2l downregulation on LT-HSC activity and that UBAP2L is part of a PcG subcomplex comprising BMI1, we propose a model in which at least 2 different BMI1-containing PcG complexes regulate HSC activity, which are distinguishable by the presence of UBAP2L.

Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAStatistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAFunctionally relevant variants in genes encoding GABAEuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Recently, we have identified a small molecule, UM171 that enables the expansion of human HSC with both short- and long-term repopulating capacity. Ongoing clinical trials further confirm the beneficial effects of this molecule in patients. Transcriptome analysis of cord blood-derived CD34+ cells and AML cell lines exposed to UM171 revealed unsuspected and strong inflammatory signatures pointing to simultaneous activation of pro-inflammatory (including NFKB and IFN signaling) and anti-inflammatory (including detoxification responses) programs. Moreover, characterisation of cell subsets expanded differentially in presence of UM171, showed a significant and preferential expansion of functional dendritic cell progenitors (CD34+CD86+CD45RA+) and mast cells (FCER1A+c-kit+). In line with this result, immuno-suppressors such as glucocorticoids (dexamethasone) or cAMP elevating agents (IBMX, forskolin) suppressed UM171-mediated pro-inflammatory signaling. These drugs also compromise the ability of UM171 to expand HSCs with long-term repopulating activity and generate dendritic and mast cell progenitors ex vivo. Moreover, knockdown of glucocorticoid receptor (NR3C1) reverts the antagonistic effect of glucocorticoids on UM171 inflammatory properties. Importantly, detrimental effects of glucocorticoid on HSC function was also observed in absence of UM171, thus indicating that inflammation is critical to HSC expansion, independently of the culture conditions. We also found that UM171 induces the expression of the inflammatory mediator CD86 on HSC subsets and knockdown of this receptor leads to a loss of long-term HSCs and substantial depletion of lymphoid compartment. Previously, we have shown that EPCR, a well known anti-inflammatory mediator, is induced by UM171 on CD34+ cord blood cells and defines a cell population with sustained short- and long-term repopulating activity (Fares et al., Blood 2017). We now show that disruption of EPCR function markedly skews UM171 effects towards pro-inflammatory response, thus exacerbating inflammation. Importantly, this uncontrolled inflammation impairs both immune cells generation and HSC activity suggesting that EPCR-driven anti-inflammatory signals provide a critical negative feedback constraining excessive inflammation in HSC and dendritic cell progenitors. Altogether our results strongly suggest that UM171-mediated positive regulation of HSC function occurs through a coordinated and biphasic mechanism allowing a controlled and adequate pro- and anti-inflammatory status, thus creating a permissive environment for stem and immune cell survival and expansion. Most importantly, our data indicate that integration of pro- and anti-inflammatory signals is essential for human HSC self-renewal in the presence or in the absence of UM171, thus revealing a critical balance of pro- and anti-inflammatory activities in human HSC. Disclosures Sauvageau: ExCellThera: Employment, Equity Ownership.

BACKGROUND: 60% to 70% of Acute Myeloid Leukemia (AML) patients enter complete remission after induction regimen, but the majority relapse within 3 years due to the outgrowth of therapy resistant Leukemia Stem Cells (LSCs). Identification of novel treatment strategies effective against these cells thus represents an outstanding medical need. We developed a cell culture method, which transiently maintains LSC activity ex vivo (Pabst et al., Nature Methods, 2014) and enables chemical interrogation of cell types relevant for the progression of the disease. Overall, HSCs and LSCs share numerous biological traits, making specific LSC eradication challenging. However, striking differences in energy metabolism between normal and leukemic stem cells have recently been suggested. While HSCs appear to rely primarily on anaerobic glycolysis for energy production, LSCs seem to depend on mitochondrial oxidative phosphorylation for their survival. Targeting mitochondrial respiration could therefore represent an effective approach for the specific eradication of LSCs. AIM: We aimed to identify novel therapeutic targets for AMLs with poor treatment outcome. The study relied on the Leucegene approach that integrates results generated by RNA sequencing analysis of primary human AML specimens, detailed clinical and cytogenetic annotations provided by the Quebec leukemia cell bank and ex vivo responses of primary AML samples to various chemical compounds. Our study specifically focused on specimens originating from patients with poor (overall survival < 3 years) and good (overall survival ≥ 3 years) response to standard chemotherapy, and did not include cases of Acute Promyelocytic Leukemia (APL). RESULTS: We identified Mubritinib, previously described as an ERBB2 inhibitor, as a novel anti-leukemic agent, which selectively inhibits the viability of leukemic cells from therapy-resistant AML patients, but does not affect normal CD34+ cord blood cells. Exposure to Mubritinib triggered apoptotic cell death in a subset of AML samples with high mitochondrial function-related gene expression, high relapse rates, and short overall survival. Sensitivity to Mubritinib also strongly associated with the intermediate cytogenetic risk category, normal karyotype (NK), and NPM1, FLT3 (ITD) and DNMT3A mutations. Conversely, resistance to Mubritinib associated with favorable cytogenetic risk AMLs, Core Binging Factor (CBF) leukemias and KIT mutations. Mubritinib has been developed as an ERBB2 kinase inhibitor. Intriguingly, we found that ERBB2 is not expressed in Mubritinib-sensitive AML specimens, suggesting that the anti-leukemic activity of this compound is likely not mediated by ERBB2 inhibition. Using a combination of functional genomics and biochemical analyses, we demonstrated that Mubritinib directly inhibits the mitochondrial Electron Transport Chain (ETC) complex I, which leads to a decrease in oxidative phosphorylation activity and to induction of oxidative stress. The impact of Mubritinib on AML progression was explored using a syngeneic mouse model (MLL-AF9 tdTomato-positive leukemia). Recipients of MLL-AF9 cells treated with Mubritinib exhibited a 19-fold decrease in the number of tdTomato-positive cells in the bone marrow and a 42-fold decrease in the spleens compared to control mice. Short-term treatment also led to a 37% increase in the median overall survival of Mubritinib exposed recipients compared to vehicle treated mice. Importantly, and in agreement with our observation that Mubritinib treatment does not impede proliferation of normal hematopoietic CD34+ cells in vitro, Mubritinib treatment had no impact on the number of non-transduced (tdTomato negative) nucleated bone marrow cells of recipients. CONCLUSIONS: We uncovered the clinical, mutational, and transcriptional landscape of mitochondrial vulnerability in AML and identified Mubritinib as a novel ETC complex I inhibitor with therapeutic potential for approximately 30% of AML cases currently lacking effective treatment options. As Mubritinib completed a phase I clinical trial in the context of ERBB2-positive solid tumors, our work suggests an opportunity to re-purpose Mubritinib's usage for this genetically distinct subgroup of poor outcome AML patients. Disclosures No relevant conflicts of interest to declare.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

In spring 2012, we were enrolled in a field-based graduate course in the International Peace and Conflict Resolution program at Arcadia University titled, Divided Cities: Nicosia, Cyprus. The cours...

International audience; The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n = 539) and controls (n = 265) from New York, and PD patients (n = 551), rapid eye movement sleep behavior disorder (RBD) patients (n = 351), and controls (n = 956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency > 0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (odds ratio = 1.22, 95% confidence interval = 1.02-1.47, p = 0.03) but with significant heterogeneity (p = 0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant association (odds ratio = 1.11, 95% confidence interval, 0.92-1.35, p = 0.27, heterogeneity p = 0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p = 0.75), and no cumulative effect of carrying more than one MC1R variant was found. The present study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD.

De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots.

Schizophrenia is a major mental disorder characterized by a deep disruption of the thinking process and of emotional response. For many decades, genetics studies have yielded little success in identifying genetic factors responsible for the disease. However, with the recent breakthroughs in genome analysis technologies, the field of the genetics of schizophrenia has progressed a lot in the last years. Both common and rare variants have been successfully associated with the disease and a particular emphasis has been made on rare copy number variations. Recently, a new paradigm linking de novo mutations to the genetic mechanism of schizophrenia has been unravelled. The aim of this review is to discuss the most important genetic studies made in the field to give a general perspective of where to go in the future.

Schizophrenia is a severe psychiatric disorder that profoundly affects cognitive, behavioral and emotional processes. The wide spectrum of symptoms and clinical variability in schizophrenia suggest a complex genetic etiology, which is consistent with the numerous loci thus far identified by linkage, copy number variation and association studies. Although schizophrenia heritability may be as high as ∼80%, the genes responsible for much of this heritability remain to be identified. Here we sequenced the exomes of 14 schizophrenia probands and their parents. We identified 15 de novo mutations (DNMs) in eight probands, which is significantly more than expected considering the previously reported DNM rate. In addition, 4 of the 15 identified DNMs are nonsense mutations, which is more than what is expected by chance. Our study supports the notion that DNMs may account for some of the heritability reported for schizophrenia while providing a list of genes possibly involved in disease pathogenesis.

Restless legs syndrome (RLS) is a frequent sleep disorder that is linked to disturbed iron homeostasis. Genetic studies identified MEIS1 as an RLS-predisposing gene, where the RLS risk haplotype is associated with decreased MEIS1 mRNA and protein expression. We show here that RNA interference treatment of the MEIS1 worm orthologue increases ferritin expression in Caenorhabditis elegans and that the RLS-associated haplotype leads to increased expression of ferritin and DMT1 in RLS brain tissues. Additionally, human cells cultured under iron-deficient conditions show reduced MEIS1 expression. Our data establish a link between the RLS MEIS1 gene and iron metabolism.

Recent results on the nature and limits of multisensory enhancement are inconsistent when stimuli are presented across spatial regions. We presented visual, tactile and visuotactile stimuli to participants in two speeded response tasks. Each unisensory stimulus was presented to either the left or right hemispace, and multisensory stimuli were presented as either aligned (e.g. visual right/tactile right) or misaligned (e.g. visual right/tactile left). The first task was a simple reaction time (SRT) paradigm where participants responded to all stimulations irrespective of spatial position. Results showed that multisensory gain and coactivation were the same for spatially aligned and misaligned visuotactile stimulation. In the second task, a choice reaction time (CRT) paradigm where participants responded to right-sided stimuli only, misaligned stimuli yielded slower reaction times. No difference in multisensory gain was found between the SRT and CRT tasks for aligned stimulation. Overall, the results suggest that when spatial information is task-irrelevant, multisensory integration of spatially aligned and misaligned stimuli is equivalent. However, manipulating task requirements can alter this effect.

It is believed that hemopoietic stem cells (HSC), which colonize the fetal liver (FL) rapidly, expand to establish a supply of HSCs adequate for maintenance of hemopoiesis throughout life. Accordingly, FL HSCs are actively cycling as opposed to their predominantly quiescent bone marrow counterparts, suggesting that the FL microenvironment provides unique signals that support HSC proliferation and self-renewal. We now report the generation and characterization of mice with a mutant allele of Baf250a lacking exons 2 and 3. Baf250aE2E3/E2E3 mice are viable until E19.5, but do not survive beyond birth. Most interestingly, FL HSC numbers are markedly higher in these mice than in control littermates, thus raising the possibility that Baf250a determines the HSC pool size in vivo. Limit dilution experiments indicate that the activity of Baf250aE2E3/E2E3 HSC is equivalent to that of the wild-type counterparts. The Baf250aE2E3/E2E3 FL-derived stroma, in contrast, exhibits a hemopoiesis-supporting potential superior to the developmentally matched controls. To our knowledge, this demonstration is the first that a mechanism operating in a cell nonautonomous manner canexpand the pool size of the fetal HSC populations.

Objective:To assess the contribution of variants in STK32B, PPARGC1A, and CTNNA3 as essential tremor (ET) predisposing factors following their association in a 2-stage genome-wide association study (GWAS).Methods:The coding regions of these genes was examined for the presence of rare variants using two approaches: (1) Looking at whole-exome and whole-genome sequencing data of 14 autosomal dominant multiplex ET families. (2) Conducting a targeted massive parallel sequencing to examine the three genes in cohorts of 269 ET cases and 287 control individuals. The cumulative impact of rare variants was assessed using SKAT-O analyses using (1) all variants, (2) only rare variants, and (3) only the rare variants altering the mRNA.Results:Thirty-four variants were identified. No difference emerged regarding the distributions of individual variants (or gene) between cases and controls.Conclusion:No rare exonic variants further validated one of these genes as a risk factor for ET. The recent GWAS offers promising avenues, but the genetic heterogeneity of ET is nonetheless challenging for the validation of risk factors, and ultimately larger cohorts of cases should help to overcome this task.

Regardless of the fact that emotions are usually recognized by combining facial and vocal expressions, the multisensory nature of affect perception has scarcely been investigated. In the present study, we show results of three experiments on multisensory perception of emotions using newly validated sets of dynamic visual and non-linguistic vocal clips of affect expressions. In Experiment 1, participants were required to categorize fear and disgust expressions displayed auditorily, visually, or using congruent or incongruent audio-visual stimuli. Results showed faster and more accurate categorisation in the bimodal congruent situation than in the unimodal conditions. In the incongruent situation, participant preferentially categorized the affective expression based on the visual modality, demonstrating a visual dominance in emotional processing. However, when the reliability of the visual stimuli was diminished, participants categorized incongruent bimodal stimuli preferentially via the auditory modality. These results demonstrate that visual dominance in affect perception does not occur in a rigid manner, but follows flexible situation-dependent rules. In Experiment 2, we requested the participants to pay attention to only one sensory modality at a time in order to test the putative mandatory nature of multisensory affective interactions. We observed that even if they were asked to ignore concurrent sensory information, the irrelevant information significantly affected the processing of the target. This observation was especially true when the target modality was less reliable. Altogether, these findings indicate that the perception of emotion expressions is a robust multisensory situation which follows rules that have been previously observed in other perceptual domains.

We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family.

International audience; Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.

BACKGROUND: Schizophrenia (SCZ) is a very heterogeneous disease that affects approximately 1% of the general population. Recently, the genetic complexity thought to underlie this condition was further supported by three independent studies that identified an increased number of damaging de novo mutations DNM in different SCZ probands. While these three reports support the implication of DNM in the pathogenesis of SCZ, the absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion that has been supported by the moderate success of Genome-Wide Association Studies (GWAS). METHODS: To further examine the genetic heterogeneity of this disease, we resequenced 62 genes that were found to have a DNM in SCZ patients, and 40 genes that encode for proteins known to interact with the products of the genes with DNM, in a cohort of 235 SCZ cases and 233 controls. RESULTS: We found an enrichment of private nonsense mutations amongst schizophrenia patients. Using a kernel association method, we were able to assess for association for different sets. Although our power of detection was limited, we observed an increased mutation burden in the genes that have DNM.