Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Aerosol-Assisted Sol-Gel Synthesis of Mesoporous TiO2 Materials, and Their Use as Support for Ru-Based Methanation Catalysts

Mesoporous TiO2 materials have been prepared by an aerosol process, which leverages on the acetic acid-mediated sol-gel chemistry and on the evaporation-induced self-assembly phenomenon to obtain materials with high specific surface area and large mesoporous volume. The obtained spherical particles are calcined to release the porosity. It is shown that the mesoscopic order can be preserved when the calcination is carried out at relatively low temperature (375 °C and below). Harsher calcination conditions lead to the progressive destruction of the mesostructured, concomitant with a progressive drop of textural properties and with the crystallization of larger anatase domains. The mesoporous TiO2 material calcined at 350°C (specific surface area = 260 m².g-1; pore volume = 0.36 cm³.-1; mean pore diameter = 5.4 nm) was selected as a promising support for preformed RuO2 nanoparticles, and subsequently annealed in air. It is shown that the presence of RuO2 nanoparticles and subsequent annealing provoke further intense modification of the texture and crystallinity of the TiO2 materials. In addition to a drop in the textural parameters, a RuO2-mediated crystallization of rutile TiO2 is highlighted at temperature as low as 250°C. After an in situ reduction in H2, the catalysts containing TiO2 rutile and relatively small RuO2 crystals showed the highest activity in the methanation of CO2. </div

Mesoporous TiO2 Support Materials for Ru-Based CO2 Methanation Catalysts

Mesoporous TiO2 materials have been prepared by an aerosol process, which leverages on acetic acid mediated sol–gel chemistry and on the evaporation-induced self-assembly of surfactants to obtain materials with high specific surface area (SSA) and large mesoporous volume. The obtained spherical particles are calcined to release the porosity. It is shown that the mesoscopic order can be preserved when calcination is carried out at relatively low temperature (375 °C and below). Harsher calcination conditions provoke the progressive destruction of the mesostructure, concomitant with a progressive drop of the textural properties and with the crystallization of larger anatase domains. The mesoporous TiO2 material calcined at 350 °C (SSA = 260 m2·g–1; pore volume = 0.36 cm3·g–1; mean pore diameter = 5.4 nm) was selected as a promising support for preformed RuO2 nanoparticles. It is shown that the impregnation of RuO2 nanoparticles and subsequent annealing provoke intense modifications of the texture and crystallinity of the TiO2 materials. In addition to a drop in the textural parameters, RuO2-mediated crystallization of rutile TiO2 is highlighted at a temperature as low as 250 °C. After an in situ reduction in H2, the catalysts containing rutile TiO2 and maintaining relatively small RuO2 crystals showed the highest activity in the methanation of CO2 (up to 2.05 μmolCH4·gcat.–1·s–1)

Coupling of solvent-free synthesis and reactive extrusion of alumina: an ecologically efficient integration for heterogenous catalyst synthesis

Innovation in materials manufacturing processes is a challenge to reduce the environmental impact of the chemical industry in line with sustainable development objectives, such as promoting sustainable industrialization and ensuring responsible consumption and production patterns. One of the ways to reach this goal is to revisit the main synthesis processes and to rethink their use. Reactive extrusion is a well-known continuous process used to produce and shape various materials in the polymer and food industries, but hardly leads to the direct synthesis and shaping of metal oxide materials (ceramics). In contrast, sol–gel chemistry offers tremendous opportunities to synthesize metal oxide networks by polycondensation of molecular precursors at a low temperature, but it is mostly operated in sluggish batch processes, using massive amounts of solvent contaminants and producing large amounts of chemical waste (E-factor > 40). In this work, for the first time, we coupled extrusion with sol–gel chemistry to produce high surface area shaped alumina-based materials that meet or exceed the requirements to be used as heterogeneous catalysts or catalyst supports. The necessity to adapt sol–gel chemistry – usually done in a diluted environment – to meet the twin-extruder technical constraints – usually working in a viscous environment – led to a peculiar choice of reaction conditions little discussed in the literature: the hydrolysis/condensation of (solid) alkoxide precursors without a solvent. We were able to synthesize and shaped high specific surface area boehmite (γ-AlOOH) at room temperature, in a continuous mode, and under solvent-free conditions. The solids are directly shaped in the form of self-standing “spaghetti” or extrudates. Upon calcination, the shaped hydroxides are converted into mesoporous and high specific surface area gamma alumina (γ-Al2O3) materials. We show that such materials exhibit high catalytic activity in the dehydration of ethanol. The process intensification presented here paves the way towards very low-waste, low-energy, and – all in all – more sustainable manufacturing practices for shaped high surface area metal oxides. In addition, it could be potentially less expensive since the simplification of the equipment and the lower energy consumption will contribute to drastically reduce the production costs even if the reagents are more expensive

Wnt/β-catenin pathway and cell adhesion deregulation in CSDE1-related intellectual disability and autism spectrum disorders

International audienc

Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay

International audiencePARP6, a member of a family of enzymes (17 in humans) known as poly-ADP-ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that Parp6 is a regulator of dendrite morphogenesis in rat hippocampal neurons, its function in the nervous system in vivo is poorly understood. Here, we describe the generation of a Parp6 loss-of-function mouse model for examining the function of Parp6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, we generated a mouse line that expressed a Parp6 truncated variant (Parp6TR) in place of Parp6WT. Unlike Parp6WT, Parp6TR is devoid of catalytic activity. Homozygous Parp6TR do not exhibit obvious neuromorphological defects during development, but nevertheless die perinatally. This suggests that Parp6 catalytic activity is important for postnatal survival. We also report PARP6 mutations in six patients with several neurodevelopmental disorders, including microencephaly, intellectual disabilities, and epilepsy. The most severe mutation in PARP6 (C563R) results in the loss of catalytic activity. Expression of Parp6C563R in hippocampal neurons decreases dendrite morphogenesis. To gain further insight into PARP6 function in neurons we also performed a BioID proximity labeling experiment in hippocampal neurons and identified several microtubule-binding proteins (e.g., MAP-2) using proteomics. Taken together, our results suggest that PARP6 is an essential microtubule-regulatory gene in mice, and that the loss of PARP6 catalytic activity has detrimental effects on neuronal function in humans

Familial transmission of chromoanagenesis leads to unpredictable unbalanced rearrangements through meiotic recombination

Abstract Chromoanagenesis is a cellular mechanism that leads to complex chromosomal rearrangements (CCR) during a single catastrophic event. It may result in loss and/or gain of genetic material and may be responsible for various phenotypes. These rearrangements are usually sporadic. However, some familial cases have been reported. Here, we studied six families in whom an asymptomatic or paucisymptomatic parent transmitted a CCR to its offspring in an unbalanced manner. The rearrangements were characterized by karyotyping, fluorescent in situ hybridization, chromosomal microarray (CMA) and/or whole genome sequencing (WGS) in the carrier parents and offspring. We then hypothesized meiosis‐pairing figures between normal and abnormal parental chromosomes that may have led to the formation of new unbalanced rearrangements through meiotic recombination. Our work indicates that chromoanagenesis might be associated with a normal phenotype and normal fertility, even in males, and that WGS may be the only way to identify these events when there is no imbalance. Subsequently, the CCR can be transmitted to the next generation in an unbalanced and unpredictable manner following meiotic recombination. Thereby, prenatal diagnosis using CMA should be proposed to these families to detect any pathogenic imbalances in the offspring

Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth

International audienceThe 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira+/- mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira+/- mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development

Using deep-neural-network-driven facial recognition to identify distinct Kabuki syndrome 1 and 2 gestalt

International audienceKabuki syndrome (KS) is a rare genetic disorder caused by mutations in two major genes, KMT2D and KDM6A, that are responsible for Kabuki syndrome 1 (KS1, OMIM147920) and Kabuki syndrome 2 (KS2, OMIM300867), respectively. We lack a description of clinical signs to distinguish KS1 and KS2. We used facial morphology analysis to detect any facial morphological differences between the two KS types. We used a facial-recognition algorithm to explore any facial morphologic differences between the two types of KS. We compared several image series of KS1 and KS2 individuals, then compared images of those of Caucasian origin only (12 individuals for each gene) because this was the main ethnicity in this series. We also collected 32 images from the literature to amass a large series. We externally validated results obtained by the algorithm with evaluations by trained clinical geneticists using the same set of pictures. Use of the algorithm revealed a statistically significant difference between each group for our series of images, demonstrating a different facial morphotype between KS1 and KS2 individuals (mean area under the receiver operating characteristic curve = 0.85 [p = 0.027] between KS1 and KS2). The algorithm was better at discriminating between the two types of KS with images from our series than those from the literature (p = 0.0007). Clinical geneticists trained to distinguished KS1 and KS2 significantly recognised a unique facial morphotype, which validated algorithm findings (p = 1.6e-11). Our deep-neural-network-driven facial-recognition algorithm can reveal specific composite gestalt images for KS1 and KS2 individuals