Exploring thienothiadiazine dioxides as isosteric analogues of benzo-and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

peer reviewedThe synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators

Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease

International audienceWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Unusual clinical description of adult with Timothy syndrome, carrier of a new heterozygote mutation of CACNA1C

International audienceCANAC1C encodes for the main cardiac L-type calcium channel and mutations on it lead to a prolonged QT interval in Timothy Syndrome (TS). We provide a new de novo constitutional heterozygote missense variation in CACNA1C in a living adult woman, also carrier of the known c.2146-1G>C heterozygous variation of PKP2 inherited from her father. To our knowledge, this patient is the first to have the two variations in these genes. Theses clinical and molecular findings expand the clinical and molecular spectrum of TS and show the interest of next generation sequencing or whole exome sequencing in rare disorders, atypical or novel phenotype

HALOGENATION OF ETHANOL EXTRACT FROM PAEONIA SUFFRUTICOSA: EXPLORING PROMISING PATHWAYS FOR ANTI-SARS-COV-2 MEDICATION DEVELOPMENT

peer reviewedThe COVID-19 pandemic is now considered as an established and ongoing health issue according to the World Health Organization, presenting challenges worldwide despite available pharmaceutical interventions. In response to the pandemic, the Chinese government has proposed the use of Traditional Chinese Medicine (TCM) as a complementary approach to conventional treatments. TCM, deeply rooted in Asian healthcare, has gathered interest for its potential application in Western countries. The present study focuses on preliminary investigations of halogenation processes applied to the ethanol extract obtained from Paeonia suffruticosa, a traditional Chinese plant, with the aim of enhancing its biological activity, particularly against SARS-CoV-2. Before achieving hemisynthesis on the crude extract, quercetin was choosen to find the optimal reaction conditions of the halogenation step, considering its presence in Paeonia suffruticosa, its abundance and cost-effectiveness. Various halogenation methods were evaluated, including the use of N-bromosuccinimide and an environmentally friendly (green) approach using sodium bromide and hydrogen peroxide. Both methods yielded promising results after LC-MS monitoring. The green methodology was then used on the Paeonia suffruticosa ethanol extract, successfully generating brominated derivatives, such as dibromopaeonol and dibromooxypaeoniflorin. In conclusion, this preliminary study highlights the potential of halogenation processes to modify the ethanol extract from Paeonia suffruticosa and potentially enhance its anti-SARS-CoV-2 properties. These findings provide insights into the potential interest of TCM in the development of new lead compounds to fight the ongoing global COVID-19 pandemic. Further investigations are however needed to validate these results and explore other promising late-stage functionalization strategies, using innovative green synthetic approaches

Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review

Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long‐term follow‐up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis

Caractérisation phénotypique et génotypique des réarrangements chromosomiques en 1q21.1: description d'une nouvelle cohorte de 34 patients et revue de la littérature

International audienc

P040 : TANC2 : un nouveau gène responsable de troubles neuro développementaux ?

National audienceDes études d’exome de larges cohortes de patients avec phénotype caractérisé ont fortement contribué à l'identification degènes candidats dans les troubles neuro développementaux (TND) et à la caractérisation de nouveaux syndromes avecdéficience intellectuelle (DI). Plusieurs de ces gènes codent pour des protéines d’échaffaudage jouant un rôle critique dans laneurotransmission glutamatérgique, organisant la composition post-synaptique des complexes de récepteur glutamate et jouantun rôle clé au niveau des synapses ainsi que sur la plasticité neuronale. Parmi ceux-ci, le gène TANC2 (Tetratricopeptiderepeat-, Ankyrin repeat-, and coiled-coil-containing protein 2, OMIM 615047) est un possible gène candidat de TND avec desvariations faux sens identifiées dans le spectre phénotypique des TND à savoir DI isolée, trouble du spectre autistique etschizophrénie. Récemment, l'analyse in silico de la famille de protéines TANC a conduit à préciser leurs interactions et àcomprendre les conséquences neurobiologiques possibles de leur perturbation. Nous rapportons un frère et une sœurprésentant tous les deux un syndrome de Rett atypique et porteurs de la même délétion intragénique de TANC2, identifiée parCGHarray, non retrouvées chez les parents asymptomatiques. Par ailleurs, l'étude moléculaire des gènes impliqués dans lesencéphalopathies épileptiques est négatives dans la limite des techniques utilisées. Cette observation évoque un mosaïscismegerminal parental et la possible implication de TANC2 dans le phénotype observé. L’analyse des transcrits dans le sangpériphérique chez les deux patients comparés aux parents a permis d’identifier un transcrit mutant emportant les exons 2 à 7 deTANC2, avec des études in silico indiquant une protéine tronquée de 290 acides aminés sans décalage du cadre de lecture.D’autre part, l’étude d’expression du transcrit TANC2 indique une double expression avec contribution non altérée du transcritsauvage chez ces 2 patients. Le mécanisme suggéré est une perte de fonction par effet dominant négatif. L’ensemble de ceséléments est en faveur de l’implication du gène TANC2 dans les TND

Primary Failure of Dental Eruption Due to Variants Parathyroid Hormone Receptor 1: Retrospective Study and Proposal of Guidelines Treatment

Objective: Primary failure of eruption is characterized by a nonsyndromic defect in tooth eruption in the absence of mechanical obstruction. It is correlated to rare heterozygous variants in the parathyroid hormone receptor 1 gene. The management of primary failure of eruption is complex because many therapies are ineffective. The present study aimed to compare the clinical outcomes of our patients with the findings reported in the literature, and to propose a treatment guideline based on the literature and our experience. Methods: Retrospective study of patients affected by primary dental eruption failure in the department and analyse of the results and compare with those of the litterature. Results: Twelve patients belonging to 5 families (9 males, 3 females; 13–52 y old) diagnosed and treated in the maxillofacial surgery and stomatology department of the Lille University Hospital were included. All patients showed posterior tooth involvement, and most patients showed bilateral defects. None of the affected teeth had coronal alveolar bone, whereas 6 patients showed root resorption in the affected teeth. Genetic analyses, performed on 11 patients, identified a parathyroid hormone receptor 1 disease-causing variant in 7 of them (63%). Multidisciplinary treatment was required to rehabilitate these patients. Orthodontic interventions, even at an early age, are difficult in affected teeth, which are often blocked or have internal resorption. Moreover, retention of these affected teeth during growth leads to dentoskeletal malocclusions, requiring difficult surgical management in the long term. Therefore, early extraction of these teeth is frequently recommended once the diagnosis has been confirmed. An implant-borne prosthetic rehabilitation can then be achieved at the end of growth after correction of the jaw discrepancy. In case of a late diagnosis, other surgical or noninvasive techniques may be used depending on the clinical situation. Distraction osteogenesis or segmental osteotomy could be discussed for patients with mild phenotypes. Conclusions: Early diagnosis of primary eruption defects is crucial to offer appropriate management as early as possible, and so to avoid late complicated treatments

Loss of Methylation at GNAS Exon A/B Is Associated With Increased Intrauterine Growth

International audienceGNAS is one of few genetic loci that undergo allelic-specific methylation resulting in the parent-specific expression of at least four different transcripts. Due to monoallelic expression, heterozygous GNAS mutations affecting either paternally or maternally derived transcripts cause different forms of pseudohypoparathyroidism (PHP), including autosomal-dominant PHP type Ib (AD-PHP1B) associated with loss of methylation (LOM) at exon A/B alone or sporadic PHP1B (sporPHP1B) associated with broad GNAS methylation changes. Similar to effects other imprinted genes have on early development, we recently observed severe intrauterine growth retardation in newborns, later diagnosed with pseudopseudohypoparathyroidism (PPHP) because of paternal GNAS loss-of-function mutations