Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with intellectual disability.

International audienceBACKGROUND: Intellectual disability (ID) is frequently associated with sleep disorders. Treatment with melatonin demonstrated efficacy, suggesting that, at least in a subgroup of patients, the endogenous melatonin level may not be sufficient to adequately set the sleep-wake cycles. Mutations in ASMT gene, coding the last enzyme of the melatonin pathway have been reported as a risk factor for autism spectrum disorders (ASD), which are often comorbid with ID. Thus the aim of the study was to ascertain the genetic variability of ASMT in a large cohort of patients with ID and controls. METHODS: Here, we sequenced all exons of ASMT in a sample of 361 patients with ID and 440 controls. We then measured the ASMT activity in B lymphoblastoid cell lines (BLCL) of patients with ID carrying an ASMT variant and compared it to controls. RESULTS: We could identify eleven variations modifying the protein sequence of ASMT (ID only: N13H, N17K, V171M, E288D; controls only: E61Q, D210G, K219R, P243L, C273S, R291Q; ID and controls: L298F) and two deleterious splice site mutations (IVS5+2T>C and IVS7+1G>T) only observed in patients with ID. We then ascertained ASMT activity in B lymphoblastoid cell lines from patients carrying the mutations and showed significantly lower enzyme activity in patients carrying mutations compared to controls (p = 0.004). CONCLUSIONS: We could identify patients with deleterious ASMT mutations as well as decreased ASMT activity. However, this study does not support ASMT as a causative gene for ID since we observed no significant enrichment in the frequency of ASMT variants in ID compared to controls. Nevertheless, given the impact of sleep difficulties in patients with ID, melatonin supplementation might be of great benefit for a subgroup of patients with low melatonin synthesis

Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation.

International audienceChromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome

Conduire le changement en bibliothèque

Comment conduire le changement de manière efficace dans le contexte très particulier introduit par les révolutions du numérique et des réseaux dans les bibliothèques ? Comment assurer le bon fonctionnement d’un équipement lorsque le rythme des changements à conduire s’accélère ? Ce volume apporte des éléments de réponses pratiques, tirées de réalisations concrètes et propose une réflexion plus générale sur les modalités du management en bibliothèque, centrée sur la notion émergente, dans les institutions publiques, d’organisation apprenante

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

Historique et actualités de l'environnement juridique de la réglementation de la recherche biomédicale en France

Depuis la nuit des temps, des recherches biomédicales sont pratiquées sur l'être humain. Ce n'est, pourtant, qu'après la seconde guerre mondiale qu'un code éthique est mis en place afin de protéger les personnes s'y prêtant: le Code de Nüremberg, complété par la suite par la Déclaration d'Helsinki. Dans les années 60, l'affaire de la Thalidomide® met en exergue la faiblesse du contrôle des médicaments. L'autorisation de mise sur le marché est alors exigée en 1965, pour tous les médicaments et impose que les résultats des essais cliniques soient fournis avec la demande. En France, la loi Huriet-Sérusclat est adoptée le 20 décembre 1988 et avec elle, la mise en place de la première législation encadrant les essais cliniques. Celle-ci a été modifiée en 2004 par la loi n2004-806 du 9 août 2004 suite à la transposition en droit français de la Directive 2001/20/CE de la Commission européenne du 4 avril 2001.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

The S locus receptor kinase and the self-incompatibility response in Brassica

International audienc

Prospective a long terme des equilibres alimentaires mondiaux : le cas des pays en developpement

SIGLEAvailable at INIST (FR), Document Supply Service, under shelf-number : RP 12870 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Sensorineural hearing loss in OPA1-linked disorders

International audienceNo abstract availabl