Diagnostic prénatal et diagnostic pré-implantatoire : arbre décisionnel, nouvelles pratiques ?

Le diagnostic pré-implantatoire (DPI) a pour objectif l’étude des caractéristiques génétiques d’un embryon âgé de trois jours. Il offre ainsi à des couples ayant un risque élevé de transmettre une maladie héréditaire une alternative au diagnostic prénatal (DPN). Si, au début de son application, les pathologies et les couples pris en charge ainsi que le cadre réglementaire du DPI étaient très proches de ceux du DPN, des indications propres au DPI émergent peu à peu. Les pathologies prises en charge, notamment, se diversifient, en particulier dans les pays où l’absence de réglementation autorise toutes les pratiques. Certaines de ces applications ne sont d’ailleurs pas sans poser de sérieux problèmes éthiques. Même en France, où cette activité est particulièrement encadrée, la récente modification de la loi reflète cette évolution.Preimplantation genetic diagnosis (PGD) purpose is to assess the genetic status of 3 day-old embryos. PGD offers thus to couples « at-risk » of a genetic disorder an earlier option to prenatal diagnosis (PND). At the beginning, PGD’s indications, patients and law were very closed to PND, but PGD specificities are gradually raising. Particularly, indications vary considerably in countries where the absence of law authorizes all the practices. Some of these applications are moreover raising serious ethical issues. Even in France, where this activity is particularly supervised, the recent modification to the law marks this evolution

Incontinentia Pigmenti in a Newborn with NEMO Mutation

Incontinentia pigmenti (IP) (OMIM #308300) is a rare X-linked dominant neuroectodermal multisystemic syndrome due to mutations in the gene for NF-κB essential modulator (NEMO). A term newborn girl who was born with erythematous vesicular eruptions developed recurrent seizures during the first and second weeks of her life. The serial MRIs demonstrated diffuse, progressive brain infarctions and subsequent encephalomalacia as well as brain atrophy. Skin biopsy found it was consistent with the vesicular stage of IP. Genetic analysis revealed a deletion exon 4-10 in NEMO gene associated with IP. We hereby report a Korean female baby with IP confirmed by mutation analysis of NEMO gene

Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism

Dangerous damage to mitochondrial DNA (mtDNA) can be ameliorated during mammalian development through a highly debated mechanism called the mtDNA bottleneck. Uncertainty surrounding this process limits our ability to address inherited mtDNA diseases. We produce a new, physically motivated, generalisable theoretical model for mtDNA populations during development, allowing the first statistical comparison of proposed bottleneck mechanisms. Using approximate Bayesian computation and mouse data, we find most statistical support for a combination of binomial partitioning of mtDNAs at cell divisions and random mtDNA turnover, meaning that the debated exact magnitude of mtDNA copy number depletion is flexible. New experimental measurements from a wild-derived mtDNA pairing in mice confirm the theoretical predictions of this model. We analytically solve a mathematical description of this mechanism, computing probabilities of mtDNA disease onset, efficacy of clinical sampling strategies, and effects of potential dynamic interventions, thus developing a quantitative and experimentally-supported stochastic theory of the bottleneck.Comment: Main text: 14 pages, 5 figures; Supplement: 17 pages, 4 figures; Total: 31 pages, 9 figure

A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome

AbstractIsolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population

The Common NF-κB Essential Modulator (NEMO) Gene Rearrangement in Korean Patients with Incontinentia Pigmenti

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder characterized by highly variable abnormalities of the skin, eyes and central nervous system. A mutation of the nuclear factor-κB essential modulator (NEMO) located at Xq28 is believed to play a role in pathogenesis and the mutation occurs mostly in female patients due to fatal consequence of the mutation in males in utero. This study was designed to identify the common NEMO rearrangement in four Korean patients with IP. Deletion of exons 4 to 10 in the NEMO, the most common mutation in IP patients, was detected in all of the patients by the use of long-range PCR analysis. This method enabled us to discriminate between NEMO and pseudogene rearrangements. Furthermore, all of the patients showed skewed XCI patterns, indicating pathogenicity of IP was due to cells carrying the mutant X chromosome. This is the first report of genetically confirmed cases of IP in Korea

Segregation of mtDNA Throughout Human Embryofetal Development: m.3243A > G as a Model System

Mitochondrial DNA (mtDNA) mutations cause a wide range of serious diseases with high transmission risk and maternal inheritance. Tissue heterogeneity of the heteroplasmy rate (“mutant load”) accounts for the wide phenotypic spectrum observed in carriers. Owing to the absence of therapy, couples at risk to transmit such disorders commonly ask for prenatal (PND) or preimplantation diagnosis (PGD). The lack of data regarding heteroplasmy distribution throughout intrauterine development, however, hampers the implementation of such procedures. We tracked the segregation of the m.3243A > G mutation (MT-TL1 gene) responsible for the MELAS syndrome in the developing embryo/fetus, using tissues and cells from eight carrier females, their 38 embryos and 12 fetuses. Mutant mtDNA segregation was found to be governed by random genetic drift, during oogenesis and somatic tissue development. The size of the bottleneck operating for m.3243A > G during oogenesis was shown to be individual-dependent. Comparison with data we achieved for the m.8993T > G mutation (MT-ATP6 gene), responsible for the NARP/Leigh syndrome, indicates that these mutations differentially influence mtDNA segregation during oogenesis, while their impact is similar in developing somatic tissues. These data have major consequences for PND and PGD procedures in mtDNA inherited disorders. Hum Mutat 32:116–125, 2011. © 2010 Wiley-Liss, Inc

Former les professionnels de l’information et de la documentation aux données de la recherche en 45 minutes

Ce document est un outil clef en main pour réaliser, en interne, une formation basique aux données de la recherche en 45 minutes. Elle a été pensée pour des personnels des bibliothèques ou centre de documentation qui sont novices dans le domaine et ont besoin d’être sensibilisés. En effet, dans le monde universitaire, les données sont un élément à connaître, au moins de nom, par tout agent en situation d’accueil dans une bibliothèque. Les parties « l’essentiel » permettent de former des agents aux bases en 45 minutes. La formation peut être étendue à 1h30 en utilisant également les parties « pour développer ». Il est également possible de faire la formation en 45 minutes puis de distribuer la trame pour que les participants lisent les parties « pour développer » ultérieurement

S’autoformer aux données de la recherche : guide à destination des professionnels de l\u27information et de la documentation

Ce guide d\u27autoformation est destiné aux professionnels de l\u27information et de la documentation qui souhaitent faire progresser leurs compétences dans le domaine des données de la recherche, qu\u27ils soient débutants ou confirmés