La recherche scientifique

More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/martinederycke.php

Our aim in this study is to acquire more fundamental knowledge of the epigenetic rearrangements in gametes and in-vitro pre-implantation human embryos, particularly about overall DNA methylation patterns, chromatin organisation and the expression and intracellular trafficking of DNA methyltransferases. We also wish to find out whether abnormalities in these processes may be a possible cause of impaired development of some pre-implantation embryos in ART, and whether hormonal stimulation and culture media are implicated.

As well as the overall analysis, the number of specific genes are also studied in this project. Experiments on animal models in underfed conditions which are restricted to the pre-implantation period indicate impaired epigenetic regulation of cardiometabolic genes and DNMT1, the 'maintenance' DNA methyltransferase, which results in altered postnatal phenotypes and an increased risk of cardiovascular disorders. By analogy, assisted reproduction techniques could result in impaired expression of DNMT1 and cardiometabolic loci.

The study considers the extent to which differences arise in the epigenetic status of selected loci (DNMT1, imprinted genes and cardiometabolic genes) after intracytoplasmic sperm injection (ICSI) as compared with spontaneous pregnancy. The epigenetic status of the selected genes is determined on the basis of DNA methylation and expression patterns on DNA and RNA prepared from blood samples. The relative quantification of mRNA transcripts will be carried out using quantitative real-time RT-PCR. Pyrosequencing will be used to quantify DNA methylation. The research results can then be linked to the data from the follow-up study of IVF/ICSI children to study the correlation between expression/methylation patterns in the genes being researched and cardiometabolic markers.

This research will yield an answer to recent questions about the safety of ART and may help to optimise the ART protocols that are used on the basis of the epigenetic stability and safety.

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Funding of the project:
FWO Flanders Researcher Loan 1.5.005.02
Concerted Action 21
Promoters: Prof. A. Van Steirteghem, Prof. I. Liebaers
Project leader: Prof. Dr. K. Sermon (postdoctoral staff member, FWO)

Huntington's disease, fragile X syndrome and Steinert's myotonic dystrophy are three different hereditary disorders. They do, however, have one thing in common: they are caused by the same type of mutation, a so-called dynamic mutation. Genes contain pieces of DNA which consist of repeated sequences of three letters, for example CAG. If these three letters are repeated less than a specific number of times, no problem arises. If, however – depending on the disorder – they are repeated tens or even thousands of times, they impair the correct functioning of the gene in which they occur and give rise to the disease.

The number of repeats of these three letters increases from one generation to the next, so the severity of the condition also increases. It is not clear at precisely what point this increase occurs. Previous research has shown that it occurs reasonably early in fetal development. We are therefore studying embryos whose pre-implantation genetic diagnosis has shown that they carry one of these diseases. In this way we have already been able to demonstrate that in Steinert's myotonic dystrophy, for example, the immature oocyte already contains a larger number of repetitions of the three letters. This type of research is important in order to understand how such mutations arise and how they cause the disease.

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More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/saraseneca.php
 

Mitochondria are the energy powerhouses of the cell. They carry their own genetic material, which is separate from the nuclear genome in human cell nuclei. MtDNA is organised into double-stranded, circular molecules. It codes for individual subunits of the oxidative phosphorylation system or respiratory chain.
If energy delivery to cells does not function correctly, this may be either due to errors in nuclear DNA or errors in mtDNA. One typical feature of mitochondrial dysfunction is that patients suffer from multisystem disorders as a result.
By means of this research the Medical Genetics laboratory wishes to identify and study the mutations underlying dysfunction. The research is taking place in collaboration with laboratories from other hospitals, such as UZ Gent and UZ Leuven.

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Financement du projet
1. FWO Vlaanderen
2. Wetenschappelijk Fonds Willy Gepts
3. Educational Grant from MSD Merck, IBSA, Ferring
Chef du projet: Prof. Dr. Bonduelle
Collaborateurs: Dr. F. Belva, Dr. F. De Schrijver, Dr. S. Desmyttere, Dr. Wet. J. Nekkebroeck, C. Winter, L. Ausloos, A. Buysse, E. Van Moer

Les enfants ART sont des enfants nés d’un traitement de procréation médicalement assistée. En anglais, on parle d’Artificial Reproductive Techniques, d’où ART.

Pourquoi de telles recherches sont-elles nécessaires ?

Au niveau international, l’UZ Brussel joue un rôle de pionnier dans la médecine de la fertilité. Plus d’une fois, nous avons été à la source de nouvelles techniques de PMA, comme l’ICSI (l’injection d’un seul spermatozoïde dans l’ovocyte) et le DPI (diagnostic génétique de l’embryon).
Cette satisfaction médicale et scientifique entraîne toutefois aussi des responsabilités. C’est pourquoi, en guise de contrôle de qualité, l’UZ Brussel a toujours suivi tous les enfants qui étaient nés de l’application des techniques de PMA. Ce suivi est réalisé par le CMG. Cette recherche soutenue depuis des années nous permet de donner une image aussi complète que possible des implications des traitements de fertilité au monde scientifique et aux parents.
Tenir à jour une base de données de suivi n’est pas une obligation légale en Belgique, de même que dans la plupart des autres pays. En Belgique, les centres de fertilité et de génétique sont uniquement obligés de tenir à jour combien d’enfants sont nés des traitements de fertilité, mais pas d’avoir des renseignements quant à leur état de santé.
Pourtant, il va de soi qu’une telle recherche est particulièrement importante. C’est pourquoi le CMG repose pour sa recherche en grande partie sur du sponsoring. Elle obtient une partie du Fonds flamand pour la Recherche Scientifique (Fonds voor Wetenschappelijk Onderzoek) et l’autre partie de firmes du secteur privé.

Quoi et comment ?

Notre centre suit systématiquement les populations d’enfants FIV et ICSI : entre-temps, ils sont plus de 15.000 (jusqu’à juillet 2010). Il en va de même pour les enfants nés de l’application des techniques les plus récentes telles que le DPI et le DPI-SA. Un médecin réalise un examen clinique des enfants à l’âge de deux mois, d’un an et de deux ans. En même temps, il suit leur développement psychomoteur.
Vers l’âge de 5, 8 et 10 ans, des études plus détaillées sur le développement physique, intellectuel et moteur sont menées. En outre, le fonctionnement au sein de la famille est aussi étudié, en collaboration avec le service de Psychologie de la VUB. Cela se fait aussi bien chez des enfants conçus par FIV ou ICSI que chez des enfants conçus naturellement. Ensuite, vers l’âge de 14 ans intervient une étude sur l’évolution de la puberté chez les enfants nés d’une ICSI et chez des enfants contrôle. Et enfin, vers l’âge de 18 as, nous étudions l’héritage éventuel de problèmes de fertilité qui étaient déjà présents chez les parents.
Un certain nombre de ces études sont réalisées en collaboration avec des universités étrangères. De ce fait, les résultats gagnent en valeur sur le plan statistique et d’éventuelles différences entre les centres de PMA peuvent être décelées.

Résultats

Un certain nombre de résultats sont déjà connus.

• Globalement, les différences entre les enfants conçus par ICSI et par FIV sont minimes. Il n’y a pas de risque accru de malformations.
• Il y a par contre un risque accru de grossesses multiples lorsque l’on transfère plus d’un embryon.
• Même dans les grossesses uniques, il y a un risque légèrement augmenté de naissance prématurée et de faible poids de naissance, et ce, dans les deux groupes.
• La carte chromosomique des enfants ICSI montre un risque légèrement accru d’anomalies. Nous pouvons toutefois les dépister tôt dans la grossesse au moyen d’une choriocentèse ou d’une amniocentèse. Ces anomalies sont surtout la conséquence d’une qualité souvent inférieure des spermatozoïdes des hommes pour qui une procédure d’ICSI est la seule possibilité pour devenir le père biologique d’un enfant.
• Les enfants nés après DPI chez qui, au stade embryonnaire à huit cellules, une ou deux cellules ont été prélevées, demeurent bien sûr un groupe qui est suivi de près. Bien qu’à l’échelle mondiale, seuls quelques dizaines de milliers d’enfants sont nés après DPI, les résultats jusqu’à présent sont rassurants. Chez le millier d’enfants nés après être passés dans la clinique DPI de l’UZ Brussel (une collaboration entre le CMG et le CRG), aucun risque accru d’anomalies n’a été constaté.

More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/katrienstouffs.php

In many cases the factors that cause infertility in men are unknown. We now know, however, that in about 10% of men who produce few or no sperm cells, specific parts of the Y chromosome are missing. When DNA is missing this is called a deletion. Deletions occur on the long arm of the Y chromosome and can be divided into three different regions. In each region there are a number of genes that are important for sperm cell development.

In collaboration with the CRG at UZ Brussel, the CMG is carrying out research into genetic causes of infertility in a population of infertile men who have consulted the CRG for fertility treatment. One of the studies incorporates an analysis of the whole genome to identify the presence of abnormalities that may possibly be related to male infertility. A second part of the study then looks at genes whose function is not yet known. This is intended both to determine the normal function of these gene products and also to ascertain whether they are actually important in fertility.

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More information about this project, the principal investigator and the research team on http://emgerege.vub.ac.be/Cardiogenetics.php

Cardiac arrhythmias are among the major causes of morbidity and mortality throughout the world. Although environmental factors play an important part in the development of cardiac arrhythmias, family and population studies have shown that there is also a genetic component. Congenital primary cardiac arrhythmias are caused by defects in the electrical properties of the – structurally normal – heart. This disturbs the coordinated process of opening and closing ion channels and consequently affects the action potentials in the chambers of the heart.
Brugada syndrome is one of the most common cardiac arrhythmias and is inherited in an autosomal dominant pattern with variable penetrance and expression. Using functional analyses we have been able to partly account for the precise mechanism underlying the syndrome. So far, however, genetic studies have not been able to unravel it any further. On the contrary, the handful of genes that have been identified as being implicated offer an explanation for only about 20 to 30% of patients with Brugada syndrome. This means that it is now time to look for other possible causal genes. Thanks to recent revolutionary technological developments in molecular genetics, this is now possible. Not long ago we had to carry out analyses on a gene-by-gene basis, but 'Next-generation sequencing' now allows us to study the many candidate genes simultaneously and in parallel, and we can even include all the coding regions of the entire genome, which are known collectively as the exome.

The impact of the mutations and/or polymorphisms that are found will be correlated with phenotypes. There will also be further in-vitro study of the way in which these are transcribed and expressed as well as their electrophysiological characteristics.
The main benefit to the hospital will come from extrapolating our mutation analysis and in-vitro studies to patient management. We expect the main impacts to be seen in prevention, risk stratification, presymptomatic, prenatal and pre-implantation genetic diagnosis, and also in treatment and stratification of specific groups of patients.

This cardiogenetic study is being conducted in close collaboration with the CHVZ (Centre for Cardiovascular Diseases)

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More information about this project, the principal investigator and the research team on http://rgrg.vub.ac.be/NEGE.php

The development of the cerebral cortex is extremely complex but can nevertheless be divided into different, partly overlapping stages. Interference with one or more of these processes by genetic or external factors may result in malformations of cortical development (MCD). The most prevalent MCDs include lissencephaly/subcortical band heterotopia, polymicrogyria, periventricular heterotopia and focal cortical dysplasia. MCDs are an important cause of mental and motor impairment, severe epilepsy, learning disorders, and autism. Patients require a lifelong multidisciplinary follow-up and treatment is restricted to symptom relief. Most MCD have a genetic etiology but there is extensive heterogeneity both with respect to genotypes and phenotypes. For the large majority of patients with MCDs, the exact etiology of their disorder is still unknown, leaving a considerable number of families not having access to counseling or prenatal diagnosis in order to prevent recurrence.

This project aims at the further identification of genes involved in the regulation of neuronal migration and the study of the functional consequences of mutations in these genes by combining patient-driven molecular genetic studies and comparative genetic research in zebrafish models. This will result in mapping of major pathways involved in cortical development and function.

The project is performed in collaboration with the research groups of Prof. Peter De Witte (Laboratory for Pharmaceutical Biology, KUL - zebrafish models), Peter De Jonghe (VIB Department of Molecular Genetics, UA - NGS), and Ilse Smolders (Center for Neurosciences, VUB - mouse models).

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