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IGF System and Foetal and Postnatal growth

Principal investigator :
Yves Le Bouc, Ph.D.

Research team :

Irène Netchine, Laurent Kappeler et Sylvie Rossignol.

Identification of novel genetic and imprinting anomalies leading to foetal growth disorders
This team has identified anomalies in the growth axis genes: IGFI, IGFALS, IGF type 1 receptor, IGFII region in cohorts of child born with intra uterine growth retardation (IUGR) , overgrowth syndromes and in patients with post natal growth disorders. Genetic defects within the imprinting center regions controlling the methylation of the 11p15 imprinted region (where is located IGF II) including small copy number variation and mutations of the OCT-binding sequence have been identified. Thus we have participated to decipher 80% of the molecular anomalies of the clinical cases of the Beckwith Wiede- mann overgrowth syndrome (BWS), and more than than 50% of the IUGR Sylver Russell syndrome (SRS) patients.

Identification of multilocus loss of methylation in 11p15 imprin- ting disorders (SWB and SRS) highlighting a probable trans factor anomaly due to genetic or environmental impact
We have shown that about in 25% of the BWS, the imprinting defect is not restricted to the loss of methylation (LOM) of the maternal 11p15 ICR2 region and we have recently shown that a LOM is also identified in 10% of the SRS patients with paternal 11p15 ICR1 LOM , demonstrating thereby that many patients with a given syndrome have multilocus imprinting defects affecting maternal as well paternal alleles. This new evidence demonstrates that these anomalies involve a trans factor involved in the maintenance and/or the establishment of imprinting marks. An abnormally high prevalence of assisted reproductive technologies (ART) among patients with BWS (loss of methylation of the maternal KCNQ1OT allele) as well as SRS (demethylation of the paternal ICR1 allele) have been observed, suggesting that ART may favour imprinting alterations at the imprin- ted loci. Imprinting disorders occurs with a mosaic pattern and could be due to a defect during the early post-fertilization period.

Development of clinical, diagnostic and therapeutic translatio- nal tools
After the identification of these molecular anomalies shown in BWS and SRS we have translated these results for diagnosis tools in the molecular lab of our paediatric trousseau hospital. Then as the quantitative assessment of partial DNA methylation anomalies is a challenge, we have developed a powerful quantitative Allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), and developed test for many imprinting disorders.This rapid technique very accurate, necessitates very small amount of DNA and can be adapted to set up a prenatal diagnosis for imprinting disorders. The genotype –phenotype relation in our large cohorts has allowed us to defined a clinical diagnosis scoring system for SRS for which clinical diagnosis is difficult and we were able to identified in BWS among the various molecular defects that which is predictive of the risk of tumour occurrence.Moreover, we have developed sensitive and specific methods to assay IGF and IGF-Binding Proteins , IGFBP, using in house fusion products (IGF I, IGF II, big IGF II, IGFBP3, and IGFBP6). We have produced a set of protease-resistant muteins of human IGFBP-3 (IGF-TRAP) for which a European patent application has been filed by Inserm-Transfert. Preliminary data have been obtained indicating in vitro as well in vivo anti-proliferative properties. Thus, this modified IGF binding protein could offer, a valuable alternative to receptor-oriented agents

Nutrition, via IGF-I signalling, controls development of the Somatotropic Axis by epigenetic mechanisms.
We have shown in mouse experimentations, that nutrition, via IGF-I signalling, controls the development of the somatotropic axis by epigenetic mechanisms during a very short window in early post natal period. Our results suggest that programming of GH occurs following 2 waves of development. First, IGF signalling decreases GHRH neuropeptide in brain, which induces hypoplasia of GH producing cells in pituitary. Second, the neuropeptide SRIH is permanently increased by 40 days of age onward and maintains GH low. Deciphering mechanisms involved in the permanent inhibition of GH in adulthood, we highlighted that srih is regulated through epigenetic mechanisms (DNA methylation and histone post-transla- tional modification changes). The alteration of this programming by early post natal nutritional restriction is associated with latter-on diseases, notably cardiovascular and metabolic ones.

FOCUS

Foetal growth is a complex process involving multiple environmental, epigenetic and genetic factors. This team focuses on the IGF system implication during normal and pathological development and has identified new causes and mechanisms of foetal growth disorders and achieved some translational research providing new clinical guidelines and molecular tools for patients diagnosis, treatment and follow-up.