Department of Preventive Medicine

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Some of publications in Department of Preventive Medicine

Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith–Wiedemann syndrome upon maternal transmission.

Background Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith–Wiedemann (BWS; MIM 130650) and the Silver–Russell (SRS; MIM 180860) syndromes. DNA methylation defects account for 60% of BWS and SRS cases and, in most cases, occur without any identified mutation in a cis-acting regulatory sequence or a trans-acting factor. Methods We investigated whether 11p15 cis-acting sequence variants account for primary DNA methylation defects in patients with SRS and BWS with loss of DNA methylation at ICR1 and ICR2, respectively. Results We identified a 4.5 kb haplotype that, upon maternal transmission, is associated with a risk of ICR2 loss of DNA methylation in patients with BWS. This novel region is located within the second intron of the KCNQ1 gene, 170 kb upstream of the ICR2 imprinting centre and encompasses two CTCF binding sites. We showed that, within the 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motif. Conclusions This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain. arabic 26 English 132
Julie Demars, Mansur Ennuri Moftah Shmela, Abdul Waheed Khan , Kai Syin Lee, Salah Azzi, Patrice Dehais, Irène Netchine, Sylvie Rossignol, Yves Le Bouc, Assam El-Osta, Christine Gicquel(7-2014)
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Système IGF et croissance fœtale.

La croissance fœtale est un processus complexe dépendant de facteurs génétiques, environnementaux, nutritionnels et hormonaux d’origine maternelle, placentaire et fœtale. Le système IGF est l’un des systèmes hormonaux les plus importants pour la régulation de la croissance fœtale et placentaire [1]. Le gène IGF-II est régulé par le phénomène d’empreinte parentale et est exprimé seulement à partir de l’allèle paternel dans la majorité des tissus pendant la vie fœtale. Les gènes soumis à empreinte parentale sont régulés de manière spécifique et sont particulièrement vulnérables aux signaux environnementaux et nutritionnels. La dérégulation d’un groupe de gènes de la région 11p15 soumise à empreinte parentale, incluant le gène IGF-II, est responsable de deux pathologies de croissance fœtale (les syndromes de Silver-Russell, OMIM 180860 et de Wiedemann-Beckwith, OMIM 130650) qui ont une présentation phénotypique opposée. Ces deux syndromes représentent d’excellents modèles de pathologies humaines pour l’étude de la régulation de l’empreinte parentale. arabic 9 English 26
- Demars, J , S. Rossignol, Mansur Ennuri Moftah Shmela, I. Netchine, S. Azzi, A. El-Osta, Y. Le Bouc, C. Gicquel(1-2012)
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Analysis of the IGF2/H19 imprinting control region uncovers new genetic defects, including mutations of OCT-binding sequences, in patients with 11p15 fetal growth disorders.

The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. This methylation-sensitive chromatin insulator works by binding the zincfinger protein CTCF in a parent-specific manner. DNA methylation defects involving the ICR1 H19/IGF2 domain result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith– Wiedemann syndrome (maternal ICR1 gain of methylation in 10% of BWS cases) and a growth retardation disorder, the Silver–Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). Although a few deletions removing part of ICR1 have been described in some familial BWS cases, little information is available regarding the mechanism of ICR1 DNA methylation defects. We investigated the CTCF gene and the ICR1 domain in 21 BWS patients with ICR1 gain of methylation and 16 SRS patients with ICR1 loss of methylation. We identified four constitutional ICR1 genetic defects in BWS patients, including a familial case. Three of those defects are newly identified imprinting defects consisting of small deletions and a single mutation, which do not involve one of the CTCF binding sites. Moreover, two of those defects affect OCT-binding sequences which are suggested to maintain the unmethylated state of the maternal allele. A single-nucleotide variation was identified in a SRS patient. Our data extends the spectrum of constitutive genetic ICR1 abnormalities and suggests that extensive and accurate analysis of ICR1 is required for appropriate genetic counseling in BWS patients with ICR1 gain of methylation.
Demars, J., Mansur Ennuri Moftah Shmela, S. Rossignol, J. Okabe, I. Netchine, S. Azzi, S. Cabrol, C. Le Caignec, A. David , Y. Le Bouc, A. El-Osta , C. Gicquel(9-2010)
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