Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission
Research output: Contribution to journal › Article › Research › peer-review
Check for full text(opens in a new window) Library catalogue(opens in a new window) View at Publisher Export Download More... Journal of Medical Genetics Volume 51, Issue 8, 2014, Pages 502-511 Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission (Article) Demars, J.ab, Shmela, M.E.ac, Khan, A.W.ad, Lee, K.S.a, Azzi, S.e, Dehais, P.b, Netchine, I.ef, Rossignol, S.ef, Bouc, Y.L.ef, El-Osta, A.acd, Gicquel, C.ac a Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia b INRA, GenPhySE (Genetique, Physiologie et Systemes d Elevage), Castanet-Tolosan, France c Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia d University of Melbourne, Parkville, Australia e APHP, Armand Trousseau Hopital, Pediatric Endocrinology, INSERM, UMR-S 938, CDR, Saint-Antoine, F-75012, France f Sorbonne Universites, UPMC Univ Paris 06, UMR-S 938 CDR, Saint-Antoine, F-75012, Paris, France View additional affiliations View references (46) Abstract 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 transacting 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.