title: Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission.
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 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.
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia INRA, GenPhySE (Génétique, Physiologie et Systèmes d'Elevage), Castanet-Tolosan, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Demars
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Mansur Ennuri
authors.initials: ME
authors.lastname: Shmela
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia University of Melbourne, Parkville, Australia.
authors.forename: Abdul Waheed
authors.initials: AW
authors.lastname: Khan
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Kai Syin
authors.initials: KS
authors.lastname: Lee
authors.affiliation: APHP, Armand Trousseau Hôpital, Pediatric Endocrinology, INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.
authors.forename: Salah
authors.initials: S
authors.lastname: Azzi
authors.affiliation: INRA, GenPhySE (Génétique, Physiologie et Systèmes d'Elevage), Castanet-Tolosan, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Dehais
authors.affiliation: APHP, Armand Trousseau Hôpital, Pediatric Endocrinology, INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Netchine
authors.affiliation: APHP, Armand Trousseau Hôpital, Pediatric Endocrinology, INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rossignol
authors.affiliation: APHP, Armand Trousseau Hôpital, Pediatric Endocrinology, INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia University of Melbourne, Parkville, Australia.
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.affiliation: Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Gicquel
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D000076246:CCCTC-Binding Factor; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D012097:Repressor Proteins
keywords: Imprinting; Molecular genetics