title: The KCNQ1OT1 imprinting control region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases.
abstract: A cluster of imprinted genes at chromosome 11p15.5 is associated with the growth disorders, Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). The cluster is divided into two domains with independent imprinting control regions (ICRs). We describe two maternal 11p15.5 microduplications with contrasting phenotypes. The first is an inverted and in cis duplication of the entire 11p15.5 cluster associated with the maintenance of genomic imprinting and with the SRS phenotype. The second is a 160 kb duplication also inverted and in cis, but resulting in the imprinting alteration of the centromeric domain. It includes the centromeric ICR (ICR2) and the most 5' 20 kb of the non-coding KCNQ1OT1 gene. Its maternal transmission is associated with ICR2 hypomethylation and the BWS phenotype. By excluding epigenetic mosaicism, cell clones analysis indicated that the two closely located ICR2 sequences resulting from the 160 kb duplication carried discordant DNA methylation on the maternal chromosome and supported the hypothesis that the ICR2 sequence is not sufficient for establishing imprinted methylation and some other property, possibly orientation-dependent, is needed. Furthermore, the 1.2 Mb duplication demonstrated that all features are present for correct imprinting at ICR2 when this is duplicated and inverted within the entire cluster. In the individuals maternally inheriting the 160 kb duplication, ICR2 hypomethylation led to the expression of a truncated KCNQ1OT1 transcript and to down-regulation of CDKN1C. We demonstrated by chromatin RNA immunopurification that the KCNQ1OT1 RNA interacts with chromatin through its most 5' 20 kb sequence, providing a mechanism likely mediating the silencing activity of this long non-coding RNA.
authors.affiliation: Dipartimento di Scienze Pediatriche e dell’Adolescenza, Università di Torino, Torino, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Chiesa
authors.forename: Agostina
authors.initials: A
authors.lastname: De Crescenzo
authors.forename: Kankadeb
authors.initials: K
authors.lastname: Mishra
authors.forename: Lucia
authors.initials: L
authors.lastname: Perone
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.forename: Orazio
authors.initials: O
authors.lastname: Palumbo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mussa
authors.forename: Angela
authors.initials: A
authors.lastname: Sparago
authors.forename: Flavia
authors.initials: F
authors.lastname: Cerrato
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lapi
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kanduri
authors.forename: Margherita
authors.initials: M
authors.lastname: Cirillo Silengo
authors.forename: Andrea
authors.initials: A
authors.lastname: Riccio
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
mesh_terms: D000328:Adult; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D020440:Gene Duplication; D020868:Gene Silencing; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D011485:Protein Binding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D056730:Silver-Russell Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; C485621:KCNQ1OT1 long non-coding RNA, human; D024642:Potassium Channels, Voltage-Gated; D022661:RNA, Untranslated