A maternally methylated CpG island in <i>KvLQT1</i> is associated with an antisense paternal transcript and loss of imprinting in Beckwith–Wiedemann syndrome

TLDR

Loss of imprinting at IGF2, often H19‑independent, contributes to Beckwith–Wiedemann syndrome, and imprinting control elements are suspected within the KvLQT1 locus due to BWS‑associated rearrangements. The study proposes that the maternally methylated CpG island KvDMR1 and its antisense RNA KvLQT1‑AS constitute an additional imprinting control element in human 11p15.5 and mouse distal 7. Reverse‑transcription PCR revealed a paternal‑allele‑specific antisense transcript originating from KvDMR1, supporting its role as an imprinting control element. KvDMR1 is evolutionarily conserved and demethylated in a subset of BWS patients with normal H19 methylation, whereas H19 hypermethylation is associated with normal KvDMR1 methylation, indicating distinct epigenetic mechanisms driving IGF2 biallelic expression.

Abstract

Loss of imprinting at IGF2 , generally through an H19 -independent mechanism, is associated with a large percentage of patients with the overgrowth and cancer predisposition condition Beckwith–Wiedemann syndrome (BWS). Imprinting control elements are proposed to exist within the KvLQT1 locus, because multiple BWS-associated chromosome rearrangements disrupt this gene. We have identified an evolutionarily conserved, maternally methylated CpG island ( KvDMR1 ) in an intron of the KvLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KvDMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases of BWS with H19 hypermethylation, methylation at KvDMRl was normal. Thus, inactivation of H19 and hypomethylation at KvDMR1 (or an associated phenomenon) represent distinct epigenetic anomalies associated with biallelic expression of IGF2 . Reverse transcription–PCR analysis of the human and syntenic mouse loci identified the presence of a KvDMR1 -associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KvLQT1 gene. We propose that KvDMR1 and/or its associated antisense RNA ( KvLQT1-AS ) represents an additional imprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains.