A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome

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 K nu LQTL1 locus, because multiple BWS-associated chromosome rearrangements disrupt this gene. We have identified an evolutionarily conserved, maternally methylated CpG island (K nu DMR1) in an intron of the K nu LQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of K nu DMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases of BWS with H19 hypermethylation, methylation at K nu DMR1 was normal. Thus, inactivation of H19 and hypomethylation at K nu DMR1 (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 K nu DMR1-associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed K nu LQT1 gene. We propose that K nu DMR1 and/or its associated antisense RNA (K nu LQT1-AS) represents an additional imprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains.