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.