A Maternally Methylated CpG Island in KvLQT1 Is Associated with an Antisense Paternal Transcript and Loss of Imprinting in Beckwith-Wiedemann Syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 14; pp. 8064 - 8069
• Main Authors: Smilinich, Nancy J., Day, Colleen D., Fitzpatrick, Galina V., Caldwell, Germaine M., Lossie, Amy C., Cooper, P. R., Smallwood, Allan C., Joyce, Johanna A., Schofield, Paul N., Reik, Wolf, Nicholls, Robert D., Weksberg, Rosanna, Driscoll, D. J., Maher, Eamonn R., Shows, Thomas B., Higgins, Michael J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 06.07.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Base Sequence; Beckwith-Wiedemann Syndrome - genetics; Biological Sciences; Cancer; Cell Line; Cells; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 15; Complementary DNA; Deoxyribonucleic acid; Dinucleoside Phosphates - analysis; DNA; DNA - genetics; DNA Methylation; DNA, Antisense - genetics; Female; Genes; Genetic loci; Genetics; Genomic Imprinting; Genomics; Human genetics; Humans; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Long QT Syndrome - genetics; Lymphocytes - physiology; Male; Membrane Proteins; Methylation; Mice; Molecular Sequence Data; Polymerase Chain Reaction; Potassium Channels - genetics; Potassium Channels, Voltage-Gated; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.14.8064

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 KvDMR1 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.