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PMID: 10393948 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 14 ·1999-07-06 ·Pages 8064-9

Smilinich NJ, Day CD, Fitzpatrick GV, Caldwell GM, Lossie AC, Cooper PR, Smallwood AC, Joyce JA, Schofield PN, Reik W, Nicholls RD, Weksberg R, Driscoll DJ, Maher ER, Shows TB, Higgins MJ

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.

MeSH Terms
Animals Base Sequence Beckwith-Wiedemann Syndrome/genetics Cell Line Chromosome Mapping Chromosomes, Human, Pair 15 DNA/genetics DNA Methylation DNA, Antisense/genetics Dinucleoside Phosphates/analysis Female Genomic Imprinting Humans KCNQ Potassium Channels KCNQ1 Potassium Channel Long QT Syndrome/genetics Lymphocytes/physiology Male Membrane Proteins Mice Molecular Sequence Data Polymerase Chain Reaction Potassium Channels/genetics Potassium Channels, Voltage-Gated Reverse Transcriptase Polymerase Chain Reaction Transcription, Genetic
Chemicals
DNA, Antisense Dinucleoside Phosphates KCNQ Potassium Channels KCNQ1 Potassium Channel KCNQ1 protein, human KCNQ1OT1 long non-coding RNA, human Kcnq1 protein, mouse Membrane Proteins Potassium Channels Potassium Channels, Voltage-Gated cytidylyl-3'-5'-guanosine DNA
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Smilinich N J
Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Day C D
Fitzpatrick G V
Caldwell G M
Lossie A C
Cooper P R
Smallwood A C
Joyce J A
Schofield P N
Reik W
Nicholls R D
Weksberg R
Driscoll D J
Maher E R
Shows T B
Higgins M J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.14.8064
Published
1999-07-06
Pages
8064-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC22188
Subset
IM
Grants
Wellcome Trust · United Kingdom
NCI NIH HHS · CA63333 · United States
Databases
GENBANK
AF119385
External Links
PubMed source DOI: 10.1073/pnas.96.14.8064 PMC Full Text View journal details
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