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Genet Med. 2014 Dec;16(12):903-12. doi: 10.1038/gim.2014.46. Epub 2014 May 8.

Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations.

Author information

1
1] Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan [2] Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
2
Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
3
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
4
Education Center, Asahikawa Medical University, Asahikawa, Japan.
5
Department of Pediatrics, Maternal, Perinatal, and Child Medical Center, Tenshi Hospital, Sapporo, Japan.
6
Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan.
7
Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan.
8
Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
9
Department of Pediatrics, Nippon Medical School, Tokyo, Japan.
10
Division of Medical Genetics, National Center for Child Health and Development, Tokyo, Japan.
11
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
12
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
13
Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
14
Nishikyushu University, Saga, Japan.

Abstract

PURPOSE:

Expression of imprinted genes is regulated by DNA methylation of differentially methylated regions (DMRs). Beckwith-Wiedemann syndrome is an imprinting disorder caused by epimutations of DMRs at 11p15.5. To date, multiple methylation defects have been reported in Beckwith-Wiedemann syndrome patients with epimutations; however, limited numbers of DMRs have been analyzed. The susceptibility of DMRs to aberrant methylation, alteration of gene expression due to aberrant methylation, and causative factors for multiple methylation defects remain undetermined.

METHODS:

Comprehensive methylation analysis with two quantitative methods, matrix-assisted laser desorption/ionization mass spectrometry and bisulfite pyrosequencing, was conducted across 29 DMRs in 54 Beckwith-Wiedemann syndrome patients with epimutations. Allelic expressions of three genes with aberrant methylation were analyzed. All DMRs with aberrant methylation were sequenced.

RESULTS:

Thirty-four percent of KvDMR1-loss of methylation patients and 30% of H19DMR-gain of methylation patients showed multiple methylation defects. Maternally methylated DMRs were susceptible to aberrant hypomethylation in KvDMR1-loss of methylation patients. Biallelic expression of the genes was associated with aberrant methylation. Cis-acting pathological variations were not found in any aberrantly methylated DMR.

CONCLUSION:

Maternally methylated DMRs may be vulnerable to DNA demethylation during the preimplantation stage, when hypomethylation of KvDMR1 occurs, and aberrant methylation of DMRs affects imprinted gene expression. Cis-acting variations of the DMRs are not involved in the multiple methylation defects.

PMID:
24810686
PMCID:
PMC4262761
DOI:
10.1038/gim.2014.46
[Indexed for MEDLINE]
Free PMC Article

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