Comprehensive and Quantitative Multilocus Methylation Analysis Reveals the Susceptibility of Specific Imprinted Differentially Methylated Regions to Aberrant Methylation in Beckwith-Wiedemann Syndrome with Epimutations

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2014 May 10

PMID 24810686

Citations 18

Authors

Toshiyuki Maeda

Ken Higashimoto

Kosuke Jozaki

Hitomi Yatsuki

Kazuhiko Nakabayashi

Yoshio Makita

Hidefumi Tonoki

Nobuhiko Okamoto

Fumio Takada

Hirofumi Ohashi

Makoto Migita

Rika Kosaki

Keiko Matsubara

Tsutomu Ogata

Muneaki Matsuo

Yuhei Hamasaki

Yasufumi Ohtsuka

Kenichi Nishioka

Keiichiro Joh

Tsunehiro Mukai

Kenichiro Hata

Hidenobu Soejima

Affiliations

Soon will be listed here.

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.

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