| Autor: |
Tomoko Kawai, Shiori Kinoshita, Yuka Takayama, Eriko Onishi, Hiromi Kamura, Kazuaki Kojima, Hiroki Kikuchi, Miho Terao, Tohru Sugawara, Ohsuke Migita, Masayo Kagami, Tsuyoshi Isojima, Yu Yamaguchi, Keiko Wakui, Hirofumi Ohashi, Kenji Shimizu, Seiji Mizuno, Nobuhiko Okamoto, Yoshimitsu Fukushima, Fumio Takada, Kenjiro Kosaki, Shuji Takada, Hidenori Akutsu, Kiyoe Ura, Kazuhiko Nakabayashi, Kenichiro Hata |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.01.06.522834 |
| Popis: |
PurposeWolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by the hemizygous deletion of the distal short arm of chromosome 4 whereNSD2is, reportedly exhibits specific DNA methylation signatures in peripheral blood cells. However, responsible genomic loci for signatures are unreported. The objective of the study is to define the loci of WHS-related DNA methylation signatures and to explore the role ofNSD2for the signatures.MethodsWe conducted genome-wide methylation analysis of individuals with WHS orNSD2variants using array. We studied genome-edited knock in mice or induced pluripotent stem cells to explore the function ofNSD2variants which are observed in congenital anomaly cases.ResultsThree undiagnosed cases withNSD2variants showed WHS-related DNA methylation signatures. These variants were validated to beNSD2loss-of-function in induced pluripotent stem cells or genome-edited knock-in mice. p.Pro905Leu variant decreased Nsd2 protein levels, and changed Histone H3-Lysine 36 demethylation levels in similar way in the same genomic regions asNsd2knock out mice regulated.Nsd2knock out mice exhibited common DNA methylation changes.ConclusionThese results revealed that WHS-related DNA methylation signatures are dependent onNSD2dysfunction and are useful in diagnosingNSD2variants of unknown significance. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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