Loss of function in NSD2 causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome

Tomoko Kawai; Shiori Kinoshita; Yuka Takayama; Eriko Ohnishi; 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

doi:10.1016/j.gimo.2024.101838

Loss of function in NSD2 causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome

Genet Med Open. 2024 Mar 14:2:101838. doi: 10.1016/j.gimo.2024.101838. eCollection 2024.

Authors

Tomoko Kawai¹, Shiori Kinoshita², Yuka Takayama², Eriko Ohnishi², Hiromi Kamura², Kazuaki Kojima², Hiroki Kikuchi², Miho Terao³, Tohru Sugawara⁴, Ohsuke Migita^{2

5}, Masayo Kagami⁶, Tsuyoshi Isojima⁷, Yu Yamaguchi⁸, Keiko Wakui⁹, Hirofumi Ohashi¹⁰, Kenji Shimizu¹⁰, Seiji Mizuno¹¹, Nobuhiko Okamoto¹², Yoshimitsu Fukushima⁹, Fumio Takada¹³, Kenjiro Kosaki¹⁴, Shuji Takada³, Hidenori Akutsu⁴, Kiyoe Ura¹⁵, Kazuhiko Nakabayashi², Kenichiro Hata^{2

16}

Affiliations

¹ Division of Fetal Development, National Research Institute for Child Health and Development, Tokyo, Japan.
² Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
³ Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
⁴ Department of Reproductive Medicine, Center for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan.
⁵ Department of Laboratory Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.
⁶ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
⁷ Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan.
⁸ Gunma Children's Medical Center, Gunma, Japan.
⁹ Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.
¹⁰ Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
¹¹ Department of Pediatrics, Central Hospital, Aichi Developmental Disability Center, Kasugai, Aichi, Japan.
¹² Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan.
¹³ Department of Medical Genetics and Genomics, Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan.
¹⁴ Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
¹⁵ Laboratory of Chromatin Metabolism and Epigenetics, Department of Biology, Chiba University, Chiba, Japan.
¹⁶ Department of Human Molecular Genetics, Gunma University Graduate School of Medicine, Gunma, Japan.

Abstract

Purpose: Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by heterozygous deletions of the distal short arm of chromosome 4 that includes NSD2, reportedly causes specific DNA methylation signatures in peripheral blood cells. However, the genomic loci responsible for these signatures have not been elucidated. The present study aims to define the loci underlying WHS-related DNA methylation signatures and explore the role of NSD2 in these signatures.

Methods: We conducted genome-wide methylation analysis of individuals with WHS or NSD2 variants using an array method. We studied genome-edited knockin mice and induced pluripotent stem cells to explore the function of NSD2 variants.

Results: Three undiagnosed cases with NSD2 variants showed WHS-related DNA methylation signatures. In patient-derived induced pluripotent stem cells and genome-edited knockin mice, these variants cause NSD2 loss of function, respectively. The p.Pro905Leu variant caused decreased Nsd2 protein levels and altered histone H3-lysine 36 dimethylation levels similarly to what was observed in Nsd2 knockout mice. Nsd2 knockout and p.Pro905Leu knockin mice exhibited common DNA methylation changes.

Conclusion: These results revealed that WHS-related DNA methylation signatures are dependent on NSD2 dysfunction and could be useful in identifying NSD2 variants of uncertain significance.

Keywords: DNA methylation signature; Histone H3-lysine 36 dimethylation; NSD2; Peripheral blood cells; Wolf-Hirschhorn syndrome.