Kawai Tomoko, Kinoshita Shiori, Takayama Yuka, Ohnishi Eriko, Kamura Hiromi, Kojima Kazuaki, Kikuchi Hiroki, Terao Miho, Sugawara Tohru, Migita Ohsuke, Kagami Masayo, Isojima Tsuyoshi, Yamaguchi Yu, Wakui Keiko, Ohashi Hirofumi, Shimizu Kenji, Mizuno Seiji, Okamoto Nobuhiko, Fukushima Yoshimitsu, Takada Fumio, Kosaki Kenjiro, Takada Shuji, Akutsu Hidenori, Ura Kiyoe, Nakabayashi Kazuhiko, Hata Kenichiro
Division of Fetal Development, National Research Institute for Child Health and Development, Tokyo, Japan.
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Genet Med Open. 2024 Mar 14;2:101838. doi: 10.1016/j.gimo.2024.101838. eCollection 2024.
Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by heterozygous deletions of the distal short arm of chromosome 4 that includes , 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 in these signatures.
We conducted genome-wide methylation analysis of individuals with WHS or variants using an array method. We studied genome-edited knockin mice and induced pluripotent stem cells to explore the function of variants.
Three undiagnosed cases with variants showed WHS-related DNA methylation signatures. In patient-derived induced pluripotent stem cells and genome-edited knockin mice, these variants cause 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 knockout mice. knockout and p.Pro905Leu knockin mice exhibited common DNA methylation changes.
These results revealed that WHS-related DNA methylation signatures are dependent on dysfunction and could be useful in identifying variants of uncertain significance.
沃尔夫-赫希霍恩综合征（WHS）是一种由4号染色体短臂远端杂合性缺失引起的邻接基因综合征，据报道，该综合征在外周血细胞中会导致特定的DNA甲基化特征。然而，导致这些特征的基因组位点尚未阐明。本研究旨在确定WHS相关DNA甲基化特征的潜在位点，并探讨[具体基因名称]在这些特征中的作用。
我们使用阵列方法对患有WHS或[具体基因名称]变体的个体进行全基因组甲基化分析。我们研究了基因编辑的敲入小鼠和诱导多能干细胞，以探索[具体基因名称]变体的功能。
3例未确诊的[具体基因名称]变体病例表现出WHS相关的DNA甲基化特征。在患者来源的诱导多能干细胞和基因编辑的敲入小鼠中，这些变体分别导致[具体基因名称]功能丧失。与在[具体基因名称]敲除小鼠中观察到的情况类似，p.Pro905Leu变体导致Nsd2蛋白水平降低，并改变了组蛋白H3赖氨酸36二甲基化水平。[具体基因名称]敲除和p.Pro905Leu敲入小鼠表现出共同的DNA甲基化变化。
这些结果表明，WHS相关的DNA甲基化特征依赖于[具体基因名称]功能障碍，并且可能有助于识别意义不确定的[具体基因名称]变体。
