| First Author | Kawai T | Year | 2024 |
| Journal | Genet Med Open | Volume | 2 |
| Mgi Jnum | J:347725 | Mgi Id | MGI:7627287 |
| Doi | 10.1016/j.gimo.2024.101838 | Citation | Kawai T, et al. (2024) Loss of function in NSD2 causes DNA methylation signature similar to that in Wolf-Hirschhorn syndrome. Genet Med Open 2 |
| abstractText | Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by hetero-zygous deletions of the distal short arm of chromosome 4 that includes NSD2, reportedly causes speciï¬c DNA methylation signatures in peripheral blood cells. However, the genomic loci responsible for these signatures have not been elucidated. The present study aims to deï¬ne 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 signiï¬canc |
