Abstract
HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for >2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.
| Original language | English |
|---|---|
| Pages (from-to) | 1040-1047 |
| Number of pages | 8 |
| Journal | European Journal of Human Genetics |
| Volume | 31 |
| Issue number | 9 |
| Early online date | 5 Jul 2023 |
| DOIs | |
| Publication status | Published - Sept 2023 |
Bibliographical note
Copyright © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.Funding
MB is funded by Medical Research Council (MR/V037307/1) academic salary support. The HNRNPU research is funded by the Sheffield Children’s Hospital Charity (CA21001). This research was co-funded by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014 and NIHR203312) and Rosetrees Trust (to EO, SL and ERM). The University of Cambridge has received salary support (ERM) from the NHS in the East of England through the Clinical Academic Reserve. The authors thank the patients and families for their participation in this study. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. The authors also acknowledge support from the NIHR UK Rare Genetic Disease Research Consortium.
| Funders | Funder number |
|---|---|
| Sheffield Children’s Hospital Charity | CA21001 |
| Medical Research Council | MR/V037307/1 |
| National Institute for Health and Care Research |
Keywords
- Humans
- DNA Methylation
- Epigenome
- Germ Cells
- Germ-Line Mutation
- Neurodevelopmental Disorders/genetics