Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.
Poznan University of Medical Sciences, Poznań, Poland.
Eur J Hum Genet. 2023 Sep;31(9):1040-1047. doi: 10.1038/s41431-023-01422-9. Epub 2023 Jul 5.
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.
HNRNPU 编码一种多功能 RNA 结合蛋白，在调节前体 mRNA 剪接、mRNA 稳定性和翻译中发挥关键作用。HNRNPU 的异常表达和失调与多种人类疾病有关，包括癌症和神经紊乱。我们应用基于下一代测序的检测方法（EPIC-NGS）对 7 名具有与 HNRNPU 种系致病性失活变异相关的神经发育障碍的个体进行了全基因组甲基化谱分析 >2M CpGs。与健康个体相比，检测到 227 个与 HNRNPU 相关的差异甲基化位置。既鉴定到了高甲基化和低甲基化改变，但是前者占主导地位。HNRNPU 相关神经发育障碍（NDD）的甲基化外显子特征的鉴定表明，HNPRNPU 相关染色质改变与该疾病的发病机制有关，并表明外显子特征谱分析作为 HNRNPU 意义不明致病性变异的预测因子可能具有临床实用性。HNRNPU 相关 NDD 的甲基化外显子特征的检测与最近关于 HNRNPK 相关 NDD 的甲基化外显子特征的报告一致。
