Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

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.

Understanding YTHDF2-mediated mRNA degradation by m6A-BERT-Deg

“…HNRNPU is a multifunctional RNA- and DNA-binding protein with a central role in regulating pre-mRNA splicing, mRNA stability, and translation. [ 32 ]. It can enhance gene expression by stabilizing mRNA [ 33 ].…”

2023 in the European Journal of Human Genetics

“…Oexle report epigenetic effects of mosaic variants and hypomorphic variants [35]. EJHG reported emerging DNA methylation signatures for HNRNPU variants [36] and Renpenning syndrome [37].…”