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Lee, Sunwoo; Ochoa, Eguzkine; Badura-Stronka, Magdalena; Donnelly, Deirdre; Lederer, Damien; Lynch, Sally A.; Gardham, Alice; Morton, Jenny; Stewart, Helen; Docquier, France; Rodger, Fay; Martin, Ezequiel; Toribio, Ana; Maher, Eamonn R.; Balasubramanian, Meena

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

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  • Medientyp: E-Artikel
  • Titel: Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome
  • Beteiligte: Lee, Sunwoo; Ochoa, Eguzkine; Badura-Stronka, Magdalena; Donnelly, Deirdre; Lederer, Damien; Lynch, Sally A.; Gardham, Alice; Morton, Jenny; Stewart, Helen; Docquier, France; Rodger, Fay; Martin, Ezequiel; Toribio, Ana; Maher, Eamonn R.; Balasubramanian, Meena
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: European Journal of Human Genetics
  • Sprache: Englisch
  • DOI: 10.1038/s41431-023-01422-9
  • ISSN: 1018-4813; 1476-5438
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p><jats:italic>HNRNPU</jats:italic> encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of <jats:italic>HNRNPU</jats:italic> 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 &gt;2 M CpGs for 7 individuals with a neurodevelopmental disorder associated with <jats:italic>HNRNPU</jats:italic> germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 <jats:italic>HNRNPU</jats:italic>-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for <jats:italic>HNRNPU</jats:italic>-associated neurodevelopmental disorder (NDD) implicates <jats:italic>HNPRNPU</jats:italic>-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 <jats:italic>HNRNPU</jats:italic> variants of uncertain significance. The detection of a methylation episignaure for <jats:italic>HNRNPU</jats:italic>-associated NDD is consistent with a recent report of a methylation episignature for <jats:italic>HNRNPK</jats:italic>-associated NDD.</jats:p>