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• W4308296710 abstract "Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function1. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease2. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a ‘disallowed gene’ in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene. De novo variants altering a conserved region in an intron of HK1 cause congenital hyperinsulinism by perturbing the activity of a putative cell type-specific regulatory element." @default.
• W4308296710 created "2022-11-10" @default.
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• W4308296710 date "2022-11-01" @default.
• W4308296710 modified "2023-10-17" @default.
• W4308296710 title "Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism" @default.
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• W4308296710 doi "https://doi.org/10.1038/s41588-022-01204-x" @default.
• W4308296710 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36333503" @default.
• W4308296710 hasPublicationYear "2022" @default.
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