Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism.

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

SUBMITTER: Wakeling MN 

PROVIDER: S-EPMC7614032 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature