| 000 | 02997 am a22004693u 4500 | ||
|---|---|---|---|
| 042 | _adc | ||
| 100 | 1 | 0 |
_aWakeling, Matthew N. _eauthor _92019 |
| 700 | 1 | 0 |
_aOwens, Nick D. L. _eauthor _92020 |
| 700 | 1 | 0 |
_aHopkinson, Jessica R. _eauthor _92021 |
| 700 | 1 | 0 |
_aJohnson, Matthew B. _eauthor _92022 |
| 700 | 1 | 0 |
_aHoughton, Jayne A.L. _eauthor _92023 |
| 700 | 1 | 0 |
_aDastamani, Antonia _eauthor _92024 |
| 700 | 1 | 0 |
_aFlaxman, Christine S. _eauthor _92025 |
| 700 | 1 | 0 |
_aWyatt, Rebecca C. _eauthor _92026 |
| 700 | 1 | 0 |
_aHewat, Thomas I. _eauthor _92027 |
| 700 | 1 | 0 |
_aHopkins, Jasmin J. _eauthor _92028 |
| 700 | 1 | 0 |
_aLaver, Thomas W. _eauthor _92029 |
| 700 | 1 | 0 |
_avan Heugten, Rachel _eauthor _92030 |
| 700 | 1 | 0 |
_aWeedon, Michael N. _eauthor _92031 |
| 700 | 1 | 0 |
_aDe Franco, Elisa _eauthor _92032 |
| 700 | 1 | 0 |
_aPatel, Kashyap A. _eauthor _92033 |
| 700 | 1 | 0 |
_aEllard, Sian _eauthor _92034 |
| 700 | 1 | 0 |
_aMorgan, Noel G. _eauthor _92035 |
| 700 | 1 | 0 |
_aCheesman, Edmund _eauthor _92036 |
| 700 | 1 | 0 |
_aBanerjee, Indraneel _eauthor _92037 |
| 700 | 1 | 0 |
_aHattersley, Andrew T. _eauthor _92038 |
| 700 | 1 | 0 |
_aDunne, Mark J. _eauthor _92039 |
| 700 | 1 | 0 |
_aRichardson, Sarah J. _eauthor _92040 |
| 700 | 1 | 0 |
_aFlanagan, Sarah E. _eauthor _92041 |
| 245 | 0 | 0 | _aNon-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism |
| 260 | _c2022-11. | ||
| 500 | _a/pmc/articles/PMC7614032/ | ||
| 500 | _a/pubmed/36333503 | ||
| 520 | _aGene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function(1). This silencing is largely controlled by non-coding elements and their disruption might cause human disease(2). 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 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1). HK1 is widely expressed across all tissues except for 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. | ||
| 540 | _a | ||
| 540 | _ahttps://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license. | ||
| 546 | _aen | ||
| 690 | _aArticle | ||
| 655 | 7 |
_aText _2local |
|
| 786 | 0 | _nNat Genet | |
| 856 | 4 | 1 |
_uhttp://dx.doi.org/10.1038/s41588-022-01204-x _zConnect to this object online. |
| 999 |
_c2136 _d2136 |
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