Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism (Record no. 2136)
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042 ## - AUTHENTICATION CODE | |
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Authentication code | dc |
100 10 - MAIN ENTRY--PERSONAL NAME | |
Personal name | Wakeling, Matthew N. |
Relator term | author |
9 (RLIN) | 2019 |
245 00 - TITLE STATEMENT | |
Title | Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism |
260 ## - PUBLICATION, DISTRIBUTION, ETC. | |
Date of publication, distribution, etc. | 2022-11. |
500 ## - GENERAL NOTE | |
General note | /pmc/articles/PMC7614032/ |
500 ## - GENERAL NOTE | |
General note | /pubmed/36333503 |
520 ## - SUMMARY, ETC. | |
Summary, etc. | Gene 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 ## - TERMS GOVERNING USE AND REPRODUCTION NOTE | |
Terms governing use and reproduction | |
540 ## - TERMS GOVERNING USE AND REPRODUCTION NOTE | |
Terms governing use and reproduction | https://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 ## - LANGUAGE NOTE | |
Language note | en |
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Topical term or geographic name as entry element | Article |
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Genre/form data or focus term | Text |
Source of term | local |
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Personal name | Owens, Nick D. L. |
Relator term | author |
9 (RLIN) | 2020 |
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Personal name | Hopkinson, Jessica R. |
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9 (RLIN) | 2021 |
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Personal name | Johnson, Matthew B. |
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9 (RLIN) | 2022 |
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Personal name | Houghton, Jayne A.L. |
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9 (RLIN) | 2023 |
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Personal name | Dastamani, Antonia |
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Personal name | Flaxman, Christine S. |
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Personal name | Wyatt, Rebecca C. |
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Personal name | Hewat, Thomas I. |
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Personal name | Hopkins, Jasmin J. |
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Personal name | Laver, Thomas W. |
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Personal name | van Heugten, Rachel |
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Personal name | Weedon, Michael N. |
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Personal name | De Franco, Elisa |
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Personal name | Patel, Kashyap A. |
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Personal name | Ellard, Sian |
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9 (RLIN) | 2034 |
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Personal name | Morgan, Noel G. |
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Personal name | Cheesman, Edmund |
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Personal name | Banerjee, Indraneel |
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Personal name | Hattersley, Andrew T. |
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Personal name | Dunne, Mark J. |
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Personal name | Richardson, Sarah J. |
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9 (RLIN) | 2040 |
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Personal name | Flanagan, Sarah E. |
Relator term | author |
9 (RLIN) | 2041 |
786 0# - DATA SOURCE ENTRY | |
Note | Nat Genet |
856 41 - ELECTRONIC LOCATION AND ACCESS | |
Uniform Resource Identifier | <a href="http://dx.doi.org/10.1038/s41588-022-01204-x">http://dx.doi.org/10.1038/s41588-022-01204-x</a> |
Public note | Connect to this object online. |
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