JOM KITA KE POLITEKNIK

Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism (Record no. 1980)

MARC details
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Personal name Wakeling, Matthew N.
Relator term author
9 (RLIN) 2019
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Title Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism
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Date of publication, distribution, etc. 2022-11.
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General note /pmc/articles/PMC7614032/
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General note /pubmed/36333503
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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.
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Terms governing use and reproduction
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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.
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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
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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.
Relator term author
9 (RLIN) 2021
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Personal name Johnson, Matthew B.
Relator term author
9 (RLIN) 2022
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Personal name Houghton, Jayne A.L.
Relator term author
9 (RLIN) 2023
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Dastamani, Antonia
Relator term author
9 (RLIN) 2024
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Flaxman, Christine S.
Relator term author
9 (RLIN) 2025
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Wyatt, Rebecca C.
Relator term author
9 (RLIN) 2026
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Hewat, Thomas I.
Relator term author
9 (RLIN) 2027
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Hopkins, Jasmin J.
Relator term author
9 (RLIN) 2028
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Laver, Thomas W.
Relator term author
9 (RLIN) 2029
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name van Heugten, Rachel
Relator term author
9 (RLIN) 2030
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Weedon, Michael N.
Relator term author
9 (RLIN) 2031
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name De Franco, Elisa
Relator term author
9 (RLIN) 2032
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Patel, Kashyap A.
Relator term author
9 (RLIN) 2033
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Ellard, Sian
Relator term author
9 (RLIN) 2034
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Morgan, Noel G.
Relator term author
9 (RLIN) 2035
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Cheesman, Edmund
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9 (RLIN) 2036
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Banerjee, Indraneel
Relator term author
9 (RLIN) 2037
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Hattersley, Andrew T.
Relator term author
9 (RLIN) 2038
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Dunne, Mark J.
Relator term author
9 (RLIN) 2039
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Richardson, Sarah J.
Relator term author
9 (RLIN) 2040
700 10 - ADDED ENTRY--PERSONAL NAME
Personal name Flanagan, Sarah E.
Relator term author
9 (RLIN) 2041
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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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