Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism
dc.contributor.author | Wakeling, MN | |
dc.contributor.author | Owens, NDL | |
dc.contributor.author | Hopkinson, JR | |
dc.contributor.author | Johnson, MB | |
dc.contributor.author | Houghton, JAL | |
dc.contributor.author | Dastamani, A | |
dc.contributor.author | Flaxman, CS | |
dc.contributor.author | Wyatt, RC | |
dc.contributor.author | Hewat, TI | |
dc.contributor.author | Hopkins, JJ | |
dc.contributor.author | Laver, TW | |
dc.contributor.author | van Heugten, R | |
dc.contributor.author | Weedon, MN | |
dc.contributor.author | De Franco, E | |
dc.contributor.author | Patel, KA | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Morgan, NG | |
dc.contributor.author | Cheesman, E | |
dc.contributor.author | Banerjee, I | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Dunne, MJ | |
dc.contributor.author | Richardson, SJ | |
dc.contributor.author | Flanagan, SE | |
dc.date.accessioned | 2023-01-20T09:10:40Z | |
dc.date.issued | 2022-11-04 | |
dc.date.updated | 2022-11-17T13:04:10Z | |
dc.description.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. | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.identifier.citation | Vol. 54, pp. 1615–1620 | en_GB |
dc.identifier.doi | https://doi.org/10.1038/s41588-022-01204-x | |
dc.identifier.grantnumber | 105636/Z/14/Z | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/132283 | |
dc.identifier | ORCID: 0000-0002-6542-9241 (Wakeling, Matthew N) | |
dc.identifier | ORCID: 0000-0002-2151-9923 (Owens, Nick DL) | |
dc.identifier | ORCID: 0000-0002-5330-760X (Hewat, Thomas I) | |
dc.identifier | ORCID: 0000-0001-6399-0089 (Laver, Thomas W) | |
dc.identifier | ORCID: 0000-0002-1437-7891 (De Franco, Elisa) | |
dc.identifier | ORCID: 0000-0003-1537-8113 (Morgan, Noel G) | |
dc.identifier | ORCID: 0000-0001-5620-473X (Hattersley, Andrew T) | |
dc.identifier | ORCID: 0000-0002-1160-6062 (Richardson, Sarah J) | |
dc.identifier | ORCID: 0000-0002-8670-6340 (Flanagan, Sarah E) | |
dc.language.iso | en | en_GB |
dc.publisher | Nature Research | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/36333503 | en_GB |
dc.relation.url | https://www.diabetesgenes.org/current‐research/genetic‐ beta‐cell‐research‐bank/ | en_GB |
dc.rights | © The Author(s), under exclusive licence to Springer Nature America, Inc. 2022. For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. | en_GB |
dc.title | Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2023-01-20T09:10:40Z | |
dc.identifier.issn | 1061-4036 | |
exeter.place-of-publication | United States | |
dc.description | This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this record | en_GB |
dc.description | Data availability statement: All non‐clinical data analysed during this study are included in this published article (and its supplementary information files). Clinical and genotype data is available only through collaboration as this can be used to identify individuals and so cannot be made openly available. Requests for collaboration will be considered following an application to the Genetic Beta Cell Research Bank (https://www.diabetesgenes.org/current‐research/genetic‐ beta‐cell‐research‐bank/). Contact by email should be directed to the Corresponding author. | en_GB |
dc.description | Code availability statement: All code and software versions used specified in Methods. | en_GB |
dc.identifier.eissn | 1546-1718 | |
dc.identifier.journal | Nature Genetics | en_GB |
dc.relation.ispartof | Nat Genet | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2022-09-16 | |
rioxxterms.version | AM | en_GB |
rioxxterms.licenseref.startdate | 2022-11-04 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2023-01-20T09:02:43Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2023-01-20T09:13:04Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2022-11-04 |
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Except where otherwise noted, this item's licence is described as © The Author(s), under exclusive licence to Springer Nature America, Inc. 2022. For the purpose of open access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission.