| Title: | Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism |
| Journal: | Nature Genetics |
| Published: | 4 Nov 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36333503/ |
| DOI: | https://doi.org/10.1038/s41588-022-01204-x |
| URL: | https://ore.exeter.ac.uk/repository/bitstream/10871/132283/2/Wakeling%20%282022%29%20Nat%20Genetics%20PMC%20Merged.pdf |
Publication 8079
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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.23 Authors
- Matthew N. Wakeling
- Nick D. L. Owens
- Jessica R. Hopkinson
- Matthew B. Johnson
- Jayne A. L. Houghton
- Antonia Dastamani
- Christine S. Flaxman
- Rebecca C. Wyatt
- Thomas I. Hewat
- Jasmin J. Hopkins
- Thomas W. Laver
- Rachel van Heugten
- Michael N. Weedon
- Elisa De Franco
- Kashyap A. Patel
- Sian Ellard
- Noel G. Morgan
- Edmund Cheesman
- Indraneel Banerjee
- Andrew T. Hattersley
- Mark J. Dunne
- Sarah J. Richardson
- Sarah E. Flanagan
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