ESPEYB20 13. Editors' Choice Section (12 abstracts)
13.8. Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism
Wakeling MN , Owens NDL , Hopkinson JR , Johnson MB , Houghton JAL , Dastamani A , Flaxman CS , Wyatt RC , Hewat TI , Hopkins JJ , Laver TW , van Heugten R , Weedon MN , De Franco E , Patel KA , Ellard S , Morgan NG , Cheesman E , Banerjee I , Hattersley AT , Dunne MJ , International Congenital Hyperinsulinism Consortium , Richardson SJ & Flanagan SE
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK. s.flanagan@exeter.ac.uk Nat Genet 2022;54:1615–1620. https://www.nature.com/articles/s41588-022-01204-x
In Brief: The authors performed whole genome sequencing on 135 patients with congenital hyperinsulinaemia (CHI) who had negative genetic testing for previously known CHI genes. They identified nine different non-coding de novo variants (carried by 14 probands) located in a regulatory region of HK1 intron 2 that co-segregated with disease in families.
Comment: HK1 is a ‘disallowed gene’ in the liver and pancreatic beta cells. This means it is expressed in all other tissues, but it is actively silenced in these two specific tissues. Here, through epigenetic and functional studies, the authors show that the CHI-associated variants cause HK1 to be inappropriately expressed in pancreatic beta cells. This leads to inappropriate insulin secretion during hypoglycemia and the cases presented with severe CHI from birth and were unresponsive to medical treatments.
Hexokinase has very high affinity for glucose, even higher than the glucose affinity of glucokinase, which is the canonical glucose sensor in pancreatic beta cells. The identified pathogenic mutations were located in a non-coding part of HK1 which appears to bind to transcription factors (including FOXA2 and NKX2) needed for the silencing of HK1. Notably, inactivating mutations in FOXA2 are a previously recognised cause of CHI with hypopituitarism. These findings indicate that disallowed genes require ongoing active silencing throughout life.
Finally, the authors note that there are a further 60 genes that are selectively silenced in beta cells. These genes, and their epigenetic regulators, should also be candidates for novel CHI genes.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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