Gene of the Month – November: HK1
HK1 encodes hexokinase 1, a pivotal enzyme in glycolysis. It is ubiquitously expressed in all tissues except for pancreatic cells and liver cells, where it is silenced. The protein has an extremely high binding affinity to glucose. If HK1 was expressed in these cells, an inappropriately high insulin secretion would occur even at normally low glucose levels. Using whole-genome sequencing, the authors of the study now identified 14 variants in a 42-bp regulatory region of HK1 in patients with severe early-onset and persisting hyperinsulinism. Their analysis of epigenomic data in public repositories showed that this specific region is crucial for cell-specific silencing of the gene. Further investigations revealed that patients carrying the variants showed HK1 expression in pancreatic beta cells.
Congenital hyperinsulinism (CHI) is a disorder characterized by increased insulin secretion, leading to life-threatening hypoglycemic episodes, which, if untreated, might result in severe and irreversible brain damage. Although variants in more than 30 different genes have been described to underlie CHI, the genetic cause remains unknown in up to 50 % of children with persistent CHI.
Wakeling MN, Owens NDL, Hopkinson JR, … Flanagan SE. Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism. Nat Genet. 2022 Nov;54(11):1615-1620. doi: 10.1038/s41588-022-01204-x. Epub 2022 Nov 4.