Variants in a regulatory region of the gene HK1 result in the rare disorder of congenital hyperinsulinism. This has been reported in a study published in Nature Genetics. Coding HK1 variants have previously been described to cause diseases such as hemolytic anemia, but they have not been associated with dysglycemia. The study provides an example of non-coding variants in a gene underlying a disease while coding mutations in the same gene do not cause the same condition.

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.