A novel pathogenic variant in the glucokinase gene found in two Japanese siblings with maturity-onset diabetes of the young 2.

Glucokinase is a glycolytic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phospate in the first step of the glycolytic pathway. It also regulates the threshold for insulin secretion from pancreatic beta cells by catalyzing the phosphorylation of glucose and plays an important role as a glucose sensor. Pathogenic variants in the glucokinase gene (GCK) cause non-progressive but persistent mild fasting hyperglycemia, also recognized as maturity-onset diabetes of the young 2 (MODY2). This report presents the case of two Japanese siblings with MODY2, who were initially diagnosed with impaired glucose intolerance at 20 and 17 years of age, and later developed diabetes mellitus. They had no history of obesity, were negative for islet-related autoantibodies and their serum C-peptide level were within the normal range. Diabetic complications were not observed. Next-generation sequencing revealed a novel heterozygous variant in GCK (NM_000162.5: c.1088A>G, p.Asp363Gly) in both siblings. This variant has not been reported previously. In silico functional analyses, using SIFT and MutationTaster, suggested that the variant was damaging. To confirm the functional impact of the mutated GCK, the HiBiT-tagged p.Asp363Gly variant and the wild-type GCK were transiently expressed in HEK293T cells. The cells expressing the variant GCK exhibited 79% less bioluminescence, compared to those expressing the wild-type GCK, suggesting that the pathophysiology of the variant was a result of haploinsufficiency.