Functional Characterization of a Novel Heterozygous Mutation in the Glucokinase Gene That Causes MODY2 in Chinese Pedigrees.

Background: Glucokinase (GCK) plays a central role in glucose regulation. The heterozygous mutations of can cause a monogenic form of diabetes, maturity-onset diabetes of the young (MODY) directly. In our study, we aimed to explore the mechanism of the novel mutation p.Ala259Thr leading to glucokinase deficiency and hyperglycemia.

Methods: Thirty early-onset diabetes pedigrees were referred to whole exome sequencing for novel mutations identification. Purified wild-type and mutant GCK proteins were obtained from systems and then subjected to the kinetic and thermal stability analysis to test the effects on GCK activity.

Results: One novel missense mutation p.Ala259Thr was identified and co-segregated with diabetes in a Chinese MODY2 pedigree. The kinetic analysis showed that this mutation result in a decreased affinity and catalytic capability for glucose. The thermal stability analysis also indicated that the mutant protein presented dramatically decreased activity at the same temperature.

Conclusion: Our study firstly identified a novel MODY2 mutation p.Ala259Thr in Chinese diabetes pedigrees. The kinetic and thermal stability analysis confirmed that this mutation caused hyperglycemia through severely damaging the enzyme activities and protein stability.