AUTHOR=Jiang Feng , Yan Jing , Zhang Rong , Ma Xiaojing , Bao Yuqian , Gu Yujuan , Hu Cheng 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.803992

DOI=10.3389/fendo.2021.803992

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Glucokinase (GCK) plays a central role in glucose regulation. The heterozygous mutations of <italic>GCK</italic> 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 <italic>GCK</italic> p.Ala259Thr leading to glucokinase deficiency and hyperglycemia.</p></sec><sec><title>Methods</title><p>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 <italic>E.coli</italic> systems and then subjected to the kinetic and thermal stability analysis to test the effects on GCK activity.</p></sec><sec><title>Results</title><p>One novel missense mutation <italic>GCK</italic> 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>