Mutations in GCK May Lead to MODY2 by Reducing Glycogen Synthesis

• Published in: Advanced biology 2022-11, Vol.6 (11), p.e2200097-n/a
• Main Authors: Li, Zongyue, Li, Kunxia, Sun, Yan, Jiang, Xiuyun, Liu, Jia, Li, Jingyi, Fang, Li, Li, Guimei, Guan, Qingbo, Xu, Chao
• Format: Article
• Language: English
• Subjects: Adolescent; Child, Preschool; Diabetes Mellitus, Type 2 - genetics; Female; glucokinase; Glucokinase - genetics; Glycogen; glycogen synthesis; Humans; Hyperglycemia - genetics; Kinetics; Male; maturity‐onset diabetes of the young type 2; Mutation; Young Adult
• ISSN: 2701-0198; 2701-0198
• DOI: 10.1002/adbi.202200097

Dysfunction of glucokinase (GCK) caused by mutations in the GCK gene is the main cause of maturity‐onset diabetes of the young type‐2 (MODY2, also known as GCK‐MODY), which is usually present in adolescence or young adulthood. MODY2 is characterized by mild, stable fasting hyperglycemia that presents at birth, usually 5.4–8.3 mmol L−1, and rarely develops complications from diabetes. The treatment of MODY2 prefers a manageable diet rather than the use of insulin. Previous studies have identified GCK mutations only by online software prediction or enzyme kinetic analysis and thermolability assays which are complicated to be conducted. In this study, six mutations in the GCK gene, including four novel mutations and two mutations that are previously reported, are identified. All the six locations are highly conserved according to the sequencing alignment. Moreover, missense mutations are strongly predicted to be pathogenic using online programs. Functional studies show that mutations in GCK mutation do not affect insulin secretion but affect glycogen synthesis. These findings demonstrate that GCK mutations decrease glycogen synthesis, which leads to hyperglycemia in MODY2. Meanwhile, this study provides a new perspective and methods for identifying pathogenic mutations in GCK. Six mutations in the glucokinase (GCK) gene are identified in this study, including four novel and two reported mutations in patients with hyperglycemia. Bioinformatic analysis shows that all mutations in GCK are highly conserved and pathogenic. Experiments in vitro confirm that mutant GCKs lead to (maturity‐onset diabetes of the young 2) by reducing glycogen synthesis instead of affecting insulin secretion.