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Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients
Limei Liu1, Yanjun Liu2, Xiaoxu Ge1
1Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China.
Objective:
Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secretion and/or hepatic glycogen synthesis leading to mild chronic hyperglycaemia of maturity onset diabetes of young type 2 (MODY2). However, the effect of naturally occurring GCK mutations on the pathogenesis for MODY2 hyperglycaemia remains largely unclear, especially in the Asian population. The aim of this study is to explore the potential pathogenicity of novel GCK mutations related to MODY2.
Methods:
Genetic screening for GCK mutations from 96 classical MODY families was performed, and structure-function characterization and clinical profile of identified GCK mutations were conducted.
Results:
Five novel (F195S, I211T, V222D, E236G and K458R) and five known (T49N, I159V, R186X, A188T and M381T) mutations were identified and co-segregated with hyperglycaemia in their pedigrees. R186X generates non-functional truncated form and V222D and E236G fully inactivate glucokinase due to severe structure disruptions. The other seven GCK mutations exhibited marked reductions in catalytic efficiency and thermo-stability; notably, the interaction with GKRP was significantly enhanced in I211T, I159V, T49N and K458R, reduced in F195S and M381T, and completely lost with A188T. 31% (17/55) of MODY2 patients showed signs of insulin resistance. Conventional hypoglycaemia treatment did not improve the HbA1C in MODY2 patients when insulin resistance is not present.
Conclusions:
Five novel GCK mutations have been identified in Chinese MODY. The defects in enzymatic activity and protein stability, together with alteration of GKRP binding on GCK mutants may synergistically contribute to the development of MODY2 hyperglycaemia. No treatment should be prescribed to MODY2 patients when insulin resistance is not present.
Insights
Novel glucokinase (GCK) mutations identified in Chinese MODY patients contribute to hyperglycemia. Impaired enzyme function, stability, and GKRP interaction are key pathogenic factors. Treatment should consider insulin resistance.
Area of Science:
- Genetics
- Endocrinology
- Biochemistry
Background:
- Glucokinase (GCK) mutations cause maturity onset diabetes of young type 2 (MODY2), characterized by hyperglycemia due to impaired insulin secretion and hepatic glycogen synthesis.
- The specific impact of naturally occurring GCK mutations on MODY2 pathogenesis, particularly in Asian populations, requires further investigation.
Purpose of the Study:
- To explore the potential pathogenicity of novel GCK mutations associated with MODY2.
- To characterize the structure-function relationship and clinical profiles of identified GCK mutations.
Main Methods:
- Genetic screening of GCK mutations in 96 MODY families.
- Structure-function characterization of identified mutations.
- Clinical profile assessment of affected individuals and their pedigrees.
Main Results:
- Five novel (F195S, I211T, V222D, E236G, K458R) and five known GCK mutations were identified and co-segregated with hyperglycemia.
- Mutations R186X, V222D, and E236G resulted in non-functional or inactivated glucokinase.
- Other mutations showed reduced catalytic efficiency, altered thermo-stability, and significant changes in glucokinase regulatory protein (GKRP) interaction. 31% of patients exhibited insulin resistance.
Conclusions:
- Five novel GCK mutations identified in Chinese MODY patients contribute to hyperglycemia.
- Defects in enzymatic activity, protein stability, and GKRP binding synergistically drive MODY2 pathogenesis.
- Treatment decisions for MODY2 patients should account for the presence or absence of insulin resistance.
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