King's College London

Research portal

Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients

Research output: Contribution to journalArticle

Limei Liu, Yanjun Liu, Xiaoxu Ge, Xipeng Liu, Chen Chen, Yanzhong Wang, Ming Li, Jun Yin, Juan Zhang, Yating Chen, Rong Zhang, Yanyan Jiang, Weijing Zhao, Di Yang, Taishan Zheng, Ming Lu, Langen Zhuang, Meisheng Jiang

Original languageEnglish
Pages (from-to)8-17
Number of pages10
JournalMetabolism: clinical and experimental
Volume89
Early online date23 Sep 2018
DOIs
Publication statusPublished - Dec 2018

King's Authors

Abstract

Objective
Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secretion and/or hepatic glycogen synthesis leading to mild chronic hyperglycemia of maturity onset diabetes of young type 2 (MODY2). However, the effect of naturally occurring GCK mutations on the pathogenesis for MODY2 hyperglycemia 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 (T49 N, I159V, R186X, A188T and M381 T) 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, T49 N and K458R, reduced in F195S and M381 T, and completely lost with A188T. 31% (17/55) of MODY2 patients showed signs of insulin resistance. Conventional hypoglycemia 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.

View graph of relations

© 2018 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454