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

被引：14

作者：

Liu, Limei ^{[1
]}

Liu, Yanjun ^{[2
,3
]}

Ge, Xiaoxu ^{[1
]}

Liu, Xipeng ^{[4
]}

Chen, Chen ^{[5
]}

Wang, Yanzhong ^{[6
]}

Li, Ming ^{[1
]}

Yin, Jun ^{[1
]}

Zhang, Juan ^{[1
]}

Chen, Yating ^{[1
]}

Zhang, Rong ^{[1
]}

Jiang, Yanyan ^{[1
]}

Zhao, Weijing ^{[1
]}

Yang, Di ^{[7
]}

Zheng, Taishan ^{[1
]}

Lu, Ming ^{[8
]}

Zhuang, Langen ^{[9
]}

Jiang, Meisheng ^{[10
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Key Clin Ctr Metab Dis, Affiliated Peoples Hosp 6,Shanghai Diabet Inst, Shanghai Key Lab Diabet Mellitus,Dept Endocrinol, 600 Yishan Rd, Shanghai 200233, Peoples R China

[2] Charles R Drew Univ, Dept Internal Med, Los Angeles, CA USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[4] Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, State Key Lab Microbial Metab, 800 Dong Chuan Rd, Shanghai 200240, Peoples R China

[5] Univ Calif Berkeley, Dept Mol Cell & Biol, Berkeley, CA 94720 USA

[6] Kings Coll London, Sch Populat Hlth & Environm Sci, London, England

[7] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA

[8] Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Endocrinol & Metab, Shanghai 200000, Peoples R China

[9] Bengbu Med Coll, Affiliated Hosp 1, Dept Endocrinol, Bengbu 233004, Anhui, Peoples R China

[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

来源：

METABOLISM-CLINICAL AND EXPERIMENTAL | 2018年 / 89卷

基金：

中国国家自然科学基金;

关键词：

Glucokinase (GCK); Mutation; MODY2; Glucokinase regulatory protein (GKRP); Chinese; GLUCOKINASE MUTATIONS; CLINICAL CHARACTERISTICS; YOUNG; GENE; HYPERGLYCEMIA; HYPOGLYCEMIA; PREVALENCE; MECHANISMS; OBESITY; PROFILE;

D O I：

10.1016/j.metabol.2018.09.004

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 A1881. 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. (C) 2018 Elsevier Inc. All rights reserved.

引用

页码：8 / 17

页数：10

共 44 条

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