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Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.

ABSTRACT: AIMS/INTRODUCTION:To investigate the clinical and genetic characteristics of Chinese patients with a phenotype consistent with maturity-onset diabetes of the young type 2 and explore the pathogenic mechanism of their hyperglycemia. MATERIALS AND METHODS:We studied 12 probands and their extended families referred to our center for screening mutations in the glucokinase gene (GCK). Clinical data were collected and genetic analysis was carried out. The recombinant wild-type and mutant glucokinase were generated in Escherichia coli. The kinetic parameters and thermal stability of the enzymes were determined in vitro. RESULTS:In the 12 families, 11 GCK mutations (R43C, T168A, K169N, R191W, Y215X, E221K, M235T, R250H, W257X, G261R and A379E) and one variant of uncertain significance (R275H) were identified. R191W was detected in two unrelated families. Of the 11 GCK mutations, three mutations (c.507G>C, K169N; c.645C>A, Y215X; c.771G>A, W257X; NM_000162.3, NP_000153.1) are novel. Basic kinetics analysis explained the pathogenicity of the five mutants (R43C, K169N, R191W, E221K and A379E), which showed reduced enzyme activity with relative activity indexes between ~0.001 and 0.5 compared with the wild-type (1.0). In addition, the thermal stabilities of these five mutants were also decreased to varying degrees. However, for R250H and R275H, there was no significant difference in the enzyme activity and thermal stability between the mutants and the wild type. CONCLUSIONS:We have identified 11 GCK mutations and one variant of uncertain significance in 12 Chinese families with hyperglycemia. For five GCK mutations (R43C, K169N, R191W, E221K and A379E), the changes in enzyme kinetics and thermostability might be the pathogenic mechanisms by which mutations cause hyperglycemia.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6626954 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.

Wang Zhixin Z Diao Chengming C Liu Yijing Y Li Mingmin M Zheng Jia J Zhang Qian Q Yu Miao M Zhang Huabing H Ping Fan F Li Ming M Xiao Xinhua X

Journal of diabetes investigation 20190201 4

<h4>Aims/introduction</h4>To investigate the clinical and genetic characteristics of Chinese patients with a phenotype consistent with maturity-onset diabetes of the young type 2 and explore the pathogenic mechanism of their hyperglycemia.<h4>Materials and methods</h4>We studied 12 probands and their extended families referred to our center for screening mutations in the glucokinase gene (GCK). Clinical data were collected and genetic analysis was carried out. The recombinant wild-type and mutan ...[more]

PMID: 30592380

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Project description:To characterize the spectrum of CYP4V2 gene mutations in 92 unrelated Chinese probands with Bietti's crystalline dystrophy (BCD) and to describe the molecular and clinical characteristics of four novel CYP4V2 mutations associated with BCD.All study participants underwent a complete ophthalmological examination. Mutational screening of CYP4V2 coding regions and flanking intron sequences was examined via directional Sanger sequencing, with allele separation confirmed by screening other family members. Subsequent in silico analysis of the mutational consequence on protein function was undertaken, with the impact of the novel mutation on pre-mRNA splicing examined via RT-PCR.Fifteen disease-causing variants were identified in 92 probands with BCD, including four novel mutations and eleven previously reported mutations. The most prevalent mutation was c.802_810del17insGC, which was detected in 69 unrelated families, with an allele frequency of 52.7% (97/184). Homozygosity was revealed in 35 unrelated families, and compound heterozygosity was observed in 43 subjects. Four patients harbored four novel variants, with these mutations cosegregated within all affected individuals and were not found in unaffected family members and 100 unrelated controls. Transcriptional analysis of a novel splice mutation revealed altered RNA splicing. In silico analysis predicted that the missense variant, p.Tyr343Asp, disrupted the CYP4V2 surface electrostatic potential distribution and spatial conformation. Among the patients with four novel mutations, genotype did not always correlate with age at onset, disease course, or electroretinogram (ERG) changes, with phenotypic variations even noted within the same genotype.The c.802_810del17insCG mutation was the most common mutation in the 92 Chinese probands with BCD examined. Four novel mutations were identified, contributing to the spectrum of CYP4V2 mutations associated with BCD, with no clear link established between disease phenotype and genotype.

Dataset Information

Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.

Publications

Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia.

Similar Datasets

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