MODY2 in Asia: analysis of GCK mutations and clinical characteristics

Zhou, Yuan; Wang, Shengnan; Wu, Jing; Dong, Jianjun; Liao, Lin

doi:10.1530/ec-20-0074

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…Indeed, the c.571C>T mutation has been previously identified in individuals (pregnant women, children and adolescent) with MODY2 phenotype of British ( 46 ), Italian ( 47 ), Korean ( 48 ), Belgian ( 49 ), Norwegian ( 50 ), French ( 51 ), Japanese ( 52 ), Brazilian ( 53 ), Chinese ( 45 ) and Tunisian ( 20 ) descent. HGMD Professional has also reported three other amino acid substitutions on the same residue (p.Arg191Leu/Gln/Glu) related to MODY2 ( 47 , 54 , 55 ).…”

Section: Resultsmentioning

confidence: 99%

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

et al. 2021

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Introduction/AimsMaturity-Onset Diabetes of the Young (MODY) is a monogenic non-autoimmune diabetes with 14 different genetic forms. MODY-related mutations are rarely found in the Tunisian population. Here, we explored MODY related genes sequences among seventeen unrelated Tunisian probands qualifying the MODY clinical criteria.Materials and MethodsThe GCK and HNF1A genes were systematically analyzed by direct sequencing in all probands. Then, clinical exome sequencing of 4,813 genes was performed on three unrelated patients. Among them, 130 genes have been reported to be involved in the regulation of glucose metabolism, β-cell development, differentiation and function. All identified variants were analyzed according to their frequencies in the GnomAD database and validated by direct sequencing.ResultsWe identified the previously reported GCK mutation (rs1085307455) in one patient. The clinical features of the MODY2 proband were similar to previous reports. In this study, we revealed rare and novel alterations in GCK (rs780806456) and ABCC8 (rs201499958) genes with uncertain significance. We also found two likely benign alterations in HNF1A (rs1800574) and KLF11 (rs35927125) genes with minor allele frequencies similar to those depicted in public databases. No pathogenic variants have been identified through clinical exome analysis.ConclusionsThe most appropriate patients were selected, following a strict clinical screening approach, for genetic testing. However, the known MODY1-13 genes could not explain most of the Tunisian MODY cases, suggesting the involvement of unidentified genes in the majority of Tunisian affected families.

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Section: Resultsmentioning

confidence: 99%

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

et al. 2021

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“…HbA1c is usually 5.6-7.6%, and fasting glucose is always 5.5-8.5 mmol/L. 75.8% of patients had a level of 2h-postprandial blood sugar below 11.1 mmol/L, and the increments of blood glucose were 2.82 ± 2.03 mmol/L during OGTT (20). Multiple studies showed MODY 2 patients do not require antihyperglycemic medication except during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Maturity Onset Diabetes of the Young of eleven Chinese Children

Ma,

Li,

Liu

et al. 2024

Preprint

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Objective To identify characteristics of eleven children with Maturity Onset Diabetes of the Young (MODY) and reveal the correlation between phenotypes and genotypes for these patients. Methods We collected clinical characteristics including age at diagnosis, gender, clinical symptoms, physical examinations, development histories, laboratory data, and family histories, etc. Next-generation sequencing (NGS) panels were used to reveal the genetic variants for these patients. Results There were 6 male and 5 female patients in this study, age at diagnosis ranged from 5.1 to 14.5 years old, and body mass index (BMI) ranged from 18.1 kg/m2 to 31.6 kg/m2, 6 of them were overweight or obese. 13 mutations were identified from 11 patients in 8 genes: HNF4A and INSR (n = 1), GCK (n = 3), HNF1A (n = 2), PAX4 (n = 1), HNF1B (n = 2), BLK and ABCC8 (n = 1), and ABCC8 (n = 1). 2 patients obtained two mutations those could cause diabetes. Glutamate decarboxylase antibody (GADA) and islet associated antibody (IAA) were positive in the patient with PAX4-MODY. And clinical features of patients with the same MODY type were still different from each other. Insulin was used for patients with MODY 3, MODY 5, MODY 9, and 3 MODY 12 patients in this study. Conclusion Family history of hyperglycemia is not an exact clinical feature of every MODY, genetic sequencing should be applied for more patients with diabetes. The proportions of GCK-MODY were greater than others, and treatment for children with MODY is still challenging.

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“…The c.574C>T (p.R192W) mutation was located in exon 5 and the other two were located in exon 7. Exons 5 and 7 were common mutation sites in 110 Asian patients with GCK-MODY based on a literature search in PubMed, Embase, MEDLINE, Web of Science, CNKI, and Wanfang ( Zhou et al, 2020 ), suggesting that the hotspot mutation sites of GCK in Asian patients might be located in exons 5 and 7, whereas the hotspot mutation sites of GCK in Europe patients might be located in exons 7 and 10 ( Pruhova et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

GCK exonic mutations induce abnormal biochemical activities and result in GCK-MODY

et al. 2023

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Objective: Glucokinase-maturity-onset diabetes of the young (GCK-MODY; MODY2) is a rare genetic disorder caused by mutations in the glucokinase (GCK) gene. It is often under- or misdiagnosed in clinical practice, but correct diagnosis can be facilitated by genetic testing. In this study, we examined the genes of three patients diagnosed with GCK-MODY and tested their biochemical properties, such as protein stability and half-life, to explore the function of the mutant proteins and identify the pathogenic mechanism of GCK-MODY.Methods: Three patients with increased blood glucose levels were diagnosed with MODY2 according to the diagnostic guidelines of GCK-MODY proposed by the International Society for Pediatric and Adolescent Diabetes (ISPAD) in 2018. Next-generation sequencing (whole exome detection) was performed to detect gene mutations. The GCK gene and its mutations were introduced into the pCDNA3.0 and pGEX-4T-1 vectors. Following protein purification, enzyme activity assay, and protein immunoblotting, the enzyme activity of GCK was determined, along with the ubiquitination level of the mutant GCK protein.Results: Genetic testing revealed three mutations in the GCK gene of the three patients, including c.574C>T (p.R192W), c.758G>A (p.C253Y), and c.794G>A (p.G265D). The biochemical characteristics of the protein encoded by wild-type GCK and mutant GCK were different, compared to wild-type GCK, the enzyme activity encoded by the mutant GCK was reduced, suggesting thermal instability of the mutant GST-GCK. The protein stability and expression levels of the mutant GCK were reduced, and the enzyme activity of GCK was negatively correlated with the levels of fasting blood glucose and HbA1c. In addition, ubiquitination of the mutant GCK protein was higher than that of the wild-type, suggesting a higher degradation rate of mutant GCK than WT-GCK.Conclusion:GCK mutations lead to changes in the biochemical characteristics of its encoded proteins. The enzyme activities, protein expression, and protein stability of GCK may be reduced in patients with GCK gene mutations, which further causes glucose metabolism disorders and induces MODY2.

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MODY2 in Asia: analysis of GCK mutations and clinical characteristics

Cited by 9 publications

References 33 publications

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

Maturity Onset Diabetes of the Young of eleven Chinese Children

GCK exonic mutations induce abnormal biochemical activities and result in GCK-MODY

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