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Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ~65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing pathogenicity for missense variants these have only bee...
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To demonstrate the importance of using a combined genetic and functional approach to correctly interpret a genetic test for monogenic diabetes.
We identified three probands with a phenotype consistent with maturity-onset diabetes of the young (MODY) subtype GCK-MODY, in whom two potential pathogenic mutations were identified: [R43H/G68D], [E248 K/I...
Citations
... Later, the variant was reported in several patients and families with MODY or mild hyperglycemia (PMID: 25555642, 35592779, 28012402, and 33477506) [17][18][19][20]. [22]. In a functional study, the p.Arg36Trp mutant protein had similar kinetic properties to the wild-type protein and no effect on thermal stability compared to the wild-type (PMID: 10426385) [23]. ...
Maturity-onset diabetes of the young (MODY) is part of the heterogeneous group of monogenic diabetes (MD) characterized by the non-immune dysfunction of pancreatic β-cells. The diagnosis of MODY still remains a challenge for clinicians, with many cases being misdiagnosed as type 1 or type 2 diabetes mellitus (T1DM/T2DM), and over 80% of cases remaining undiagnosed. With the introduction of modern technologies, important progress has been made in deciphering the molecular mechanisms and heterogeneous etiology of MD, including MODY. The aim of our study was to identify genetic variants associated with MODY in a group of patients with early-onset diabetes/prediabetes in whom a form of MD was clinically suspected. Genetic testing, based on next-generation sequencing (NGS) technology, was carried out either in a targeted manner, using gene panels for monogenic diabetes, or by analyzing the entire exome (whole-exome sequencing). GKC-MODY 2 was the most frequently detected variant, but rare forms of KCNJ11-MODY 13, specifically, HNF4A-MODY 1, were also identified. We have emphasized the importance of genetic testing for early diagnosis, MODY subtype differentiation, and genetic counseling. We presented the genotype–phenotype correlations, especially related to the clinical evolution and personalized therapy, also emphasizing the particularities of each patient in the family context.
... Eight of them (p.Val227Met, p.Ser282Ala, p.Val183Met, p.Met239Thr, p.Arg304Gln, p.Thr229Met, p.Gly163Asp, p.Cys130Ter) have been previously reported in the literature and 4 variants (c.582+4delA, p.Glu436Ter, p.His106ThrfsTer11, p.Asp133Gly) were novel. While the most frequently reported mutation among GCK-MODY mutations are missense mutation, followed by nonsense, frameshift or splice site mutations; pancreatic islet promoter mutations and partial or complete gene deletions are the rare mutations that cause GCK-MODY (20,21). In a study conducted in our country, among 45 GCK mutations, 32 were missense mutations, 5 were nonsense mutations, 6 small deletions/insertions resulting in frameshifts and 2 splice site mutation (18). ...
Objective: The aim of the study was to investigate the clinical and molecular genetic characteristics of children with maturity-onset diabetes of the youth-glucokinase (MODY-GCK, MODY type 2). Method: Medical files of 21 patients with suspected MODY-GCK were reviewed retrospectively. The file records of the clinical findings, laboratory results and the suspected clinical diagnoses of MODY were based on (1) asymptomatic fasting hyperglycemia (glucose ≥100mg/dl, HbA1c < 7.5% (at least twice measurement) 2) parents with a history of diabetes without complications or mild fasting hyperglycemia (100-144mg/dL). Results: The mean age at diagnosis was 11.5±4.3 years (min-max, 1.9-17.2). The mean (SD) fasting blood glucose level was 119.1 (9.8) mg/dL. The mean (SD) fasting C-peptide level was 1.3 (0.7) ng/mL, the mean (SD) insulin level was 5.9 (2.3) IU/ml, and the mean (SD) HbA1c level at diagnosis was 6.2 (0.5) %. Among 12 variants detected in the GCK gene, 8 were missense mutation, 2 were non-sense mutation, 1 of them was splice site and 1 of them was frameshift mutation. Eight of them (p. Val227Met, p. Ser282Ala, p.Val183Met, p.Met239Thr, p.Arg304Gln, p.Thr229Met, p.Gly163Asp, p.Cys130Ter) have been previously reported in the literature and 4 variants (c.582+4delA, p.Glu436Ter, p.His106ThrfsTer11, p.Asp133Gly) were novel. Conclusion: We found similar phenotype characteristic of children with GCK-MODY among the children with different variants. The most common mutation type was missense and followed by nonsense, splice site and frameshift mutations. Detection of the molecular defect in patients with MODY is vital for the implementation of appropriate treatment approaches.
... In this study, all the mutations in the three patients were located in the two structural domains, with one in the small domain and two in the large domain. In this study, R192W, C253Y and G265D are located in close proximity to the glucose binding site, resulting in obstruction of the glucose binding pocket (Valentínová et al., 2012). We believe that enzyme activity of the mutant GCKs is reduced because they do not bind to glucose as effectively as WT-GCK, resulting in an increase in the patients' blood glucose (Zelent et al., 2008). ...
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.
... Glucokinase variant-induced maturity-onset diabetes of the young (GCK-MODY), discovered nearly three decades ago (1)(2)(3)(4), is one of the most common subtypes of MODY (5). Patients with GCK-MODY exhibit mild, stable hyperglycaemia and a very low risk of chronic diabetic complications (6,7). ...
Glucokinase variant-induced maturity-onset diabetes of the young (GCK-MODY) exhibits the unique clinical features of mild fasting hyperglycaemia. However, formal studies of its glucose excursion pattern in daily life in comparison with those with or without other types of diabetes are lacking. We conducted a case-control study including 25 patients with GCK-MODY, 25 A1c-matched, drug naive patients with type 2 diabetes (T2DM) and 25 age-, BMI- and sex-matched subjects with normal glucose tolerance (NGT). All the subjects wore flash glucose monitoring (FGM) sensors for 2 weeks, and glucose readings were masked. Glucose excursion was significantly lower in the GCK-MODY than that in A1c-matched T2DM during the daytime, but was similar during the nighttime. The daytime coefficient of variation [CV] driven by postprandial glucose could separate GCK-MODY from well-controlled T2DM, but the nighttime CV could not. In discriminating between GCK-MODY and T2DM, the area under the curve (AUC) of the CV was 0.875. However, in GCK-MODY and NGT subjects, the CVs were similar at 24h, whereas the other four excursion parameters were significantly higher in GCK-MODY than those in NGT subjects. FGM confirmed the stability and mildness of hyperglycemia in GCK-MODY patients. Postprandial regulation is a key driver of the difference in excursion between GCK-MODY and T2DM.
... The elevated glucose level is present from birth, therefore it is mostly detected incidentally [8,9]. Performing an oral glucose tolerance test (OGTT) can help to distinguish GCK-MODY patients from other types of MODY as in the case of GCK-MODY, patients generally have a small (<3.5 mmol/L) 2 h glucose increment [10]. ...
MODY2 is caused by heterozygous inactivating mutations in the glucokinase (GCK) gene that result in persistent, stable and mild fasting hyperglycaemia (5.6–8.0 mmol/L, glycosylated haemoglobin range of 5.6–7.3%). Patients with GCK mutations usually do not require any drug treatment, except during pregnancy. The GCK gene is considered to be responsible for about 20% of all MODY cases, transcription factors for 67% and other genes for 13% of the cases. Based on our findings, GCK and HNF1A mutations together are responsible for about 90% of the cases in Hungary, this ratio being higher than the 70% reported in the literature. More than 70% of these patients have a mutation in the GCK gene, this means that GCK-MODY is the most prevalent form of MODY in Hungary. In the 91 index patients and their 72 family members examined, we have identified a total of 65 different pathogenic (18) and likely pathogenic (47) GCK mutations of which 28 were novel. In two families, de novo GCK mutations were detected. About 30% of the GCK-MODY patients examined were receiving unnecessary OAD or insulin therapy at the time of requesting their genetic testing, therefore the importance of having a molecular genetic diagnosis can lead to a major improvement in their quality of life.
... In some GCK-MODY mutations, the kinetics of glucokinase is not impaired; rather the stability of the molecule is decreased. Binding with regulatory molecules such as GKRP, bi-functional enzyme PFK2/FBPase-2 (6-phosphofructo-2kinase/fructose-2,6-biphosphatase) may be altered, too (Osbak et al. 2009, Valentínová et al. 2012. ...
Heterozygous inactivating mutations of the glucokinase (GCK) gene are causing GCK-MODY, one of the most common forms of the Maturity Onset Diabetes of the Young (MODY). GCK-MODY is characterized by fasting hyperglycemia without apparent worsening with aging and low risk for chronic vascular complications. Despite the mild clinical course, GCK-MODY could be misdiagnosed as type 1 or type 2 diabetes. In the diagnostic process, the clinical suspicion is often based on the clinical diagnostic criteria for GCK-MODY and should be confirmed by DNA analysis. However, there are several issues in the clinical and also in genetic part that could complicate the diagnostic process. Most of the people with GCK-MODY do not require any pharmacotherapy. The exception are pregnant women with a fetus which did not inherit GCK mutation from the mother. Such a child has accelerated growth, and has increased risk for diabetic foetopathy. In this situation the mother should be treated with substitutional doses of insulin. Therefore, distinguishing GCK-MODY from gestational diabetes in pregnancy is very important. For this purpose, special clinical diagnostic criteria for clinical identification of GCK-MODY in pregnancy are used. This review updates information on GCK-MODY and discusses several currently not solved problems in the clinical diagnostic process, genetics, and treatment of this type of monogenic diabetes.
... Glucokinase catalyzes adenosine triphosphate (ATP)dependent phosphorylation of glucose to produce glucose-6-phosphate, which is the rate-limiting reaction of glucose metabolism. Heterozygous mutations may either reduce enzymatic activity [90][91][92] or promote glucokinase misfolding, aggregation, and degradation [93][94][95], leading to defective glucose sensing in beta cells, elevated threshold for glucose-stimulated insulin secretion, and impaired postprandial hepatic glycogen storage [47,49,58,96]. GCK-MODY is generally non-progressive and characterized by preserved insulin secretion, mild fasting hyperglycemia present from birth, and minor postprandial glucose excursions. ...
Background
The most common type of monogenic diabetes is maturity-onset diabetes of the young (MODY), a clinically and genetically heterogeneous group of endocrine disorders that affect 1–5% of all patients with diabetes mellitus. MODY is characterized by autosomal dominant inheritance but de novo mutations have been reported. Clinical features of MODY include young-onset hyperglycemia, evidence of residual pancreatic function, and lack of beta cell autoimmunity or insulin resistance. Glucose-lowering medications are the main treatment options for MODY. The growing recognition of the clinical and public health significance of MODY by clinicians, researchers, and governments may lead to improved screening and diagnostic practices. Consequently, this review article aims to discuss the epidemiology, pathogenesis, diagnosis, and treatment of MODY based on relevant literature published from 1975 to 2020.
Main body
The estimated prevalence of MODY from European cohorts is 1 per 10,000 in adults and 1 per 23,000 in children. Since little is known about the prevalence of MODY in African, Asian, South American, and Middle Eastern populations, further research in non-European cohorts is needed to help elucidate MODY’s exact prevalence. Currently, 14 distinct subtypes of MODY can be diagnosed through clinical assessment and genetic analysis. Various genetic mutations and disease mechanisms contribute to the pathogenesis of MODY. Management of MODY is subtype-specific and includes diet, oral antidiabetic drugs, or insulin.
Conclusions
Incidence and prevalence estimates for MODY are derived from epidemiologic studies of young people with diabetes who live in Europe, Australia, and North America. Mechanisms involved in the pathogenesis of MODY include defective transcriptional regulation, abnormal metabolic enzymes, protein misfolding, dysfunctional ion channels, or impaired signal transduction. Clinicians should understand the epidemiology and pathogenesis of MODY because such knowledge is crucial for accurate diagnosis, individualized patient management, and screening of family members.
... Numerous genetic variants in the coding region were identified in the common MODY-related genes [7,8]. Heterozygous mutations in the genes encoding the transcription factors lead to β-cell dysfunction and hyperglycemia due to the insufficient insulin response to glucose [1,9,10], while the inactivating heterozygous mutations in the GCK gene shift the set point for glucose stimulated insulin secretion, leading to mild elevated glucose levels [5,11]. Apart from the coding variants, which affect the function of the MODY-related gene products [12,13], variants associated with MODY were also identified in the promoter region of the MODY-related genes [14][15][16][17][18][19][20]. ...
Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by the variants in MODY-related genes. In addition to coding variants, variants in the promoter region of MODY-related genes can cause the disease as well. In this study, we screened the promoter regions of the most common MODY-related genes GCK, HNF1A, HNF4A and HNF1B in our cohort of 29 MODY patients. We identified one genetic variant in the HNF1A gene, a 7 bp insertion c.-154-160insTGGGGGT, and three variants in the GCK gene, −282C>T; −194A>G; 402C>G appearing as set. Chloramphenicol acetyltransferase (CAT) assay was performed to test the effect of the 7 bp insertion and the variant set on the activity of the reporter gene in HepG2 and RIN-5F cell, respectively, where a decreasing trend was observed for both variants. In silico analysis and electrophoretic mobility shift assay showed that the 7 bp insertion did not create the binding site for new transcriptional factors, but gave rise to additional binding sites for the existing ones. Results from our study indicated that the 7 bp insertion in the HNF1A gene could be associated with the patient’s diabetes. As for the GCK variant set, it is probably not associated with diabetes in patients, but it may modify the fasting glucose level by causing small elevation in variant set carriers. We have presented two promoter variants in MODY-related genes. Variant in the HNF1A gene is presumed to be disease-causing and the GCK promoter variant set could be a phenotype modifier.
... M aturity-onset diabetes of the young (MODY) is a rare form of diabetes inherited in an autosomal dominant manner and developing secondary to beta cell dysfunction. MODY accounts for 1.1-4.2% of diabetic children and has a reported prevalence of 2.4-4.6 per 100,000 [1,2]. GCK-MODY (MODY2) and HNF1A-MODY (MODY3) constitute 90% of all MODY cases [3,4]. ...
... Most GCK-MODY mutations consist of missense (65%), nonsense, frameshift or splice site mutations [2]. Rare causes include GCK pancreatic islet promoter mutations [9] and partial or complete gene deletions [10]. ...
Objectives:
To investigate phenotype-genotype correlations in Turkish children with glucokinase gene mutations leading to Maturity-onset diabetes in young (GCK-MODY).
Methods:
Retrospective analysis of 40 patients (16 girls) aged under 18 with GCK-MODY.
Results:
Mean (SD) serum fasting blood glucose level was 6.79 (0.59) mmol/L and the mean (SD) HbA1c level at diagnosis was 6.3% (0.5). Sixteen different variations were detected in the GCK genes of the 40 cases; 33 missense mutations, 6 deletions, and one nonsense mutation. The birthweight of infants with deletion mutation was significantly lower than that of infants with other mutations [2460 (353.66) g vs 2944.11 (502.08) g].
Conclusion:
GCK-MODY patients with deletion mutation inherited from mothers had lower birthweight and higher fasting blood glucose than those with other inherited mutations but similar HbA1c values.
... GK mutations that cause MODY2 or permanent neonatal diabetes mellitus (PNDM) were previously described in terms of their enzyme kinetics, k glcmut , K Gmut , and K mATPmut , by (36,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58) and were first simulated as ...
... We next applied our computational model to examine the role of electrical coupling in the presence of GCK mutations that cause NDM or MODY. We simulated the islet and included altered GK kinetics based upon the biochemical characterization of GCK mutations that cause MODY or PNDM (Table S1; (36,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)). The majority of PNDM GCK mutations (4/5) suppressed [Ca 2þ ] at elevated glucose (Fig. 5 a). ...
Understanding how cell subpopulations in a tissue impact overall system function is challenging. There is extensive heterogeneity among insulin-secreting β-cells within islets of Langerhans, including their insulin secretory response and gene expression profile, and this heterogeneity can be altered in diabetes. Several studies have identified variations in nutrient sensing between β-cells, including glucokinase (GK) levels, mitochondrial function, or expression of genes important for glucose metabolism. Subpopulations of β-cells with defined electrical properties can disproportionately influence islet-wide free-calcium activity ([Ca2+]) and insulin secretion via gap-junction electrical coupling. However, it is poorly understood how subpopulations of β-cells with altered glucose metabolism may impact islet function. To address this, we utilized a multicellular computational model of the islet in which a population of cells deficient in GK activity and glucose metabolism was imposed on the islet or in which β-cells were heterogeneous in glucose metabolism and GK kinetics were altered. This included simulating GK gene (GCK) mutations that cause monogenic diabetes. We combined these approaches with experimental models in which gck was genetically deleted in a population of cells or GK was pharmacologically inhibited. In each case, we modulated gap-junction electrical coupling. Both the simulated islet and the experimental system required 30-50% of the cells to have near-normal glucose metabolism, fewer than cells with normal KATP conductance. Below this number, the islet lacked any glucose-stimulated [Ca2+] elevations. In the absence of electrical coupling, the change in [Ca2+] was more gradual. As such, electrical coupling allows a large minority of cells with normal glucose metabolism to promote glucose-stimulated [Ca2+]. If insufficient numbers of cells are present, which we predict can be caused by a subset of GCK mutations that cause monogenic diabetes, electrical coupling exacerbates [Ca2+] suppression. This demonstrates precisely how metabolically heterogeneous β-cell populations interact to impact islet function.
