A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young.
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ABSTRACT:
SUBMITTER: Graff SM
PROVIDER: S-EPMC8410089 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Maturity Onset Diabetes of Young (MODY) is a monogenic and autosomal dominant form of diabetes mellitus with onset of the disease often before 25 years of age. It is due to dysfunction of pancreatic beta cells characterised by non-ketotic diabetes and absence of pancreatic auto-antibodies. It is frequently mistaken for type 1 or type 2 diabetes mellitus. Diagnosis of MODY is important as the GCK subtype has better prognosis and may not require any treatment. Subtypes HNF1A and HNF4A are sensitive to sulfonylureas, however diabetes complications are common if not treated early. Moreover, there is genetic implication for the patient and family. Rare MODY subtypes can be associated with pancreatic and renal anomalies as well as exocrine dysfunction of the pancreas. So far there are six widely accepted subtypes of MODY described but the list has grown to nine. Although the majority of diabetes mellitus in youth remains type 1 and the incidence of type 2 is rising, MODY should be considered in patients with non-ketotic diabetes at presentation, and in patients with a strong family history of diabetes mellitus without pancreatic auto-antibodies. Furthermore the diagnosis must be confirmed by molecular studies. With advancement in genomic technology, rapid screening for MODY mutations will become readily available in the future.
| S-EPMC2702215 | biostudies-other
Project description:Maturity onset diabetes of the young (MODY) is a congenital form of diabetes characterized by onset at a young age and a primary defect in pancreatic-?-cell function. Currently, 14 subtypes of MODY are known, and each is associated with mutations in a specific gene: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1. The most common subtypes of MODY are associated with mutations in the genes GCK, HNF1A, HNF4A, and HNF1B. Among them, up to 70% of cases are caused by mutations in GCK and HNF1A. Here, an analysis of 14 MODY genes was performed in 178 patients with a MODY phenotype in Western Siberia. Multiplex ligation-dependent probe amplification analysis of DNA samples from 50 randomly selected patients without detectable mutations did not reveal large rearrangements in the MODY genes. In 38 patients (37% males) among the 178 subjects, mutations were identified in HNF4A, GCK, HNF1A, and ABCC8. We identified novel potentially causative mutations p.Lys142*, Leu146Val, Ala173Glnfs*30, Val181Asp, Gly261Ala, IVS7 c.864 -1G>T, Cys371*, and Glu443Lys in GCK and Ser6Arg, IVS 2 c.526 +1 G>T, IVS3 c.713 +2 T>A, and Arg238Lys in HNF1A.
| S-EPMC7831070 | biostudies-literature
Project description:BACKGROUND:Maturity onset diabetes of the young type 2 (MODY) is an inherited disorder due to mutations in glucokinase (GCK) gene, which lead to mild fasting hyperglycemia. CASE PRESENTATION:Herein an otherwise healthy 9-year old boy with hyperglycemia is presented in whom the diagnosis of MODY2 was suspected. Genetic studies showed heterozygous inactivating GCK gene mutation in exon 8 (c.1010delA) in this patient. The same mutation was found in his father as well. The patient received some dietary advices without any medication. CONCLUSION:The identification of GCK mutation and diagnosis of MODY2 helps the clinicians to predict the disease course, prognosis and to exclude other types of diabetes.
| S-EPMC3663319 | biostudies-literature
Project description: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 been performed for <10% of mutations. The aim of this study was to determine the minimum prevalence of GCK-MODY amongst diabetic subjects in Slovakia by sequencing GCK in 100 Slovakian probands with a phenotype consistent with GCK-MODY and to explore the pathogenicity of identified variants through family and functional studies. Twenty-two mutations were identified in 36 families (17 missense) of which 7 (I110N, V200A, N204D, G258R, F419S, c.580-2A>C, c.1113-1114delGC) were novel. Parental DNA was available for 22 probands (covering 14/22 mutations) and co-segregation established in all cases. Bioinformatic analysis predicted all missense mutations to be damaging. Nine (I110N, V200A, N204D, G223S, G258R, F419S, V244G, L315H, I436N) mutations were functionally evaluated. Basic kinetic analysis explained pathogenicity for 7 mutants which showed reduced glucokinase activity with relative activity indices (RAI) between 0.6 to <0.001 compared to wild-type GCK (1.0). For the remaining 2 mutants additional molecular mechanisms were investigated. Differences in glucokinase regulatory protein (GKRP) -mediated-inhibition of GCK were observed for both L315H & I436N when compared to wild type (IC(50) 14.6±0.1 mM & 20.3±1.6 mM vs.13.3±0.1 mM respectively [p<0.03]). Protein instability as assessed by thermal lability studies demonstrated that both L315H and I436N show marked thermal instability compared to wild-type GCK (RAI at 55°C 8.8±0.8% & 3.1±0.4% vs. 42.5±3.9% respectively [p<0.001]). The minimum prevalence of GCK-MODY amongst Slovakian patients with diabetes was 0.03%. In conclusion, we have identified 22 GCK mutations in 36 Slovakian probands and demonstrate that combining family, bioinformatic and functional studies can aid the interpretation of variants identified by molecular diagnostic screening.
| S-EPMC3321013 | biostudies-literature
Project description:BackgroundThe molecular basis of the Turkish population with suspected maturity-onset diabetes of the young (MODY) has not been identified. This is the first study to investigate the association between HNF1A-gene single-nucleotide polymorphisms (SNPs) and having early-onset, MODY-like diabetes mellitus in the Turkish population.MethodsAll diabetic patients (N = 565) who presented to our clinic between 2012 and 2015 with a clinical suspicion of MODY were included in the study. Analysis of HNF1A, HNFB, HNF4A, GCK gene mutations was performed using real-time polymerase chain reaction sequencing. After genetic analysis, diabetics (n = 46) with HNF1A, HNF1B, HNF4A, GCK gene mutations (diagnosed as MODY) and diabetics (n = 30) with HNF1B, HNF4A, GCK gene SNPs were excluded. Patients with early-onset, MODY-like diabetes (n = 486) and non-diabetic controls (n = 263) were included. Genetic analyses for the HNF1A gene p.S487 N (rs2464196), p.A98V (rs1800574) and p.I27L (rs1169288) SNPs were performed using Sanger-based DNA sequencing among the control group.Resultsp.S487 N and p.A98V was similar between the diabetics and controls in dominant and recessive models with no association (each, p > 0.05). p.I27L GT/TT carriers (GT/TT vs. GG, OR = 1.68, 95% CI: [1. 21-2.13]; p = 0.035) and p.I27L TT carriers had increased risk of having MODY-like diabetes (GT/GG vs. TT, OR = 1.56, 95% CI: [1. 14-2.57]; p = 0.048). Family inheritance of diabetes was significantly more common in patients with the p.I27L TT genotype. The p.I27L SNP was modestly associated with having diabetes after adjusting for body mass index and age (β = 1.45, 95% CI: [1. 2-4.2]; p = 0.036).ConclusionsThe HNF1A gene p.I27L SNP was modestly associated with having early-onset, MODY-like diabetes in the Turkish population. HNF1A gene p.I27L SNP might contribute to age at diabetes diagnosis and family inheritance.
| S-EPMC6528345 | biostudies-literature
Project description:AimTo investigate the prevalence of variants within selected maturity-onset diabetes of the young (MODY)-genes among Algerian patients initially diagnosed with type 1 diabetes (T1D) or type 2 diabetes (T2D), yet presenting with a MODY-like phenotype.MethodsEight unrelated patients with early-onset diabetes (before 30 years) and six relatives with diabetes were examined by targeted re-sequencing for variants in genes known to be involved in MODY (HNF1A, GCK, HNF4A, HNF1B, INS, ABCC8, KCNJ1). Clinical data for probands were retrieved from hospital records.ResultsA total of 12 variants were identified, of which three were classified as pathogenic and one as a variant of uncertain clinical significance (VUS). Two of the pathogenic variants were found in GCK (p.Gly261Arg and p.Met210Lys, respectively) in one proband each and the remaining pathogenic variant was found in HNF1B (p.Gly76Cys) in a proband also carrying the VUS in HNF1A (p.Thr156Met).ConclusionVariants in known MODY-genes can be the cause of early-onset diabetes in Algerians diagnosed with T1D or T2D among patients presenting with a MODY-like phenotype; thus, genetic screening should be considered.
| S-EPMC7733395 | biostudies-literature
Project description:Purpose: The goal of this study is to conduct and compare NGS-derived transcriptome profiling (RNA-seq) of progenitor lines derived from 3 HNF1A-WT and 3 HNF1A-CRISPR (with p291fsinsC mutation) human induced pluripotent stem cell lines. Methods: mRNA profiles of WT/CRISPR pancreatic progenitor cells obtained after in-vitro differentiation for 14 days were generated by deep sequencing using Illumina HiSeq 2000 sequencer. The raw RNA-sequencing read files were processed using the research computing facility at King’s College London, Rosalind (https://rosalind.kcl.ac.uk). RNA-sequencing reads were trimmed from adapters using Trimmomatic/0.39 (Bolger et al., 2014) and quality control was done using FASTQC/0.11.8 (Andrews, 2010). Reads were mapped to a concatenated genome sequence of human GRCh38/hg38 using STAR/2.4.2 (Dobin and Gingeras, 2015). Transcript abundance was measured using featureCount in Subread package (Liao et al., 2013). Results: The DESeq2 package (Love et al., 2014) was used to identify differentially expressed genes. We found 919 significantly regulated genes (271 upregulated, 648 downregulated), with 16 HNF1B targets and 19 HNF1A specific targets within the significantly dysregulated genes when comparing HNF1A-CRISPR versus HNF1A-WT groups. Conclusions: HNF1A and HNF1B gene targets are disturbed by the p291fsinsC mutation engineered in the CRISPR-Cas9 lines.
2022-01-25 | GSE166822 | GEO
Project description:Hepatocyte nuclear factor 4? (HNF4A) is a member of the nuclear receptor family of ligand-activated transcription factors. HNF4A mutations cause hyperinsulinaemic hypoglycaemia in early life and maturity-onset diabetes of the young. Regular screening of HNF4A mutation carriers using the oral glucose tolerance test has been recommended to diagnose diabetes mellitus at an early stage. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are incretin hormones, responsible for up to 70% of the secreted insulin after a meal in healthy individuals. We describe, for the first time, gradual alteration of glucose homeostasis in a patient with HNF4A mutation after resolution of hyperinsulinaemic hypoglycaemia, on serial oral glucose tolerance testing. We also measured the incretin response to a mixed meal in our patient.Our patient was born with macrosomia and developed hyperinsulinaemic hypoglycaemia in the neonatal period. Molecular genetic analysis confirmed HNF4A mutation (p.M116I, c.317G>A) as an underlying cause of hyperinsulinaemic hypoglycaemia. Serial oral glucose tolerance testing, after the resolution of hyperinsulinaemic hypoglycaemia, confirmed the diagnosis of maturity-onset diabetes of the young at the age of 10 years. Interestingly, the intravenous glucose tolerance test revealed normal glucose disappearance rate and first-phase insulin secretion. Incretin hormones showed a suboptimal rise in response to the mixed meal, potentially explaining the discrepancy between the oral glucose tolerance test and the intravenous glucose tolerance test.Maturity-onset diabetes of the young can develop as early as the first decade of life in persons with an HNF4A mutation. Impaired incretin response might be contributory in the early stages of HNF4A maturity-onset diabetes of the young.
| S-EPMC4305198 | biostudies-literature
Project description:Aims/introductionGiven that mutations related to maturity-onset diabetes of the young (MODY) are rarely found in Chinese populations, we aim to characterize the mutation spectrum of MODY pedigrees.Materials and methodsMaturity-onset diabetes of the young candidate gene- or exome-targeted capture sequencing was carried out in 76 probands from unrelated families fulfilling the clinical diagnostic criteria for MODY. MAF <0.01 in the GnomAD or ExAC database was used to filter significant variants. Sanger sequencing was then carried out to validate findings. Function prediction by SIFT, PolyPhen-2 and PROVEAN or CADD was carried out in missense mutations.ResultsA total of 32 mutations in six genes were identified in 31 families, accounting for 40.79% of the potential MODY families. The MODY subtype detection rate was 18.42% for GCK, 15.79% for HNF1A, 2.63% for HNF4A, and 1.32% for KLF11, PAX4 and NEUROG3. Seven nonsense/frameshift mutations and four missense mutations with damaging prediction were newly identified novel mutations. The clinical features of MODY2, MODY3/1 and MODYX are similar to previous reports. Clinical phenotype of NEUROG3 p.Arg55Glufs*23 is characterized by hyperglycemia and mild intermittent abdominal pain.ConclusionsThis study adds to the emerging pattern of MODY epidemiology that the proportion of MODY explained by known pathogenic genes is higher than that previously reported, and found NEUROG3 as a new causative gene for MODY.
| S-EPMC8015824 | biostudies-literature
Project description:Maturity onset diabetes of the young (MODY) accounts for up to 4% of all cases of diabetes in pediatric patients. MODY is usually characterized by autosomal dominant inheritance, impaired insulin secretion, and an average age at diagnosis of 18-26 years. Mutations in the hepatocyte nuclear factor 1-alpha (HNF1A), glucokinase, hepatocyte nuclear factor 4-alpha, and hepatocyte nuclear factor 1-beta genes are the mutations most frequently observed in cases of MODY. We herein report a case of HNF1A-MODY characterized by an early onset of diabetes. Genetic investigations revealed a de novo heterozygous substitution, N237D (HNF1A c.709A>G), in exon 3 of the HNF1A gene. Our case supports the hypothesis that de novo mutations are more frequent than expected. This recent evidence may suggest that conventional clinical diagnostic criteria for MODY should be revised and personalized according to the individual patient.
| S-EPMC6612332 | biostudies-literature