Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR34063245_1.fastq.gz | Fastqsanger.gz | |||
| SRR34063245_2.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Maturity-onset Diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. Using next generation sequencing, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Our findings report that HNF1A and ABCC8 are among the most frequently mutated MODY genes in south India.
| EGAS00001001699 | EGA
Project description:Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes. We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4. Primary islets were isolated from pancretic beta cell- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice. Gene expression was analyzed by microarray.
2014-08-20 | E-GEOD-60505 | biostudies-arrayexpress
Project description:Diabetes is a complex genetic disease affecting millions of people worldwide. A common monogenic form of diabetes is glucokinase (GCK) maturity-onset diabetes of the young (GCK-MODY), which is caused by heterozygous inactivating variants in the gene encoding GCK. GCK catalyzes the phosphorylation of glucose and is known as the pancreatic glucose sensor. Patients with GCK-MODY, in contrast to other diabetics, often do not require treatment but are frequently misdiagnosed and treated unnecessarily. Genetic testing can prevent this, but is hampered by the challenge of interpreting genetic variants. To address this challenge, we generated a comprehensive map of human GCK variant activity. The activity map includes 97% of the possible missense and nonsense variants and correlate with in vitro catalytic efficiency, fasting glucose levels in patients and evolutionary conservation analysis. Activity scores include both hyper- and hypoactive variants.
2022-06-16 | GSE198878 | GEO
Project description:A strong association of the gain-of-function mutation in the TALK-1 K+ channel (p.L114P) with maturity-onset diabetes of the young (MODY) was recently reported in two distinct families. TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion (GSIS). KCNK16, the gene that encodes TALK-1, is the most abundant and β-cell–restricted K+ channel transcript and KCNK16 locus is strongly associated to type-2 diabetes. To investigate the impact of TALK-1-L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the TALK-1-L114P mutation was generated. Heterozygous and homozygous TALK-1-L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous TALK-1-L114P neonates due to lack of GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increases whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and a complete loss of glucose-induced Ca2+ oscillations. Thus, adult TALK-1-L114P mice have reduced GSIS and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated TALK-1-L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by altering islet hormone secretion during development. These data strongly suggest that TALK-1 is an islet-restricted target for the treatment for diabetes
2023-09-26 | GSE239566 | GEO
Project description:Mutations in several transcription factors lead to a subtype of type 2 diabetes called maturity-onset diabetes of the young (MODY), which are characterized by autosomal dominant inheritance, an early age of disease onset, and development of marked hyperglycemia with a progressive impairment in insulin secretion (Shih and Stoffel, 2002). The most frequent form of MODY is caused by mutations in the gene encoding hepatocyte nuclear factor-1a (HNF-1a, TCF1). Mutant mice with loss of Tcf1 function as well as transgenic mice expressing a naturally occurring dominant-negative form of human TCF1(P291fsinsC) in pancreatic beta cells develop progressive hyperglycemia due to impaired glucose-stimulated insulin secretion (Hagenfeldt-Johansson et al., 2001; Yamagata et al., 2002). Importantly, these mice exhibit a progressive reduction in beta cell number, proliferation rate, and pancreatic insulin content. These data indicate that Tcf-1 target genes are also required for maintenance of normal beta cell mass. In this study we sought to identify target genes of Tcf-1 that may be responsible of mediating beta cell growth by comparing gene expression profiles of Tcf-1 knock-out and wild-type littermates in isolated pancreatic islets.
2007-02-27 | E-CBIL-21 | biostudies-arrayexpress
Project description:Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes. We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4.
2014-08-20 | GSE60505 | GEO
Project description:Missense mutations in coding region of PDX1 predispose to type-2 diabetes mellitus as well as cause MODY through largely unexplored mechanisms. Here, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying heterozygous missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1P33T/+, PDX1C18R/+ mutations and engineered isogenic cell lines carrying homozygous PDX1P33T/P33T, PDX1C18R/C18R mutations and a heterozygous PDX1 loss-of-function mutation (PDX1+/-). Using an in vitro β-cell differentiation protocol, we demonstrated that both PDX1P33T/+, PDX1C18R/+ and PDX1P33T/P33T, PDX1C18R/C18R mutations impair β-cell differentiation and function. Furthermore, PDX1+/- and PDX1P33T/P33T mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1P33T/+ and PDX1P33T/P33T mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NEURONATIN, both involved in insulin synthesis and secretion. Our results reveal mechanistic details of how diabetes-associated PDX1 point mutations impair human pancreatic endocrine lineage formation and β-cell function and contribute to pre-disposition for diabetes.
2019-06-19 | GSE125768 | GEO
Project description:Studies of monogenic diabetes are particularly useful as we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes form, caused by a mutation in the HNF4A gene. Human induced pluripotent stem cells (hiPSC) provide an excellent tool for disease modelling by subsequent directed differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (3D) environment may facilitate phenotype detection. In this study, we studied MODY1 using hiPSC-derived pancreatic β-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules we showed that the 3D context was critical to facilitate the detection of mutation-specific phenotypes. In 3D cell aggregates we identified irregular cell clusters and lower levels of structural proteins by proteome analysis, whereas in 3D alginate capsules we identified altered levels of glycolytic proteins in the glucose sensing apparatus by proteome analysis. Our study provides novel knowledge on normal and abnormal function of HNF4A paving the way for translational studies of new drug targets that can be used in precision diabetes medicine of MODY.
2022-04-04 | GSE188827 | GEO