Understanding the role of GLUT2 in dysglycemia associated with Fanconi-Bickel syndrome
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ABSTRACT:
PROVIDER: PRJNA816441 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18331358.fastq.gz | Fastqsanger.gz | |||
| SRR18331359.fastq.gz | Fastqsanger.gz | |||
| SRR18331360.fastq.gz | Fastqsanger.gz | |||
| SRR18331361.fastq.gz | Fastqsanger.gz |
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Project description:Fanconi–Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C > T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.
2022-09-28 | GSE198676 | GEO
Project description:Understanding the role of GLUT2 in dysglycemia associated with Fanconi-Bickel syndrome (RNA-Seq)
| PRJNA816447 | ENA
Project description:Understanding the role of GLUT2 in dysglycemia associated with Fanconi-Bickel syndrome (NanoString miRNA profiling)
| PRJNA816446 | ENA
Project description:Since the intronic mutation in SLC2A2 did not influence the activity of GLUT2, we undertook more investigation to understand the underlying molecular mechanisms of dysglycemia in FBS. We ran Nanostring miRNA panel v3b covering ~800 miRNAs in the patient, mother, and aged- and gender-matching healthy controls with no family history of dysglycemia. We noticed a higher degree of correlation between the patient and the gender and age-matched healthy control, rather than between the patient and the mother, suggesting that the miRNA expression profile might be more influenced by the age and gender rather than relatedness (Supplementary Fig. S5). The unsupervised hierarchical clustering revealed 123 miRs expressed specifically in the patient sample (Supplementary Table S2). The function of these miRNAs was interrogated by using Ingenuity Pathway (IPA) analysis software which returned 118 mapped miRs (Fig. 10). Here we report 30 miRNAs with the highest number of counts difference in the patient in comparison to controls (Fig. 11). We found that 14 of them were correlated with T1DM: 10 miRNAs (miR-199a, miR-25-3p, miR-93-5p, miR-19b-3p, miR-107, miR-24-3p. miR-18a-5p, miR-125b-5p, miR-324-5p, miR-331-3p, and hsa-miR-143-3p) were overexpressed in the control as compared to the patient, and 3 miRNAs (miR-144-3p , let-7e-5p, hsa-miR-29a-3p) were significantly overexpressed in the patient in comparison to the control. Molecular networks, including molecules inferred from previous studies, were generated by IPA functional analysis software (Supplementary Fig. S6). The molecular networks were given a score based on the number of molecules represented in the study dataset as compared to the literature. Network 1 (score 33) includes the genes and miRNAs implicated in organismal injury and abnormalities, skeletal and muscular system development and function, and tissue morphology. The miR-144 family integrated into the network 1. Network 2 (score 31) includes insulin and other genes and miRNAs implicated in glomerular injury, inflammatory disease, inflammatory response, and included miR-29 and let-7 families. These results suggest that dysglycemia in the patient with intronic mutation might be associated with the deregulation of miRNAs involved in insulin production and secretion in beta cells.
2022-09-28 | GSE198677 | GEO
Project description:Fanconi-Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.
| S-EPMC9495670 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-09-28 | GSE198678 | GEO
Project description:To analyze gene expression differences between WT proximal tubule cells and cells in which, by siRNA transfection, we blunted the expression of GLUT2 gene to mimic Fanconi Bickel Syndrome
2023-10-16 | GSE223364 | GEO
Project description:Glucose transporter 2 (GLUT2) is a key player in the regulation of glucose dynamics in organs central to metabolism, namely the liver, pancreas and intestine In humans, mutations of the GLUT2 gene (Fanconi-Bickel syndrome) cause important defects in glucose homeostasis. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, to date it is still unclear which role it plays in the brain. In this regard, in order to shed some light on the function of GLUT2 in the vertebrate brain, we have knocked down the functional ortholog of human GLUT2 in zebrafish. Our results show that abrogation of glut2 in vivo leads to defective brain organogenesis coinciding with reduced glucose uptake and increased programmed cell death in the brain region. Interestingly, coinciding with the observed localization of glut2 expression in the hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a that are the source of glutamatergic and GABAergic neurons, respectively. In addition, progenitor cells expressing neurod, a marker for immature and mature granule cells, were not affected by the lack of glut2. Furthermore, transcriptome analysis of glut2 knockdown embryos supports the notion that the lack of glut2 impacts brain development. Overall, the results of this study highlight the physiological relevance of glut2 in glucose uptake and availability during brain development, supporting the important role of glut2 in brain glucose sensing, and demonstrate the usefulness of a novel in vivo model of GLUT2 deficiency. Control and ATG morphant embryos were harvested at 72 hpf and RNA samples were obtained from pools of 20 embryos per condition and three pooled biological replicates of control and ATG morphants were analyzed.
2014-12-23 | E-GEOD-57836 | biostudies-arrayexpress
Project description:Glucose transporter 2 (GLUT2) is a key player in the regulation of glucose dynamics in organs central to metabolism, namely the liver, pancreas and intestine In humans, mutations of the GLUT2 gene (Fanconi-Bickel syndrome) cause important defects in glucose homeostasis. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, to date it is still unclear which role it plays in the brain. In this regard, in order to shed some light on the function of GLUT2 in the vertebrate brain, we have knocked down the functional ortholog of human GLUT2 in zebrafish. Our results show that abrogation of glut2 in vivo leads to defective brain organogenesis coinciding with reduced glucose uptake and increased programmed cell death in the brain region. Interestingly, coinciding with the observed localization of glut2 expression in the hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a that are the source of glutamatergic and GABAergic neurons, respectively. In addition, progenitor cells expressing neurod, a marker for immature and mature granule cells, were not affected by the lack of glut2. Furthermore, transcriptome analysis of glut2 knockdown embryos supports the notion that the lack of glut2 impacts brain development. Overall, the results of this study highlight the physiological relevance of glut2 in glucose uptake and availability during brain development, supporting the important role of glut2 in brain glucose sensing, and demonstrate the usefulness of a novel in vivo model of GLUT2 deficiency.
2014-12-23 | GSE57836 | GEO
Project description:Fanconi-Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized mainly by the accumulation of glycogen in the liver and kidney. It is inherited as an autosomal recessive disorder caused by mutations in the SLC2A2 gene, which encodes for GLUT2. Patients with FBS have dysglycemia but the molecular mechanisms of dysglycemia are still not clearly understood. Therefore, we aimed to understand the underlying molecular mechanisms of dysglycemia in a patient with FBS. Genomic DNA was isolated from a peripheral blood sample and analyzed by whole genome and Sanger sequencing. CRISPR-Cas9 was used to introduce a mutation that mimics the patient's mutation in a human kidney cell line expressing GLUT2 (HEK293T). Mutant cells were used for molecular analysis to investigate the effects of the mutation on the expression and function of GLUT2, as well as the expression of other genes implicated in dysglycemia. The patient was found to have a homozygous nonsense mutation (c.901C>T, R301X) in the SLC2A2 gene. CRISPR-Cas9 successfully mimicked the patient's mutation in HEK293T cells. The mutant cells showed overexpression of a dysfunctional GLUT2 protein, resulting in reduced glucose release activity and enhanced intracellular glucose accumulation. In addition, other glucose transporters (SGLT1 and SGLT2 in the kidney) were found to be induced in the mutant cells. These findings suggest the last loops (loops 9-12) of GLUT2 are essential for glucose transport activity and indicate that GLUT2 dysfunction is associated with dysglycemia in FBS.
| S-EPMC9159359 | biostudies-literature