Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome
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 <i>SLC2A2</i> gene. <i>SLC2A2</i> encodes for the gl...
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MDPI AG
2022-08-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/9/2114 |
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| author | Sanaa Sharari Basirudeen Kabeer Idris Mohammed Basma Haris Igor Pavlovski Iman Hawari Ajaz Ahmad Bhat Mohammed Toufiq Sara Tomei Rebecca Mathew Najeeb Syed Sabah Nisar Selma Maacha Jean-Charles Grivel Damien Chaussabel Johan Ericsson Khalid Hussain |
| author_facet | Sanaa Sharari Basirudeen Kabeer Idris Mohammed Basma Haris Igor Pavlovski Iman Hawari Ajaz Ahmad Bhat Mohammed Toufiq Sara Tomei Rebecca Mathew Najeeb Syed Sabah Nisar Selma Maacha Jean-Charles Grivel Damien Chaussabel Johan Ericsson Khalid Hussain |
| author_sort | Sanaa Sharari |
| collection | DOAJ |
| 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 <i>SLC2A2</i> gene. <i>SLC2A2</i> 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 <i>SLC2A2</i> mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic <i>SLC2A2</i> 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 <i>SLC2A2</i> 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. |
| first_indexed | 2024-03-10T00:40:49Z |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T00:40:49Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-fdc507a460194407a6173afa34a196b82023-11-23T15:09:21ZengMDPI AGBiomedicines2227-90592022-08-01109211410.3390/biomedicines10092114Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel SyndromeSanaa Sharari0Basirudeen Kabeer1Idris Mohammed2Basma Haris3Igor Pavlovski4Iman Hawari5Ajaz Ahmad Bhat6Mohammed Toufiq7Sara Tomei8Rebecca Mathew9Najeeb Syed10Sabah Nisar11Selma Maacha12Jean-Charles Grivel13Damien Chaussabel14Johan Ericsson15Khalid Hussain16Division of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarDivision of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, QatarDepartment of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarDivision of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarResearch Branch, Sidra Medicine, Doha 26999, QatarDivision of Biological and Biomedical Sciences, College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, QatarDepartment of Pediatric Medicine, Division of Endocrinology, Sidra Medicine, Doha 26999, QatarFanconi–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 <i>SLC2A2</i> gene. <i>SLC2A2</i> 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 <i>SLC2A2</i> mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic <i>SLC2A2</i> 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 <i>SLC2A2</i> 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.https://www.mdpi.com/2227-9059/10/9/2114Fanconi–Bickel syndrome (FBS)dysglycemiaglucose transporter 2 (GLUT2)PBMCs (peripheral blood mononuclear cells)miRNAs |
| spellingShingle | Sanaa Sharari Basirudeen Kabeer Idris Mohammed Basma Haris Igor Pavlovski Iman Hawari Ajaz Ahmad Bhat Mohammed Toufiq Sara Tomei Rebecca Mathew Najeeb Syed Sabah Nisar Selma Maacha Jean-Charles Grivel Damien Chaussabel Johan Ericsson Khalid Hussain Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome Biomedicines Fanconi–Bickel syndrome (FBS) dysglycemia glucose transporter 2 (GLUT2) PBMCs (peripheral blood mononuclear cells) miRNAs |
| title | Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome |
| title_full | Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome |
| title_fullStr | Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome |
| title_full_unstemmed | Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome |
| title_short | Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome |
| title_sort | understanding the role of glut2 in dysglycemia associated with fanconi bickel syndrome |
| topic | Fanconi–Bickel syndrome (FBS) dysglycemia glucose transporter 2 (GLUT2) PBMCs (peripheral blood mononuclear cells) miRNAs |
| url | https://www.mdpi.com/2227-9059/10/9/2114 |
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