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Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi–Bickel Syndrome

journal contribution
submitted on 2024-08-29, 11:31 and posted on 2024-08-29, 11:31 authored by 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

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.

Other Information

Published in: Biomedicines
License: https://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.3390/biomedicines10092114

Funding

Qatar National Research Fund (NPRP 10-6100017-AXX).

Qatar National Research Fund (NPRP13S-0127-200178), Exploring new therapeutic targets in cardiometabolic disease.

History

Language

  • English

Publisher

MDPI

Publication Year

  • 2022

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Sidra Medicine
  • Clinical Research Centre - Sidra Medicine