UNDERSTANDING THE MOLECULAR MECHANISMS OF DYSGLYCEMIA IN PATIENTS WITH FANCONI-BICKEL SYNDROME

Abstract

Fanconi􀂱Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized mainly by the accumulation of glycogen in the kidney and liver. It is inherited in an autosomal recessive manner due to SLC2A2 gene mutations. Approximately 160 FBS cases with 75 different SLC2A2 gene variants have been reported so far. SLC2A2 encodes for glucose transporter 2 (GLUT2) which is a low-affinity facilitative transporter of glucose; it is mainly expressed in tissues that are significantly involved in glucose homeostasis, such as renal tubular cells, enterocytes, panc􀁕ea􀁗ic 􀈕-cells, hepatocytes, and discrete regions of the brain. The classical phenotypes of FBS are dysglycaemia (fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, and rarely diabetes mellitus), hepatomegaly, galactose intolerance, rickets, poor growth, and tubular acidosis. The molecular mechanisms of dysglycaemia in FBS are still not clearly understood. In this study, we report three new cases of FBS in Qatar with classical phenotypes of FBS associated with dysglycemia. Our results showed that two patients had exonic SLC2A2 mutations [db-bl-1164 (c.901C>T, R301X) and db-bl-1538 (c.1093C􀯗>􀯗T in e􀁛on 9, R365X)]; and one pa􀁗ien􀁗 had an in􀁗􀁕onic SLC2A2 mutation [db-bl-0008 (c.613-7T>G)]. Both of the exonic mutations had overexpression of dysfunctional GLUT2 (characterized by decreased glucose uptake activity in PBMCs and mitigated glucose release activity in HEK293T). As a result, other glucose transporters (GLUT1 and GLUT3 in PBMCs, SGLT1, and SGLT2 in the kidney) were found to be overexpressed. These findings confirm the essential role of the last loops (9-12) of the GLUT2 in glucose transport activity. However, in the patient with the intronic mutation, the mutation did not affect the GLUT2 coding sequence or its expression; glucose uptake activity was also intact. However, it stimulated the expression of miRNAs that are correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p, which is implicated in insulin production and secretion. These results propose that the non-coding SLC2A2 mutations might affect the expression of other genes implicated in insulin secretion or resistance. Therefore, we can conclude that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression or activity or by the indirect effect of GLUT2 on other genes implicated in dysglycemia.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences