The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome

Abstract

We report a total of 23 novel mutations of the SLC2A2 ( GLUT2) gene in 49 patients with a clinical diagnosis of Fanconi-Bickel syndrome (FBS). Molecular genetic analysis has now been performed in more than 50% of the 109 FBS cases from 88 families that we have been able to locate world-wide since the original report in 1949. In these 49 patients, 33 different SLC2A2 mutations (9 missense, 7 nonsense, 10 frameshift, 7 splice-site) have been detected. Thus, our results confirm that mutations of SLC2A2 are the basic defect in patients with FBS. Mutations of SLC2A2 were detected in historical FBS patients in whom some of the characteristic clinical features (hepatorenal glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy) and the effect of therapy were described for the first time. Mutations were also found in patients with atypical clinical signs such as intestinal malabsorption, failure to thrive, the absence of hepatomegaly, or renal hyperfiltration. No single prevalent SLC2A2 mutation was responsible for a significant number of cases. In a high percentage (74%) of FBS patients, the mutation is homozygous, so we conclude that the prevalence of SLC2A2 mutations is relatively low in most populations. No mutational hot spots within SLC2A2 or even within homologous sequences among the genes for facilitative glucose transporters were detected.

Phenotypic Variability in Patients with Fanconi–Bickel Syndrome with Identical Mutations

“…FTT and/or hepatomegaly, prominent fluctuations in blood glucose levels, and proximal tubulopathy were found at presentation or during diagnosis or both in all our patients, similar to other series of FBS (Santer et al , 2002b. Although there were only mild differences in age at diagnosis, skeletal involvement ranged from none to radiological and/or clinical signs of rickets and osteopenia.…”

“…Signs and symptoms of FBS begin in infancy and include failure to thrive (FTT), hepatomegaly, hypophosphatemic rickets, and short stature (Santer et al 2002b). Biochemically, the disease is characterized by a general renal proximal tubular defect (glycosuria, bicarbonate wasting, aminoaciduria, renal tubular acidosis, hyperphosphaturia) and carbohydrate abnormalities that include postprandial hyperglycemia, fasting hypoglycemia, and hypergalactosemia (Odièvre et al 2002).…”

“…Long-term follow-up studies have focused mainly on specific disease characteristics, such as renal (Manz et al 1987) and hepatic complications (Saltik-Temizel et al 2005). In a study of the genotype-phenotype correlation in FBS, Santer et al (2002b) investigated the various possible presentations of FBS due to null versus missense mutations.…”

Familial Renal Glucosuria and SGLT2

“…The first mutation in the SLC5A2 gene, positioned in 16p11.2, was reported by Santer et al (43), and more case series have confirmed that mutations in SLC5A2 are indeed responsible for the large majority of cases of FRG (44 -46). Additional support has come from several case reports (47-51).…”

Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria

“…We then performed mutation analysis in patients with isolated, massive glucosuria. It turned out that homozygosity or compound heterozygosity for SGLT2 mutations may account for this condition, which was reported in abstract form in the same year (7). On the basis of these reports, a single patient with glucosuria and homozygosity for an SGLT2 mutation has meanwhile been published (8).…”