Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome

Abstract

Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose. To date, no underlying enzymatic defect in carbohydrate metabolism has been identified. Therefore, and because of the impairment of both glucose and galactose metabolism, a primary defect of monosaccharide transport across membranes has been suggested. Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel. Homozygous mutations were found in affected individuals, whereas all parents tested were heterozygous for the respective mutation. Because all detected mutations (delta T446-449, C1251T and C1405T) predict truncated translation products that cannot be expected to have functional monosaccharide transport activity, GLUT2 mutations are probably the cause of FBS.

Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria

“…The only locations where naturally occurring mutations have been observed both in SGLT1 and SGLT2 are R137 and R499. 2 A patient with glucose-galactose malabsorption and compound heterozygosity for SGLT1 R499H (together with R379X) was severely affected clinically, and the functional expression of this mutant in oocytes has been shown to result in a significant decrease of sugar affinity and trafficking to the membrane. It has been reported, however, that replacing this residue by cysteine restored trafficking and resulted in a functional sugar transporter (32).…”

“…In general, urinary glucose concentration had been repeatedly determined by dipstick before it was quantified by the glucose oxidase method in aliquots of 24-h urine collected on a free diet. It ranged from a minimal elevation of Ͻ1 g/1.73 m 2 (9)). None of these subjects had any signs of a generalized tubular dysfunction or of any other type of renal disease.…”

“…The molecular bases of three congenital defects of cellular glucose transport, affecting either facilitative ("passive") or sodium-dependent ("active") transport, have been elucidated in recent years (1)(2)(3). In addition, a defect of the renal lowaffinity sodium/glucose cotransporter SGLT2 gene (also referred to as SLC5A2, [OMIM 182381]) has long been proposed to cause renal glucosuria (OMIM 233100) (4).…”

Positron emission tomography probe demonstrates a striking concentration of ribose salvage in the liver

“…These mice have impaired glycogen mobilization during fasting, liver hyperplasia, and glucose intolerance (45,46). Fanconi-Bickel syndrome is an autosomal recessive disorder in humans associated with mutations in Slc2a2 (47). Hepatic phenotypes of patients with Fanconi-Bickel syndrome include hepatomegaly and enhanced glycogen accumulation (48).…”

Neonatal diabetes mellitus with hypergalactosemia

“…An increased serum concentration of galactose in a newborn occurs in classical galactosemia and deficiency of galactokinase. The combination of both an impaired glucose tolerance and a hypergalactosemia may be due to a defect of the facilitative glucose transporter 2 (Glut2), which is the underlying cause of Fanconi-Bickel syndrome (2).…”