Abstract
Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by hepatic glycogen accumulation and renal Fanconi syndrome first described in 1949. Patients of this disorder also have impaired galactose metabolism and are sometimes discovered by their high serum galactose level by means of Guthrie test during newborn screening. The gene responsible for this disorder was identified and three homozygous mutations were found in the GLUT2 gene, a facilitative glucose transporter, all of which predicted truncated translation products. The primary structure of GLUT2 was determined and it consisted of 524 amino acids. The GLUT2 gene is mapped in chromosome 3, q26.1-26.3 and has 11 exons spanning approximately 30 kb. This protein has been studied and speculated to be one of the candidate proteins for non-insulin dependent diabetes mellitus (NIDDM). Although one missense mutation (V197I) was reported in a NIDDM patient, GLUT2 may not play an important role in the development of IDDM in humans.
Molecular analyses have been performed for FBS patients and reported several mutations. Most mutations are homozygous. The first mutation analyses by Santer et al. reported two nonsense mutations and one frame shift mutation all of which predicted truncated translation products that could not be expected to have functional transporter activity.
Akagi et al. analyzed two Japanese patients with FBS. No mutation in the entire coding region was detected in one patient. Another patient had a novel homozygous nonsense mutation (W420X). Sanjad et al. reported a family with FBS associated with phosphorylase b kinase deficiency. However the coding sequence of all three Phk subunits genes were all normal and they identified a homozygous missense mutation (P417L) in GLUT2 gene.
We have analyzed two Japanese patients with FBS. Compound heterozygous mutations (R365X and W444A) were found in one patient with the W444A mutation being the second missense mutation. The other patient had a novel homozygous nonsense mutation (R53X). Both R365X and R53X nonsesnse mutations seem to produce non-functional truncated GLUT2 protein. Trp at amino acid position 444 resides in 11th membrane spanning region. This glucose transporter region is highly homologous. Especially Trp at 444 is conserved in all glucose transporters through 1 to 5. A missense mutation changing Trp at 412 of the GLUT1 severely impairs glucose transport by modulating the inward-facing binding site. Trp at 412 of the GLUT1 corresponds to Trp at 444 of the GLUT2. Taken together it is reasonable to think that Trp at 444 is an important amino acid for functioning glucose transporter activity.
Mutations in the GLUT2 gene in FBS appear to be heterogeneous. Accumulations of mutations may help in the understanding of the functional domains of the GLUT2.
