A mutation in GLUT2, not in phosphorylase kinase subunits, in hepato-renalglycogenosis with Fanconi syndrome and low phosphorylase kinase activity

Fanconi-Bickel syndrome is characterized by hepato-renal glycogenosis with severe renal tubular dysfunction and rickets. It has recently been found to be associated with GLUT2 mutations in three families. In another family, l ow activities of liver phosphorylase kinase (Phk) have been observed, sugge sting that Fanconi-Bickel syndrome might be genetically heterogeneous. We h ave analyzed this family for mutations in the GLUT;! gene and in the three Phk subunit genes that can cause liver glycogenosis (PHKA2, PHKB, and PHKG2 ). The coding sequences of all three Phk genes are normal but we have ident ified a homozygous missense mutation (Pro417Leu) in GLUT2. The affected pro line residue is completely conserved in all mammalian glucose permease isof orms and even in bacterial sugar transporters and is believed to be critica l for the passage of glucose through the permease. Seven affected individua ls from different branches of the same large consanguineous sibship all are homozygous for this mutation. These findings indicate that there is no spe cific subtype of genetic Phk deficiency giving rise to hepato-renal glycoge nosis. Rather, they provide further evidence that Fanconi-Bickel syndrome i s caused by GLUT2 mutations. The low Phk activity is probably a secondary p henomenon that contributes to the deposition of glycogen in response to the intracellular glucose retention caused by GLUT2 deficiency.