*In humans GLUT9 is involved in renal uric acid reabsorption-mutations in the GLUT9 gene have consequences on plasma uric acid levels*

Various genome wide association studies uncovered polymorphisms in *SLC2A9* as being one of the most significantly associated genes that can be linked to gout and increased serum uric acid concentrations. Although the identified SNPs are located in intronic regions of the gene, evidence exists that increased RNA expression for GLUT9 positively correlates with increased serum uric acid concentrations. In contrast, exonic mutations in GLUT9 suggested that loss of GLUT9 function is associated with hypouricemia. Two distinct heterozygous missense mutations (R380W and R198C in GLUT9a) were described in three patients with hypouricemia. The two mutations were shown to result in loss of function when uric acid transport was studied in *Xenopus laevis* oocyes. A genome-wide homozygosity screen linked hereditary hypouricemia to two homozygous SLC2A9 mutations that lead to a missense mutation (L75R) or a 36-kb deletion. The homozygous loss-of-function mutations of GLUT9 caused a total defect of uric acid absorption, leading to severe hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. Therefore, GLUT9 is essential for renal reabsorption of uric acid-increased expression is associated with hyperuricemia and gout, while loss of function leads to severe hypouricemia.

**4.12. Class III family members**

**4.13. GLUT6** *(SLC2A6)*

been published for this isoform.

physiology for this cell lineage.

**4.14. GLUT8** *(SLC2A8)*

Class III isoforms share specific features that are unique to this Class. First, structurally all Class III members carry their N-glycosylation site at the fifth extracellular loop. Common to all the isoforms is the presence of an internalization signal (dileucine or YSRI in case of GLUT10) that retains these transporters at an intracellular localization under steady state conditions. Thus far, a stimulus for translocation of Class III isoforms leading to plasma membrane localization has only been proposed for GLUT13 which has not been confirmed.

Mammalian Sugar Transporters http://dx.doi.org/10.5772/58325 29

GLUT6 (formerly designated GLUT9) was cloned from human leucoyte cDNA by (RACE)- PCR on the basis of murine ESTs and the human genomic sequence. GLUT6 mRNA is expressed predominantly in the brain, spleen and peripheral leucocytes. Hexose transport for GLUT6 was only shown when reconstituted in liposomes, where GLUT6 transport activity was found in the presence of 5 mM but not 1 mM glucose. GLUT6 exhibits a low cytochalasin B binding affinity. Thus far, no other data on kinetics of transport and potential substrates have

GLUT6 contains an N-terminal dileucine motif that is responsible for intracellular retention of the protein when overexpressed in primary rat adipocytes. GLUT6 is only detected at the plasma membrane when the dileucine residues are mutated to alanine or when clathrin dependent endocytosis is blocked by overexpression of a dominant-negative dynamin mutant. However, no cell-surface translocation of GLUT6 is observed in response to stimuli such as insulin, phorbol ester or hyperosmolarity. A gene expression profiling study aimed to identify deregulated in chronic lymphocytic leukaemia associated with Trisomy 12 identified Slc2a6 among the seven genes with the strongest correlation. Although a significant deregulation was not confirmed subsequently by real-time PCR analysis, the specific expression of GLUT6 in leucocytes and the spleen might indicate an important role for this transporter in normal

The biochemistry, cell biology and physiology of GLUT6 is currently not well understood.

GLUT8 (formerly GLUTX1) was the first isoform of the extended *SLC2A* family to be identified by database mining. The human, rat and mouse cDNA were cloned by 5' and 3' RACE-PCR from testis cDNA samples. The transporter is mainly expressed in the testes, and lower levels are found in the brain (cerebellum), adrenal gland, liver, spleen, brown adipose tissue and lung. Functional characterization of GLUT8 in *Xenopus laevis* oocytes immediately revealed the intracellular retention of the transporter due to the presence of a dileucine based motif in its N-terminus. When the two leucine residues are changed to alanines GLUT8 localizes to the plasma membrane in mammalian cells and *Xenopus laevis* oocytes that allowed the determination of transport kinetics for the protein. GLUT8 shows a high affinity for glucose with a Km of ~2 mM. Glucose transport can be competitively inhibited with fructose, galactose, and cytochalasin B. The intracellular localization of

#### *Mouse Models of GLUT9 deficiency*

GLUT9 deficiency in mice leads to hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, which his is in contrast to the condition in humans where dysfunctional GLUT9 is associated with hypouricemia. Hyperuricemia in mice due to GLUT9 deficiency appears to be a result of impaired urid acid uptake by the liver and therefore inability to be degraded to allantoin by uricase. The nephropathy in GLUT9 knockout animals is characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex. In contrast, liver-specific GLUT9 inactivation in adult mice results in severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. The deficiency of GLUT9 in mice showed that it represents a functional uric acid transporter *in vivo,* allowing GLUT9 to be identified as a major player in urate homeostasis due to its dual role in uric acid handling in the kidney and in the liver. Whether GLUT9 at all plays a role as a (glucose)/fructose transporter that potentially links fructose uptake by the liver and uric acid metabolism remains to be seen (Figure 4A).
