*GLUT10 and Arterial tortuosity syndrome (ATS, OMIM# 208050) in Humans*

Deficiency for GLUT10 in humans has been found to be associated with ATS, a rare autosomal recessive connective tissue disease that is characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the arteries. Homozygous mutations (deletion, non-sense, and missense) for GLUT10 were found in six families with ATS. It is currently unknown how loss of GLUT10 leads to this connective tissue disorder [33].

## *Mouse models of GLUT10 deficiency*

Two groups reported the phenotypic analysis of mice with amino acid substitutions G128E or S150F in GLUT10 [34, 35]. Both substitutions are located in exon2 of GLUT10 and are conserved among the rodent and human protein. Based on predictions, the substitutions G128E and S150F were expected to interfere with the helix structure of transmembrane regions 4 and 5, respec‐ tively. The mice strains were generated after screening a mutant mouse library that was based on N-ethyl-N-nitrosurea (ENU) mutagenesis in healthy C3HeB/FeJ males. Callewaert et al. [34] did not report any of the vascular, anatomical, or immunohistological abnormalities as encountered in patients with ATS. Both mutant strains appear normal at birth, gained weight appropriately and survived to adulthood. The animals showed normal heart rhythm, heart structure, and ventricular function. No specific arterial tortuosity, stenosis, dilatation, or aneurysm in cerebral vessel pattern was noted. However, histopathology revealed thickening and an irregular vessel wall shape of arteries with increased elastic fibers. Furthermore, the animals displayed endothelial hypertrophy and disarranged elastic fibers that resulted in disruption of internal elastic lamina in the aorta. Neither group analyzed whether the muta‐ tions caused any dysfunction or loss of the target protein, therefore the reported phenotype of those mice remains inconclusive with respect to GLUT10 function.

**4.17. GLUT13; HMIT** *(SLC2A13)*

hypothalamus, cerebellum and brainstem.

Screening of public expressed sequence databases with the GLUT8 protein sequence identified a rat EST clone that allowed cloning of the rat and human HMIT (*SLC2A13*) cDNAs from spleen and frontal cortex cDNA libraries. Despite low level expression in adipose tissue and kidney, HMIT is predominantly expressed in the brain, with high expression found in hippocampus,

The HMIT amino acid sequence contains all motifs known to be important for glucose transport activity. As for other Class III GLUT family members, HMIT is restricted to an intracellular location. Functional characterization of the protein in *Xenopus laevis* oocytes and in mammalian cells has been possible through the introduction of various mutations that yielded significant plasma membrane expression. Surprisingly, no sugar transport

myoinositol symporter with a *Km* of about 100 µM. More recently, HMIT has been shown to transport inositol-3-phosphate (IP3). HMIT is inhibited by the common GLUT inhibi‐ tors phloretin, phlorizin and cytochalasin B, although at high concentrations. Transloca‐ tion of HMIT to the plasma membrane has been demonstrated to occur in PC12 cells or primary neurons upon depolarization or protein kinase C (PKC) activation resulting in functional HMIT at the plasma membrane evidenced by increased myoinositol uptake in those cells. However, those initial findings were not reproduced by other groups leaving uncertainty about a stimulus that induces plasma membrane translocation of the transport‐ er. In the brain, myo-inositol serves as the precursor for phosphatidylinositol, a key regulator for various signaling pathways. Dysregulation of the phosphatidylinositol signaling has been implicated in psychiatric illness such as bipolar disorder. Standard therapies (lithium, valproic acid and carbamazepine) alter neuronal growth cone morphol‐ ogy, a phenotype that is reversed by extracellular myo-inositol. Because of its predomi‐ nant expression in the brain compared to two other myo-inositol transporters that are sodium-coupled (SMIT1 and SMIT2), interest has been raised as to whether HMIT might play a role in the regulation of myo-inositol/phosphatidylinositol physiology in neurons. Mice deficient for the transporter demonstrated that HMIT is not involved in the neuro‐


Mammalian Sugar Transporters http://dx.doi.org/10.5772/58325 33

activity has been found for HMIT. Instead, HMIT has been identified as a H+

nal transport of inositol from the extracellular environment.

\*Address all correspondence to: Robert.Augustin@boehringer-ingelheim.com

Department of Cardiometabolic Diseases Research, Boehringer-Ingelheim Pharma

and Eric Mayoux

**Author details**

Robert Augustin\*

GmbH&Co KG, Germany
