Gaceta Médica de México. 2016;152 Contents available at PubMed www.anmm.org.mx PERMANYER Gac Med Mex. 2016;152:492-501 www.permanyer.com GACETA MÉDICA DE MÉXICO REVIEW ARTICLE Glucotransporters: clinical, molecular and genetic aspects Roberto de Jesús Sandoval-Muñiz, Belinda Vargas-Guerrero, Luis Javier Flores-Alvarado and Carmen Magdalena Gurrola-Díaz* Health Sciences Campus, University of Guadalajara, Guadalajara, Jal., Mexico Abstract Oxidation of glucose is the major source of obtaining cell energy, this process requires glucose transport into the cell. However, cell membranes are not permeable to polar molecules such as glucose; therefore its internalization is accomplished by transporter proteins coupled to the cell membrane. In eukaryotic cells, there are two types of carriers coupled to the membrane: 1) cotransporter Na+-glucose (SGLT) where Na+ ion provides motive power for the glucose´s internalization, and 2) the glucotransporters (GLUT) act by facilitated diffusion. This review will focus on the 14 GLUT so far described. Despite the structural homology of GLUT, different genetic alterations of each GLUT cause specific clinical entities. Therefore, the aim of this review is to gather the molecular and biochemical available information of each GLUT as well as the particular syndromes and pathologies related with GLUT´s alterations and their clinical approaches. (Gac Med Mex. 2016;152:492-501) Corresponding author: Carmen Magdalena Gurrola-Díaz, [email protected] KEY WORDS: Sugar transport facilitators. GLUT. Glucose transporters. SLC2A. different affinity for carbohydrates1. In eukaryote cells ntroduction I there are two membrane-coupled transporter proteins: 1) Sodium-glucose co-transporters (SGLT), located in Glucose metabolism provides energy to the cell by the small bowel and renal tissue, mainly responsible means of adenosine-5’-triphosphate (ATP) biosynthe- for the absorption and reabsorption of nutrients, and sis, with glycolysis as the catabolic pathway. Glycemia 2) glucotransporters (GLUT), which act by facilitated homeostasis involves three processes: 1) glucose ab- diffusion and are differentially distributed in body tis- sorption in the small intestine; 2) glucose internalization sues4-6. The latter are included in the solute carriers and consumption by body tissues, and 3) hepatic pro- (SLC) family 27. duction of glucose1-3. So far, 14 GLUTs have been described, which ex- For the above processes to be carried out, glucose hibit common structural features: 12 transmembrane internalization to the cell is primordially required. How- alpha helix domains, whose amino and carboxyl end- ever, cell membrane is not permeable to polar mole- groups are intracytoplasmically located, one highly cules such as glucose, so it is necessary the partici- glycosylated extracellular domain in the third or fifth pation of membrane-coupled carrier proteins4. Each loop, depending on the GLUT. GLUTs can be grouped transporter protein, expressed in different tissues, has in 3 main classes according to their homologous Correspondence: *Carmen Magdalena Gurrola-Díaz Centro Universitario de Ciencias de la Salud Universidad de Guadalajara Guadalajara, México E-mail: [email protected] Date of reception: 22-05-2015 Date of acceptance: 13-07-2015 492 R.J. Sandoval-Muñiz, et al.: Glucotransporters: clinical, molecular and genetic aspects sequences and the glycosylation loop position8-10. encodes for GLUT114. De Vivo et al. (1991) made the Class I comprises GLUT1 to 4 and GLUT14. Class II first clinical description of the syndrome in 2 pediatric (odd transporters) includes GLUT5, 7, 9 and 11. patients who had neurological development delay as- Class III (pair transporters) is comprised by GLUT6, 8, sociated with idiopathic epileptic encephalopathy9.14. 10 and 12 and proton-propelled myo-inositol transport- GLUT1 deficiency diagnostic criteria are the follow- er (HMIT) or GLUT1310. ing: seizures, developmental delay, complex move- GLUT classes I and II have their glycosylation site at ment disorder and fasting electroencephalographic the first extracellular loop between transmembrane he- changes15. lices 1 and 2, whereas in class III, glycosylation occurs Classic presentation, which is the most severe and in loop 9. GLUT protein sequences possess 14 to 63% common form, is characterized by encephalopathy, homology, while in preserved regions, homology in- early-onset epilepsy with developmental delay, ac- creases from 30 to 79%10. quired microcephaly, motor discoordination and Next, we will describe biochemical and molecular spasticity. In addition, patients experience periods information, protein function, as well as associated syn- of apnea, absence seizures appearing within the first dromes and phenotypes of each GLUT. 4 months of life and seizures before the first 2 years of age in 90% of cases9. GLUT1 Recently, 200 patients with this syndrome have been reported16. Both autosomal dominant and recessive GLUT1 is encoded by the SLC2A1 gene with an inheritance patterns have been identified; however, in extension of 33,802 bp and a mRNA of 3,687 bp and most described patients mutations are de novo reported14. it is located at the chromosome 1. It contains 10 exons Initial diagnostic approach of patients with suspicion and 9 introns. The protein is composed of 492 amino of this pathology involves general laboratory tests such acids and is found mainly in erythrocytes, blood-brain as urinalysis, without relevant findings, serum glu- barrier, brain, placenta and kidney. There are 2 de- cose concentration determination, where the result scribed isoforms for this GLUT, encoded by the same is normal11, which rules out hypoglycemia as the gene (SLC2A1), which differ by the number of glyco- cause of seizures. Non-conventional diagnostic tests sylated sites and molecular weight. The first 55-kDa are carried out: the immunoreactivity-mediated eryth- isoform is located in blood-brain barrier endothelial rocyte membrane glucose uptake test, using 3-O-meth- cells (also in neurons) and erythrocytes, while the sec- yl-D-glucose. In patients with GLUT1 deficiency, this ond 45-kDa isoform is found in astrocytes1,4,11-13. The uptake is lower (< 74%) than in individuals without this main function of GLUT1 is to maintain cell respiration pathology16. by means of basal glucose uptake and delivery to the The presence of seizures refractory to conventional brain. GLUT1 also carries other molecules such as treatment in these patients suggests the need to rule 1 galactose, mannose and glucosamine . The Km value out lesions at the central nervous system (CNS) level of this GLUT for glucose is 3 mM10. It has an amino with imaging studies such as magnetic resonance im- acid homology between species of 98% (human, rat, aging (MRI). GLUT-deficient patients do not exhibit rabbit and pig)9. overt structural lesion data. At the absence of CNS The pathologies related with alterations of this gene structural lesions by MRI in patients with normoglyce- are the following: Type 9 dystonia, type I and type II mia, positron-emission tomography (PET) with 18-fluo- GLUT1 deficiency syndrome, exercise-induced parox- rodeoxyglucose (18-FDG) is suggested. Patients with ysmal dyskinesia, in addition to susceptibility to suffer GLUT-1 deficiency show decreased glucose uptake at generalized idiopathic epilepsy in 1% of cases13. the cerebral cortex and increased uptake in the GLUT1 overexpression in patients with different types putamen and bitemporal and lingual cortex. Collateral- of cancer and alterations in p53 (tumor suppressor ly, a 4-6-h fasting hypoglycorrhachia (< 40 mg/dl) to- gene) expression probably contributes to an increase gether with euglycemia support the diagnosis of this in glucose delivery to the tumor1,12,13. pathology11,13,16. However, to confirm the diagnosis, exon sequences amplification has to be carried out by GLUT1 deficiency syndrome means of polymerase chain reaction (PCR), with sub- sequent direct sequencing to identify specific muta- This syndrome displays high phenotypical variability tions. For confirmatory diagnosis, the use of other tech- and is caused by SLC2A1 gene mutations, which niques has been also reported, including single-strand 493 Gaceta Médica de México. 2016;152 conformational polymorphisms (SSCP), restriction frag- described between congenital deficiency of this trans- ment length polymorphisms (RFLP) and fluorescent in porter and the Fanconi-Bickel syndrome. situ hybridization (FISH)11,13. Treatment is based on a 4:1 or 3:1 ketogenic diet Fanconi-Bickel syndrome (fat:carbohydrate and protein) from early stages of life keeping it until adolescence. Fat-rich and low-carbo- This syndrome is an autosomal recessive pathology hydrate diet causes an increase in ketone bodies that, caused by SLC2A2 gene mutations, characterized by together with anticonvulsant therapy, control seizures. hepatomegaly and glycogen accumulation in the liver An important feature of ketonic bodies is the ability to and the kidneys. Patients with Fanconi-Bickel syn- cross the blood-brain barrier. At the presence of per- drome have been reported in European, Asian and sistent hypoglycorrhachia in patients with GLUT1 defi- American populations, including Mexican patients20. ciency, ketone bodies provide an alternate energy Patients with the Fanconi-Bickel syndrome (MIM source for brain tissue metabolism11,15. 227810) show decreased function of the proximal con- Therapies with alpha-lipoic acid and triheptanoin are voluted tubule (glycosuria, hyperphosphaturia,