Research Article: Functional analysis of a triplet deletion in the gene encoding the sodium glucose transporter 3, a potential risk factor for ADHD

Date Published: October 4, 2018

Publisher: Public Library of Science

Author(s): Nadine Schäfer, Maximilian Friedrich, Morten Egevang Jørgensen, Sina Kollert, Hermann Koepsell, Erhard Wischmeyer, Klaus-Peter Lesch, Dietmar Geiger, Frank Döring, Diego Alvarez de la Rosa.


Sodium-glucose transporters (SGLT) belong to the solute carrier 5 family, which is characterized by sodium dependent transport of sugars and other solutes. In contrast, the human SGLT3 (hSGLT3) isoform, encoded by SLC5A4, acts as a glucose sensor that does not transport sugar but induces membrane depolarization by Na+ currents upon ligand binding. Whole-exome sequencing (WES) of several extended pedigrees with high density of attention-deficit/hyperactivity disorder (ADHD) identified a triplet ATG deletion in SLC5A4 leading to a single amino acid loss (ΔM500) in the hSGLT3 protein imperfectly co-segregating with the clinical phenotype of ADHD. Since mutations in homologous domains of hSGLT1 and hSGLT2 were found to affect intestinal and renal function, respectively, we analyzed the functional properties of hSGLT3[wt] and [ΔM500] by voltage clamp and current clamp recordings from cRNA-injected Xenopus laevis oocytes.

Partial Text

Membrane transport of glucose in mammalian cells is mediated either by members of the SLC2 or the SLC5 transporter family. Glucose transporters [GLUTs] of the SLC2 family facilitate diffusion of D-glucose across the plasma membrane [1]. In contrast, members of the SLC5 family (sodium-glucose transporters or symporters; SGLTs) mediate co-transport of D-glucose in expense of the electrochemical sodium gradient across the plasma membrane. The secondary active transport by SGLTs allows the accumulation of D-glucose in various cell types [2]. Genes of SGLTs code for membrane proteins that consist of 14 transmembrane segments with both amino- and carboxy-terminus located on the extracellular side as revealed by site-directed mutagenesis and crystal structure analysis (reviewed by [3]). Studies with human SGLT1 (hSGLT1) and the model homologue from Vibrio parahaemolyticus (vSGLT) have shown that fully functional transporters are formed by monomeric proteins [4, 5]. X-ray analysis of crystals from vSGLT discovered a core structure of inverted repeat topology of TM1-TM5 and TM6-TM10 with no amino acid homology but structural domains that can be superimposed [6]. The core structure is flanked by a single transmembrane segment on the amino terminal side and three of them at the carboxy terminus, named -TM1 and TM11-13, respectively (according to [7]). Within this core structure (TM1–TM10) specific amino acids were identified that are essential either for substrate or sodium binding. Moreover, mechanisms for the transfer of ions and substrate molecules from the extracellular to the intracellular side are attributed to this core element of the protein [6]. In contrast, the function and relevance of the additional TM segments (-TM1 and TM11-13) on the N- and C-termini are poorly understood. Evidence for the importance of several specific amino acids in hSGLTs was deduced from intestinal and renal diseases caused by mutations in these transporters [8, 9, 10].




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