Slc45a1, a member of the solute carrier 45 family, is a proton-associated glucose transporter implicated in the regulation of glucose homeostasis in the brain [7]. It has been linked to various biological processes, and its mutations can lead to neurological disorders, highlighting its importance in maintaining normal brain function [4].

In glioblastoma, deletion of Slc45a1 was the truncal alteration most significantly associated with the mitochondrial subtype, which has a more favorable clinical outcome. Re-introduction of Slc45a1 in mitochondrial glioma cells induced acidification and loss of fitness [1]. Mutations in Slc45a1 can cause lysosomal dysfunction, as it plays a dual role in lysosomal sugar transport and stabilization of V1 subunits of the V-ATPase. Loss of Slc45a1 elevates lysosomal pH, disrupts iron homeostasis, and causes mitochondrial dysfunction [2]. Missense mutations in Slc45a1 can lead to syndromic intellectual disability, as they change the protein's tertiary structure, fail its intracellular location, and attenuate its glucose-transporting activity [3]. Recessive mutations in Slc45a1 are also associated with intellectual disability and epilepsy, with identified missense variants reducing its intracellular glucose transport activity [5]. A gain-of-function mutation in Slc45a1, caused by the disruption of a DNA G-quadruplex, leads to upregulation of its mRNA and protein expression, potentially causing intellectual developmental disorder with neuropsychiatric features [6].

In conclusion, Slc45a1 is crucial for glucose homeostasis in the brain and its proper functioning is essential for normal neurological development and function. Studies on Slc45a1, especially through loss-of-function experiments, have revealed its role in glioblastoma, lysosomal disorders, intellectual disability, and epilepsy, providing insights into potential therapeutic targets for these diseases.