Glucose and Vitamin C are both essential nutrients for human survival and share some transmembrane transport pathways. The last discovered member SLC2A14 encodes GLUT14, a very poorly characterized protein. Five GLUT14 isoforms are identified, however, only one had been described to mediate multi-specific hexose and dehydroascorbic acid transport, while the others’ substrates remain to be identified. The apical ascorbic acid uptake in epithelia cells is mediated by SLC23A1, a very well characterized gene/protein. SLC2A14 and SLC23A1 share genetic association with inflammatory bowel disease, Alzheimer’s disease, and Parkinson’s diseases. However, it remains unclear if these are independent or related to the shared pathways. To inform on this, the characterizations of the functions of the GLUT14 isoform will be essential. It is hypothesized that all GLUT14 isoforms encode multi-specific hexose transporters. Since SLC23A1 functions are well known, the identification of functional genetic variations will be contributing to decipher the genetic associations. Currently, there are 440 missense mutations recorded in the databases, precipitating the need to prioritize them for functional testing. The 5’ region of the SLC23A1 open reading frame, corresponding to the N-terminus of the protein, seems to harbor an elevated amount of missense mutation. It is therefore hypothesized that it might be poorly conserved and redundant.
These research gaps are addressed using bioinformatic and functional studies in the Xenopus laevis expression system. Alignments and conservations were analyzed using Sequencher 5.0, SnapGene 6.0.2, and Aminode software. All the functional studies were conducted using the Xenopus laveis oocyte system for determining the uptake of C14-ascorbic acid or H3-2-D-deoxyglucose upon expression of the respective transporters. SLC23A1 30 N-terminal amino acids are redundant based on poor conservation and unaltered protein function. Moreover, the elimination of 77 N-terminal amino acids reduced SLC23A1 function by only 20%. Therefore, the 74 missense mutations in this region can be deprioritized from functional testing and are unlikely to impact the clinical relevance. All isoforms but GLUT14-C, which is non-functional, are multi-specific hexose transporters. The substrate spectrum includes glucose, galactose, mannose, and xylose, allowing further explorations into their role in disease associations.