Browsing by Author "Landoni, Juan Cruz"

Creatine is a crucial metabolite for chordates, with critical roles in energy transport and buffering, as well as in brain function. The creatine transporter (CRT) is the ubiquitous symporter of creatine in the cell membrane, allowing for the biosynthesis and trafficking of creatine between cells and tissues. Mutations in SLC6A8, the human gene encoding CRT, can cause an X-chromosome linked form of creatine deficiency syndrome, commonly leading to intellectual disability, developmental delay, and seizures. This study details the clinical report and molecular confirmation of a novel mutation in the SLC6A8 gene, Tyr553Asp, in a male patient with metabolic encephalopathy. It is the first mutation of the gene discovered in Finland, leading to a typical creatine deficiency syndrome. The genetic and biochemical confirmation of the mutation pathogenesis is followed up by the in-silico homology modelling of the CRT structure in different conformations of its transport cycle, and an interpretation of the mutation’s predicted structural and functional consequences. These interpretations then prompted a proposed model for the function of the extracellular loops in CRT. The results implicate the understudied extracellular loop 6, the locus of the mutation, as being involved in substrate luring and transient binding as the protein releases its previous substrate into the cytoplasm. These findings shed light on a previously unknown mechanism in creatine transport and elucidate potential therapeutic targets.