Structural Insights into Creatine Transport from Novel Disease Mutation

Show simple item record

dc.contributor Helsingin yliopisto, Lääketieteellinen tiedekunta fi
dc.contributor University of Helsinki, Faculty of Medicine en
dc.contributor Helsingfors universitet, Medicinska fakulteten sv Landoni, Juan Cruz 2019
dc.identifier.uri URN:NBN:fi:hulib-201901211108
dc.description.abstract 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. en
dc.language.iso eng
dc.publisher Helsingin yliopisto fi
dc.publisher University of Helsinki en
dc.publisher Helsingfors universitet sv
dc.title Structural Insights into Creatine Transport from Novel Disease Mutation en
dc.type.ontasot pro gradu -tutkielmat fi
dc.type.ontasot master's thesis en
dc.type.ontasot pro gradu-avhandlingar sv
dct.identifier.urn URN:NBN:fi:hulib-201901211108
dc.subject.specialization Ruotsinkielinen opintolinja fi
dc.subject.specialization Study orientation in Swedish en
dc.subject.specialization Svenskspråkig studieinriktning sv
dc.subject.degreeprogram Translationaalisen lääketieteen maisteriohjelma fi
dc.subject.degreeprogram Master's Programme in Translational Medicine en
dc.subject.degreeprogram sv

Files in this item

Files Size Format View
Landoni_JuanCruz_pro_gradu_2018.pdf 12.56Mb application/pdf View/Open

This item appears in the following Collection(s)

Show simple item record