Intrinsic Activity, 2018; 6 (Suppl. 1): A3.7
24th Scientific Symposium of the Austrian Pharmacological Society (APHAR)
Graz, 27 – 28 September 2018
Institute of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Austria
Background: The human creatine transporter-1 (hCRT-1, SLC6A8) is a member of the sodium-dependent neurotransmitter transporter family. Creatine transporter deficiency (CTD) has been associated with a number of disorders, ranging from epilepsy to mental retardation, autism, development delay, behavior problems, motor dysfunction to gastrointestinal symptoms. Diseases arising from misfolding of other proteins belonging to the SLC6 protein family have been reported in the literature; e. g. mutations in the dopamine transporter (DAT) cause infantile parkinsonism / dystonia. In CRT-1, sixteen mutations have been linked to the creatine deficiency syndrome in people . One of these variants is a conservative mutation G132V, associated with severe mental retardation in children. Interestingly, the mutation of an equivalent glycine residue in Drosophila melanogaster DAT (G108Q-dDAT) leads to a sleepless phenotype in flies . In the present study we examined the molecular basis of CTD-associated mutations and the pharmacological means by which these can be functionally recouped.
Methods: We generated 16 CTD-causing mutations in hCRT-1 by site-directed mutagenesis (Quickchange, Stratagene). All mutants were pharmacologically characterised by performing [3H]creatine assays, as well by confocal microscopy and biochemical techniques.
By creatine transport activity assays, we showed that most CTD mutants have less than
Treatment with the chemical chaperone
This work was supported by the Austrian Science Fund FWF (project no. P31255-B27 to