title: The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter.
abstract: Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. Michaelis-Menten kinetics yielded a Vmax of 838.8 pmol/h/oocyte and a Km of 567.4 µm. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired condition.
authors.affiliation: Institute of Medical Molecular Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Abplanalp
authors.forename: Endre
authors.initials: E
authors.lastname: Laczko
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Philp
authors.forename: John
authors.initials: J
authors.lastname: Neidhardt
authors.forename: Jurian
authors.initials: J
authors.lastname: Zuercher
authors.forename: Philipp
authors.initials: P
authors.lastname: Braun
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.forename: François
authors.initials: F
authors.lastname: Verrey
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
authors.forename: Simone M R
authors.initials: SM
authors.lastname: Camargo
authors.forename: Barbara
authors.initials: B
authors.lastname: Kloeckener-Gruissem
mesh_terms: D000818:Animals; D002386:Cataract / Q000235:genetics / Q000378:metabolism*; D003401:Creatine / Q000378:metabolism*; D005260:Female; D006030:Glycosuria, Renal / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D055432:Metabolomics; D027501:Monocarboxylic Acid Transporters / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology; D009928:Organ Specificity; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D012160:Retina / Q000378:metabolism; D014786:Vision Disorders / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C527548:SLC16A12 protein, human; C094770:SLC6A8 protein, human; C080679:creatine transporter; D003401:Creatine