title: Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria.
abstract: A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland;
authors.forename: Nasser
authors.initials: N
authors.lastname: Dhayat
authors.affiliation: Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Simonin
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and.
authors.forename: Manuel
authors.initials: M
authors.lastname: Anderegg
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Pathare
authors.affiliation: Department of Clinical Research, University of Bern, Switzerland; Swiss National Centre of Competence in Research Transcure, and Department of Obstetrics and Gynecology, University Hospital of Bern, Switzerland;
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Lüscher
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and.
authors.forename: Christine
authors.initials: C
authors.lastname: Deisl
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Albano
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland;
authors.forename: David
authors.initials: D
authors.lastname: Mordasini
authors.affiliation: Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and Department of Obstetrics and Gynecology, University Hospital of Bern, Switzerland;
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Hediger
authors.affiliation: Department of Clinical Research, University of Bern, Switzerland; Swiss National Centre of Competence in Research Transcure, and Department of Obstetrics and Gynecology, University Hospital of Bern, Switzerland;
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Surbek
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland;
authors.forename: Bruno
authors.initials: B
authors.lastname: Vogt
authors.affiliation: Division of Clinical Chemistry and Biochemistry, Children's Research Center, University Children's Hospital, Zürich, Switzerland; Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany;
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.affiliation: Institute of Medical Molecular Genetics, University of Zürich, Zürich, Switzerland; and Department of Biology, Swiss Federal Institute of Technology in Zürich, Zürich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kloeckener-Gruissem
authors.affiliation: Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and Daniel.Fuster@insel.ch.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fuster
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism; D006029:Glycosuria / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D055815:Young Adult
chemical_list: D027501:Monocarboxylic Acid Transporters; C527548:SLC16A12 protein, human; C004946:glycocyamine; D005998:Glycine
keywords: cell and transport physiology; familial nephropathy; genetic renal disease