Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria

J Am Soc Nephrol. 2016 May;27(5):1426-36. doi: 10.1681/ASN.2015040411.

Nasser Dhayat ¹, Alexandre Simonin ², Manuel Anderegg ³, Ganesh Pathare ³, Benjamin P Lüscher ⁴, Christine Deisl ³, Giuseppe Albano ³, David Mordasini ¹, Matthias A Hediger ⁵, Daniel V Surbek ⁴, Bruno Vogt ¹, Jörn Oliver Sass ⁶, Barbara Kloeckener-Gruissem ⁷, Daniel G Fuster ⁸

Affiliations

1 Division of Nephrology, Hypertension and Clinical Pharmacology, and Department of Clinical Research, University of Bern, Switzerland;
2 Institute of Biochemistry and Molecular Medicine, Swiss National Centre of Competence in Research Transcure, and.
3 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.
4 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;
5 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;
6 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;
7 Institute of Medical Molecular Genetics, University of Zürich, Zürich, Switzerland; and Department of Biology, Swiss Federal Institute of Technology in Zürich, Zürich, Switzerland.
8 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.

PMID: 26376857 DOI: 10.1681/ASN.2015040411

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.

Keywords

cell and transport physiology; familial nephropathy; genetic renal disease.

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