TY - JOUR U1 - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed) A1 - Dhayat, Nasser A1 - Simonin, Alexandre A1 - Anderegg, Manuel A1 - Pathare, Ganesh A1 - Lüscher, Benjamin P. A1 - Deisl, Christine A1 - Albano, Giuseppe A1 - Mordasini, David A1 - Hediger, Matthias A. A1 - Surbek, Daniel V. A1 - Vogt, Bruno A1 - Sass, Jörn Oliver A1 - Kloeckener-Gruissem, Barbara A1 - Fuster, Daniel G. T1 - Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria JF - Journal of the American Society of Nephrology N2 - 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. Y1 - 2016 SN - 1533-3450 SS - 1533-3450 U6 - https://doi.org/10.1681/ASN.2015040411 DO - https://doi.org/10.1681/ASN.2015040411 PM - 26376857 VL - 27 IS - 5 SP - 1426 EP - 1436 PB - American Society of Nephrology ER -