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  -