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 thekidney.Here,weexaminedMCT12inthekidneyandfoundthat it residesonbasolateralmembranes of proximal tubules.PatientswithMCT12mutation exhibited reducedplasmalevelsandincreased fractionalexcretion 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 segregatedwith 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.HeterozygousmutationofMCT12 affects systemic levels andrenalhandlingofguanidinoacetate, possibly through an indirectmechanism. 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.