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.

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…In a study re‐evaluating the original family, the cause for renal glucosuria accompanying juvenile cataract in all but three family members, was attributed to a second independent heterozygous mutation in the glucose transporter SGLT2/ SLC5A2 rather than the mutation in SLC16A12 . Interestingly, this study revealed an indirect link between the SLC16A12 mutation and reduced guanidinoacetate levels, which is a precursor of creatine but not a substrate of MCT12 70. Thus, there are still many open questions regarding the exact role and function of MCT12 in the kidneys.…”

Monocarboxylate Transporters: Therapeutic Targets and Prognostic Factors in Disease

“…Table summarizes the substrate specificity, tissue localization, and the potential clinical relevance for the MCT isoforms. It is important to note that the discrepancy between MCT isoform number and SLC16A nomenclature evolved from the order in which each cDNA sequence was determined and characterized .…”

“…More recently, MCT12 was characterized as a creatine transporter using MCT12 ‐transfected X. laevis oocytes and the utilization of a high‐resolution metabolomics approach . In order to further clarify the association of the MCT12 mutation and its relation to glucosuria, detailed in vitro studies and analysis of patients with the MCT12 mutation were performed . Although individuals with an MCT12 mutation displayed unaltered creatine levels from the wild‐type patients, there was increased renal secretion of creatine's precursor, guanidinoacetate.…”

“…Although individuals with an MCT12 mutation displayed unaltered creatine levels from the wild‐type patients, there was increased renal secretion of creatine's precursor, guanidinoacetate. The glucosuria observed in the MCT12 mutation was also evaluated and demonstrated to be more directly correlated to a heterozygous SLGT2 mutation, and not MCT12 . Further studies and more detailed data collection in vivo are still necessary, however, prior to characterizing the mechanistic effect of the MCT12 mutation on guanidinoacetate homeostasis.…”

“…Recent evidence has suggested the potential physiological role and importance of MCT12 in humans; however, there still remains some debate surrounding its association with glucosuria and cataract formation. [49][50][51] A nonsense mutation in the MCT12 gene that results in a Q215X amino acid mutation was found in a group of 12 subjects suffering from cataracts and elevated glucose levels in the urine. 50 The premature termination of the MCT12 protein sequence is suggested to yield a highly or fully dysfunctional protein, which could lead to tissue-specific defects.…”