A heterozygous mutation (c.643C.A; p.Q215X) in the creatine transporter SLC16A12 has been proposed to cause a syndrome with juvenile cataracts, microcornea, and glucosuria in humans. To further explore the role of SLC16A12 in renal physiology and decipher the mechanism underlying the phenotype of humans with the SLC16A12 mutation, we studied Slc16a12 knockout (KO) rats. Slc16a12 KO rats had lower plasma levels and increased absolute and fractional urinary excretion of creatine and its precursor guanidinoacetate (GAA). Slc16a12 KO rats displayed lower plasma and urinary creatinine levels, but the glomerular filtration rate was normal. The phenotype of heterozygous rats was indistinguishable from wild-type (WT) rats. Renal artery to vein (RAV) concentration differences in WT rats were negative for GAA and positive for creatinine. However, RAV differences for GAA were similar in Slc16a12 KO rats, indicating incomplete compensation of urinary GAA losses by renal GAA synthesis. Together, our results reveal that Slc16a12 in the basolateral membrane of the proximal tubule is critical for the reabsorption of creatine and GAA. Our data suggest a dominant-negative mechanism underlying the phenotype of humans affected by the heterozygous SLC16A12 mutation. Furthermore, in the absence of Slc16a12, urinary losses of GAA are not adequately compensated by increased tubular synthesis, likely caused by feedback inhibition of the rate-limiting enzyme l-arginine:glycine amidinotransferase by creatine in proximal tubular cells.NEW & NOTEWORTHY SLC16A12 is a recently identified creatine transporter of unknown physiological function. A heterozygous mutation in the human SLC16A12 gene causes juvenile cataracts and reduced plasma guanidinoacetate (GAA) levels with an increased fractional urinary excretion of GAA. Our study with transgenic SLC16A12-deficient rats reveals that SLC16A12 is critical for tubular reabsorption of creatine and GAA in the kidney. Our data furthermore indicate a dominant-negative mechanism underlying the phenotype of humans affected by the heterozygous SLC16A12 mutation.
Keywords: L-arginine:glycine amidinotransferase; SLC16A12; creatine; guanidinoacetate; guanidinoacetate methyltransferase.