Abstract: FR-PO998
The Solute Carrier SLC16A12 Is Critical for Creatine and Guanidinoacetate Handling in the Kidney
Session Information
- Pathology and Lab Medicine: Basic
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1601 Pathology and Lab Medicine: Basic
Authors
- Verouti, Sofia N., University of Bern, Bern, Switzerland
- Lambert, Delphine, University of Bern, Bern, Switzerland
- Geneviève, Escher, University of Bern, Bern, Switzerland
- Vogt, Bruno, University of Bern, Bern, Switzerland
- Fuster, Daniel G., University of Bern, Bern, Switzerland
Background
A heterozygous mutation (c.643C.A; p.Q215X) in the creatine transporter SLC16A12 was proposed to cause a syndrome with juvenile cataracts, microcornea and glucosuria in one Swiss family. However, we previously discovered a digenic syndrome in the index family and demonstrated that the glucosuria was due to a concomitant SCL5A2 mutation. In localization studies, we found SLC16A12 expression at the basolateral membrane of proximal tubular cells (PCT), and patients with the heterozygous SLC16A12 mutation displayed significantly reduced plasma levels and increased fractional excretion rates of guanidinoacetate (GAA).
Methods
To further explore the role of SLC16A12 in renal physiology and decipher the mechanism underlying the heterozygous SLC16A12 mutation in humans, we studied SLC16A12 deficient rats.
Results
SLC16A12 KO rats had lower plasma levels and increased 24 h urinary excretion rates of creatine and GAA compared to WT littermates. SLC16A12 KO rats also displayed lower plasma creatinine levels, but urinary creatinine excretion rates were reduced in parallel compared to WT rats. The phenotype of heterozygous rats was indistinguishable from WT rats.
Metabolic cage experiments revealed no additional signs of tubular dysfunction in SLC16A12 KO rats. In addition, glomerular filtration rate, measured by FITC-sinistrin, was unaltered in SLC16A12 KO rats. Selective renal artery and vein sampling showed similar A-V differences in GAA concentrations between WT and SLC16A12 KO rats, indicating incomplete compensation of urinary GAA losses by renal synthesis in SLC16A12 KO rats. In support of this finding, mRNA expression of L-arginine:glycine amidinotransferase (AGAT), the rate limiting enzyme in GAA synthesis, was significantly reduced in kidneys of SLC16A12 KO rats.
Conclusion
Our results reveal that SLC16A12 is critical for tubular reabsorption of creatine and its precursor GAA from the glomerular filtrate. In the absence of SLC16A12, ongoing urinary losses of GAA are not adequately compensated by increased intrarenal synthesis, possibly caused by AGAT feedback inhibition due to impaired basolateral exit of creatine from the PCT.
Furthermore, the lack of a phenotype in SLC16A12 heterozygous rats suggests a dominant-negative mechanism underlying the phenotype observed in humans with heterozygous c.643C.A; p.Q215X SLC16A12 mutation.