No evidence for point mutations in the novel renal cystine transporter AGT1/SLC7A13 contributing to the etiology of cystinuria

Abstract

BackgroundCystinuria is caused by the defective renal reabsorption of cystine and dibasic amino acids, and results in cystine stone formation. So far, mutations in two genes have been identified as causative. The SLC3A1/rBAT gene encodes the heavy subunit of the heterodimeric rBAT-b0,+AT transporter, whereas the light chain is encoded by the SLC7A9/ b0,+AT gene. In nearly 85% of patients mutations in both genes are detectable, but a significant number of patients currently remains without a molecular diagnosis. Thus, the existence of a further cystinuria gene had been suggested, and the recently identified AGT1/SLC7A13 represents the long-postulated partner of rBAT and third cystinuria candidate gene.MethodsWe screened a cohort of 17 cystinuria patients for SLC7A13 variants which were negative for SLC3A1 and SLC7A9 mutations.ResultsDespite strong evidences for an involvement of SLC7A13 mutations in cystinuria, we could not confirm a relevant role of SLC7A13 for the disease.ConclusionWith the exclusion of SLC7A13/AGT1 as the third cystinuria gene accounting for the SLC3A1 and SLC7A9 mutation negative cases, it becomes obvious that other genetic factors should be responsible for the cystinuria phenotype in nearly 15% of patients.

Establishment of a Ciliogenesis-Associated Signaling Model for Polycystic Kidney Disease

“…Genome-wide association studies have uncovered that UMOD is among the most outstanding loci associated with chronic kidney disease (CKD) in the general population, because it has a large effect on eGFR and CKD risk that is consistent across different ethnic groups [29]. The membrane protein AGT1/SLC7A13 is the second partner of rBAT, which is a heterodimeric amino acid transporter responsible for epithelial transport [30]. MIOX stands for the proximal tubular enzyme myo-inositol oxygenase.…”

The genetics of cystinuria – an update and critical reevaluation

“…International registry initiatives, such as EUROCYS, are a step into the right direction, as transnational datasets capturing the natural history of disease are urgently needed for correlation with underlying genotypes and environmental factors. Clinical nephrology patients, carrying either biallelic variants in SLC3A1 or at least one pathogenic variant in SLC7A9 [5,7,15]. The remaining <15% constitute patients with single monoallelic findings in SLC3A1 or without any variant detected in the two known disease genes.…”

“…Since the advent of massively parallel sequencing, molecular diagnoses can be found in >85% of CU patients, carrying either biallelic variants in SLC3A1 or at least one pathogenic variant in SLC7A9 [5,7,15]. The remaining <15% constitute patients with single monoallelic findings in SLC3A1 or without any variant detected in the two known disease genes.…”

“…As a result, SLC7A13 has been proposed to be a new gene candidate for cystinuria as it also had an increased expression in S3 segment [22]. Nonetheless, from a cohort of 17 genetically unresolved CU patients, none was found to carry AGT1 variants that could be attributed to the development of cystinuria in humans [15]. While it appears that AGT1 variants alone may not directly lead to the development of CU, there may be other genes in which variants could result in hyperexcretion of cystine.…”

Amino Acid Transport Defects in Human Inherited Metabolic Disorders

“…It has yet to be determined if SLC7A13 mutations could help explain the isolated cystinuria observed in patients who still do not have any detectable mutation in SLC3A1 and SLC7A9 [101].…”