Alternative titles; symbols
HGNC Approved Gene Symbol: SLC6A20
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:45,755,449-45,796,536 (from NCBI)
Na(+) and Cl(-)-coupled transporter proteins mediate transit of structurally related small hydrophilic substances across plasma membranes. These transporters are structurally related to a small subgroup of proteins with no known substrates. By screening a mouse kidney cDNA library, Nash et al. (1998) obtained cDNAs encoding 2 members of this subgroup, Xt2 and Xt3. Using mouse Xt3 to screen a human kidney cDNA library, they obtained a partial sequence encoding human XT3. Sequence analysis predicted that the mouse sequence, approximately 88% identical to human XT3 and rat B21a, contains 12 potential transmembrane domains. Northern blot analysis detected 3.2- and 4.0-kb XT3 transcripts in human kidney and small intestine, with no expression detected in other tissues. Expression was slightly higher in kidney, where an 8.5-kb transcript was also detected. Immunofluorescence microscopy demonstrated expression on the plasma membrane of transfected cells. Nash et al. (1998) tested numerous substrates but failed to identify a compound transported by Xt3.
Broer et al. (2008) performed immunofluorescence studies in adult human kidney and observed that expression of SLC6A20 was restricted to S2 segments in the renal cortex and S3 straight tubules traversing into the medulla.
Nash et al. (1998) mapped the mouse Xt3 gene to chromosome 9, near the telomere. Scott (2001) mapped the human XT3 gene to chromosome 3 based on sequence similarity between the XT3 sequence (GenBank AF075260) and a chromosome 3 clone (GenBank AC005669).
Associations Pending Confirmation
For discussion of a possible association between variation in the SLC6A20 gene and hyperglycinuria leading to nephrolithiasis, see 138500.
Reclassified Variants
The T199M variant (605616.0001) in the SLC6A20 gene identified by Broer et al. (2008) has been reclassified as a polymorphism. Broer et al. (2008) reported a variant in the SLC6A20 gene (T199M; 605616.0001) that was thought to contribute to hyperglycinuria (138500) and iminoglycinuria (242600).
This variant, formerly titled HYPERGLYCINURIA and IMINOGLYCINURIA, DIGENIC, has been reclassified as a polymorphism because it was present in 19,986 of 278,932 alleles and in 856 homozygotes in the gnomAD database (v2.1.1), for an allele frequency of 0.07165 (Hamosh, 2023).
In 2 families segregating iminoglycinuria (242600) and/or hyperglycinuria (138500), Broer et al. (2008) identified a mutation in the SLC36A2 gene (G87V; 608331.0001) that did not fully segregate with disease; in both families, they identified a heterozygous c.596C-T polymorphism in the SLC6A20 gene, resulting in a thr199-to-met (T199M) substitution, and in 1 of these families a splice site polymorphism in the SLC6A19 gene (608893.0001). The authors speculated that these polymorphisms, and perhaps polymorphisms in the SLC6A18 gene (610300), contributed to the phenotypes.
Broer, S., Bailey, C. G., Kowalczuk, S., Ng, C., Vanslambrouck, J. M., Rodgers, H., Auray-Blais, C., Cavanaugh, J. A., Broer, A., Rasko, J. E. J. Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. J. Clin. Invest. 118: 3881-3892, 2008. [PubMed: 19033659] [Full Text: https://doi.org/10.1172/JCI36625]
Hamosh, A. Personal Communication. Baltimore, Md. 4/3/2023.
Nash, S. R., Giros, B., Kingsmore, S. F., Kim, K. M., El-Mestikawy, S., Dong, Q., Fumagalli, F., Seldin, M. F., Caron, M. G. Cloning, gene structure and genomic localization of an orphan transporter from mouse kidney with six alternatively-spliced isoforms. Receptors Channels 6: 113-128, 1998. [PubMed: 9932288]
Scott, A. F. Personal Communication. Baltimore, Md. 2/5/2001.