HGNC Approved Gene Symbol:SLC28A1
Cytogenetic location:15q25.3 Genomic coordinates(GRCh38) :15:84,884,662-84,975,649 (from NCBI)
The SLC28A1 gene encodes concentrative nucleoside transporter-1 (CNT1), which preferentially transports pyrimidine nucleosides (summary byWevers et al., 2019).
Using PCR with primers based on rat Cnt1 to screen a kidney cDNA library, followed by probing the same library,Ritzel et al. (1997) isolated cDNAs encoding SLC28A1, which they called CNT1. The deduced 650-amino acid SLC28A1 protein is 83% identical to the rat protein. Northern blot analysis revealed expression of a 3.4-kb SLC28A1 transcript in kidney.Ritzel et al. (1998) detected expression of SLC28A1 in intestine, kidney, and liver by Northern blot and RT-PCR analyses.
By functional analysis,Ritzel et al. (1997) found that SLC28A1 facilitates sodium-dependent fluxes of uridine, azidodeoxythymidine (AZT), and adenosine, but not of guanosine or deoxyadenosine, which undergoes net renal secretion. They suggested that SLC28A1 represents a potential mechanism for renal reabsorption of physiologic nucleosides and synthetic nucleoside drugs.
By mutational analysis,Loewen et al. (1999) showed that when ser319-gln320 and ser353-leu354 from transmembrane helices 7 and 8 of SLC28A1 were altered to the corresponding residues of SLC28A2 (606208) (gly313-met314 and thr347-val348, respectively), the transporter specificity of SLC28A1 changed from thymidine to formycin.
Ritzel et al. (1997) mapped the SLC28A1 gene to 15q25-q26 by FISH.
In 2 brothers with highly elevated urinary excretion of uridine and cytidine (URCTU;618477),Wevers et al. (2019) detected a homozygous missense mutation in the SLC28A1 gene (S546P;606207.0001), encoding concentrative nucleoside transporter-1 (CNT1). The mutation affected a conserved residue and had been shown to abolish CNT1 nucleoside transporter function (Gray et al., 2004;Cano-Soldado et al., 2012). The mutation segregated with the phenotype in the family. The proband, who had experienced medication-responsive afebrile tonic-clonic seizures in infancy, was found also to carry a heterozygous mutation in the PRRT2 gene (c.649dup;614386.0001) that accounted for the seizure phenotype.
In a male child with URCTU,Perez-Torras et al. (2019) detected compound heterozygosity for 2 missense variants in the SLC28A1 gene, arg510 to cys (R510C;606207.0002) and arg561 to gln (R561Q;606207.0003). Functional studies showed that the variants affected the 3-dimensional structure, altered glycosylation, and decreased the half-life of the CNT1 protein. Coexpression of both variants dramatically impaired transport activity. The patient, who presented with myoclonia and fever, developed persistent lactate acidosis and severely disturbed liver enzymes, and died of multiorgan failure at 9 weeks of age, was also compound heterozygous for mutations in the PRF1 gene (e.g.,170280.0001), indicating familial hemophagocytic lymphohistiocytosis type 2 (FHL2;603553).
In 2 brothers with uridine-cytidineuria (URCTU;618477) from a nonconsanguineous Dutch family of Jordanian descent,Wevers et al. (2019) identified homozygosity for a C-to-T transition at nucleotide 1636 (c.1636T-C, NM_004213.4) resulting in a serine-to-proline substitution at codon 546 (S546P). The serine at this position is evolutionarily conserved through C. elegans.Gray et al. (2004) andCano-Soldado et al. (2012) showed in functional studies that the S546P variant abolished the nucleoside transporter function of CNT1. The mutation segregated with the phenotype in the family. The index patient, who had experienced medication-responsive afebrile tonic-clonic seizures in infancy, was found also to carry a heterozygous mutation in the PRRT2 gene (c.649dup;614386.0001) that accounted for the seizure phenotype. All mutations were identified by whole-exome sequencing.Wevers et al. (2019) cited the allele frequency of this variant in ExAC as 0.001055%.
In a male infant with uridine-cytidineuria (URCTU;618477),Perez-Torras et al. (2019) detected compound heterozygosity for 2 missense variants in the SLC28A1 gene. One was a c.1528C-T transition (c.1528C-T, NM_001287762.1) (rs2242047) in exon 14 that resulted in an arg510-to-cys (R510C) substitution. The other was a c.1682G-A transition in exon 16 that resulted in an arg561-to-gln substitution (R561Q;606207.0003). The mutations were identified by sequence analysis of genes directly involved in uridine and cytidine metabolism. Functional studies showed that the variants affected the 3-dimensional structure, altered glycosylation, and decreased the half-life of the CNT1 protein. Coexpression of both variants dramatically impaired transport activity. The patient presented with myoclonia and fever, developed persistent lactate acidosis and severely disturbed liver enzymes, and died of multiorgan failure at 9 weeks of age; the SLC28A1 mutations were found incidentally. The patient was also found by whole-genome sequencing to be compound heterozygous for mutations in the PRF1 gene (50delT,170280.0001 and 853_855del), which explained the presenting symptoms consistent with familial hemophagocytic lymphohistiocytosis type 2 (FHL2;603553).Perez-Torras et al. (2019) cited the allele frequency of the c.1528C-T variant (R510C) in ExAC as 5.7%, with a MAF in the European and East Asian populations of 1.6% and 36%, respectively. They cited the allele frequency of the c.1682G-A variant (R561Q) in ExAC as 0.0041%.
For discussion of the arg561-to-gln (R561Q) mutation, resulting from a a c.1682G-A transition (c.1682G-A, NM_001287762.1) in the SLC28A1 gene that was found in compound heterozygous state in an infant with uridine-cytidineuria (URCTU;618477) byPerez-Torras et al. (2019), see606207.0002.
Cano-Soldado, P., Gorraitz, E., Errasti-Murugarren, E., Casado, F. J., Lostao, M. P., Pastor-Anglada, M.Functional analysis of the human concentrative nucleoside transporter-1 variant hCNT1S546P provides insight into the sodium-binding pocket. Am. J. Physiol. Cell Physiol. 302: C257-C266, 2012. [PubMed:21998139,related citations] [Full Text]
Gray, J. H., Mangravite, L. M., Owen, R. P., Urban, T. J., Chan, W., Carlson, E. J., Huang, C. C., Kawamoto, M., Johns, S. J., Stryke, D., Ferrin, T. E., Giacomini, K. M.Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations. Molec. Pharm. 65: 512-519, 2004. [PubMed:14978229,related citations] [Full Text]
Loewen, S. K., Ng, A. M. L., Yao, S. Y. M., Cass, C. E., Baldwin, S. A., Young, J. D.Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na+ nucleoside cotransporters hCNT1 and hCNT2. J. Biol. Chem. 274: 24475-24484, 1999. [PubMed:10455109,related citations] [Full Text]
Perez-Torras, S., Mata-Ventosa, A., Drogemoller, B., Tarailo-Graovac, M., Meijer, J., Meinsma, R., van Cruchten, A. G., Kulik, W., Viel-Oliva, A., Bidon-Chanal, A., Ross, C. J., Wassermann, W. W., van Karnebeek, C. D. M., Pastor-Anglada, M., van Kuilenburg, A. B. P.Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure. Biochim. Biophys. Acta Molec. Basis Dis. 1865: 1182-1191, 2019. [PubMed:30658162,related citations] [Full Text]
Ritzel, M. W. L., Yao, S. Y. M., Huang, M.-Y., Elliott, J. F., Cass, C. E., Young, J. D.Molecular cloning and functional expression of cDNAs encoding a human Na(+)-nucleoside cotransporter (hCNT1). Am. J. Physiol. 272: C707-C714, 1997. [PubMed:9124315,related citations] [Full Text]
Ritzel, M. W. L., Yao, S. Y. M., Ng, A. M. L., Mackey, J. R., Cass, C. E., Young, J. D.Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Molec. Membr. Biol. 15: 203-211, 1998. [PubMed:10087507,related citations] [Full Text]
Wevers, R. A., Christensen, M., Engelke, U. F. H., Geuer, S., Coene, K. L. M., Kwast, J. T., Lund, A. M., Vissers, L. E. L. M.Functional disruption of pyrimidine nucleoside transporter CNT1 results in a novel inborn error of metabolism with high excretion of uridine and cytidine. J. Inherit. Metab. Dis. 42: 494-500, 2019. [PubMed:30847922,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: SLC28A1
Cytogenetic location: 15q25.3 Genomic coordinates(GRCh38) : 15:84,884,662-84,975,649(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 15q25.3 | [Uridine-cytidineuria] | 618477 | Autosomal recessive | 3 |
The SLC28A1 gene encodes concentrative nucleoside transporter-1 (CNT1), which preferentially transports pyrimidine nucleosides (summary by Wevers et al., 2019).
Using PCR with primers based on rat Cnt1 to screen a kidney cDNA library, followed by probing the same library, Ritzel et al. (1997) isolated cDNAs encoding SLC28A1, which they called CNT1. The deduced 650-amino acid SLC28A1 protein is 83% identical to the rat protein. Northern blot analysis revealed expression of a 3.4-kb SLC28A1 transcript in kidney. Ritzel et al. (1998) detected expression of SLC28A1 in intestine, kidney, and liver by Northern blot and RT-PCR analyses.
By functional analysis, Ritzel et al. (1997) found that SLC28A1 facilitates sodium-dependent fluxes of uridine, azidodeoxythymidine (AZT), and adenosine, but not of guanosine or deoxyadenosine, which undergoes net renal secretion. They suggested that SLC28A1 represents a potential mechanism for renal reabsorption of physiologic nucleosides and synthetic nucleoside drugs.
By mutational analysis, Loewen et al. (1999) showed that when ser319-gln320 and ser353-leu354 from transmembrane helices 7 and 8 of SLC28A1 were altered to the corresponding residues of SLC28A2 (606208) (gly313-met314 and thr347-val348, respectively), the transporter specificity of SLC28A1 changed from thymidine to formycin.
Ritzel et al. (1997) mapped the SLC28A1 gene to 15q25-q26 by FISH.
In 2 brothers with highly elevated urinary excretion of uridine and cytidine (URCTU; 618477), Wevers et al. (2019) detected a homozygous missense mutation in the SLC28A1 gene (S546P; 606207.0001), encoding concentrative nucleoside transporter-1 (CNT1). The mutation affected a conserved residue and had been shown to abolish CNT1 nucleoside transporter function (Gray et al., 2004; Cano-Soldado et al., 2012). The mutation segregated with the phenotype in the family. The proband, who had experienced medication-responsive afebrile tonic-clonic seizures in infancy, was found also to carry a heterozygous mutation in the PRRT2 gene (c.649dup; 614386.0001) that accounted for the seizure phenotype.
In a male child with URCTU, Perez-Torras et al. (2019) detected compound heterozygosity for 2 missense variants in the SLC28A1 gene, arg510 to cys (R510C; 606207.0002) and arg561 to gln (R561Q; 606207.0003). Functional studies showed that the variants affected the 3-dimensional structure, altered glycosylation, and decreased the half-life of the CNT1 protein. Coexpression of both variants dramatically impaired transport activity. The patient, who presented with myoclonia and fever, developed persistent lactate acidosis and severely disturbed liver enzymes, and died of multiorgan failure at 9 weeks of age, was also compound heterozygous for mutations in the PRF1 gene (e.g., 170280.0001), indicating familial hemophagocytic lymphohistiocytosis type 2 (FHL2; 603553).
In 2 brothers with uridine-cytidineuria (URCTU; 618477) from a nonconsanguineous Dutch family of Jordanian descent, Wevers et al. (2019) identified homozygosity for a C-to-T transition at nucleotide 1636 (c.1636T-C, NM_004213.4) resulting in a serine-to-proline substitution at codon 546 (S546P). The serine at this position is evolutionarily conserved through C. elegans. Gray et al. (2004) and Cano-Soldado et al. (2012) showed in functional studies that the S546P variant abolished the nucleoside transporter function of CNT1. The mutation segregated with the phenotype in the family. The index patient, who had experienced medication-responsive afebrile tonic-clonic seizures in infancy, was found also to carry a heterozygous mutation in the PRRT2 gene (c.649dup; 614386.0001) that accounted for the seizure phenotype. All mutations were identified by whole-exome sequencing. Wevers et al. (2019) cited the allele frequency of this variant in ExAC as 0.001055%.
In a male infant with uridine-cytidineuria (URCTU; 618477), Perez-Torras et al. (2019) detected compound heterozygosity for 2 missense variants in the SLC28A1 gene. One was a c.1528C-T transition (c.1528C-T, NM_001287762.1) (rs2242047) in exon 14 that resulted in an arg510-to-cys (R510C) substitution. The other was a c.1682G-A transition in exon 16 that resulted in an arg561-to-gln substitution (R561Q; 606207.0003). The mutations were identified by sequence analysis of genes directly involved in uridine and cytidine metabolism. Functional studies showed that the variants affected the 3-dimensional structure, altered glycosylation, and decreased the half-life of the CNT1 protein. Coexpression of both variants dramatically impaired transport activity. The patient presented with myoclonia and fever, developed persistent lactate acidosis and severely disturbed liver enzymes, and died of multiorgan failure at 9 weeks of age; the SLC28A1 mutations were found incidentally. The patient was also found by whole-genome sequencing to be compound heterozygous for mutations in the PRF1 gene (50delT, 170280.0001 and 853_855del), which explained the presenting symptoms consistent with familial hemophagocytic lymphohistiocytosis type 2 (FHL2; 603553). Perez-Torras et al. (2019) cited the allele frequency of the c.1528C-T variant (R510C) in ExAC as 5.7%, with a MAF in the European and East Asian populations of 1.6% and 36%, respectively. They cited the allele frequency of the c.1682G-A variant (R561Q) in ExAC as 0.0041%.
For discussion of the arg561-to-gln (R561Q) mutation, resulting from a a c.1682G-A transition (c.1682G-A, NM_001287762.1) in the SLC28A1 gene that was found in compound heterozygous state in an infant with uridine-cytidineuria (URCTU; 618477) by Perez-Torras et al. (2019), see 606207.0002.
Cano-Soldado, P., Gorraitz, E., Errasti-Murugarren, E., Casado, F. J., Lostao, M. P., Pastor-Anglada, M.Functional analysis of the human concentrative nucleoside transporter-1 variant hCNT1S546P provides insight into the sodium-binding pocket. Am. J. Physiol. Cell Physiol. 302: C257-C266, 2012. [PubMed: 21998139] [Full Text: https://doi.org/10.1152/ajpcell.00198.2011]
Gray, J. H., Mangravite, L. M., Owen, R. P., Urban, T. J., Chan, W., Carlson, E. J., Huang, C. C., Kawamoto, M., Johns, S. J., Stryke, D., Ferrin, T. E., Giacomini, K. M.Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations. Molec. Pharm. 65: 512-519, 2004. [PubMed: 14978229] [Full Text: https://doi.org/10.1124/mol.65.3.512]
Loewen, S. K., Ng, A. M. L., Yao, S. Y. M., Cass, C. E., Baldwin, S. A., Young, J. D.Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na+ nucleoside cotransporters hCNT1 and hCNT2. J. Biol. Chem. 274: 24475-24484, 1999. [PubMed: 10455109] [Full Text: https://doi.org/10.1074/jbc.274.35.24475]
Perez-Torras, S., Mata-Ventosa, A., Drogemoller, B., Tarailo-Graovac, M., Meijer, J., Meinsma, R., van Cruchten, A. G., Kulik, W., Viel-Oliva, A., Bidon-Chanal, A., Ross, C. J., Wassermann, W. W., van Karnebeek, C. D. M., Pastor-Anglada, M., van Kuilenburg, A. B. P.Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure. Biochim. Biophys. Acta Molec. Basis Dis. 1865: 1182-1191, 2019. [PubMed: 30658162] [Full Text: https://doi.org/10.1016/j.bbadis.2019.01.013]
Ritzel, M. W. L., Yao, S. Y. M., Huang, M.-Y., Elliott, J. F., Cass, C. E., Young, J. D.Molecular cloning and functional expression of cDNAs encoding a human Na(+)-nucleoside cotransporter (hCNT1). Am. J. Physiol. 272: C707-C714, 1997. [PubMed: 9124315] [Full Text: https://doi.org/10.1152/ajpcell.1997.272.2.C707]
Ritzel, M. W. L., Yao, S. Y. M., Ng, A. M. L., Mackey, J. R., Cass, C. E., Young, J. D.Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Molec. Membr. Biol. 15: 203-211, 1998. [PubMed: 10087507] [Full Text: https://doi.org/10.3109/09687689709044322]
Wevers, R. A., Christensen, M., Engelke, U. F. H., Geuer, S., Coene, K. L. M., Kwast, J. T., Lund, A. M., Vissers, L. E. L. M.Functional disruption of pyrimidine nucleoside transporter CNT1 results in a novel inborn error of metabolism with high excretion of uridine and cytidine. J. Inherit. Metab. Dis. 42: 494-500, 2019. [PubMed: 30847922] [Full Text: https://doi.org/10.1002/jimd.12081]
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