The amino acid transporter asc-1 is not involved in cystinuria (original) (raw)
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Proceedings of the National Academy of Sciences of the United States of America, 2016
Heterodimeric amino acid transporters play crucial roles in epithelial transport, as well as in cellular nutrition. Among them, the heterodimer of a membrane protein b(0,+)AT/SLC7A9 and its auxiliary subunit rBAT/SLC3A1 is responsible for cystine reabsorption in renal proximal tubules. The mutations in either subunit cause cystinuria, an inherited amino aciduria with impaired renal reabsorption of cystine and dibasic amino acids. However, an unsolved paradox is that rBAT is highly expressed in the S3 segment, the late proximal tubules, whereas b(0,+)AT expression is highest in the S1 segment, the early proximal tubules, so that the presence of an unknown partner of rBAT in the S3 segment has been proposed. In this study, by means of coimmunoprecipitation followed by mass spectrometry, we have found that a membrane protein AGT1/SLC7A13 is the second partner of rBAT. AGT1 is localized in the apical membrane of the S3 segment, where it forms a heterodimer with rBAT. Depletion of rBAT i...
The amino acid transport system bo,+ and cystinuria
Molecular Membrane Biology, 2001
Amino acid transport in mammalian plasma membranes is mediated by a multiplicity of amino acid transport systems. Some of them (systems L, y + L, x c Ð and b o,+) are the result of the activity of heteromeric amino acid transporters (HAT) (i.e. transport activity is elicited by the coexpression of a heavy and a light subunit). The two heavy subunits known today (HSHAT: rBAT and 4F2hc) were identified in 1992, and light subunits (LSHAT: LAT-1, LAT-2, asc-1, y + LAT-1, y + LAT-2, xCT and b o,+ AT) have been cloned in the last 2 years. Defects in two genes of this family (SLC3A1, encoding rBAT and SLC7A9, encoding b o,+ AT) are responsible for cystinuria, an inherited aminoaciduria of cystine and dibasic amino acids. This finding and functional studies of rBAT and b o,+ AT suggested that these two proteins encompas s ed the high-affinity renal reabsorption system of cystine. In contrast to this view, immunofluorescence studies showed that rBAT is most abundant in the proximal straight tubule, and b o,+ AT is most abundant in the proximal convoluted tubule of the nephron. The need for a new light subunit for rBAT and a heavy subunit for b o,+ AT is discussed.
Kidney International, 1997
Genomic organization of a human cystine transporter gene (SLC3AI) and identification of novel mutations causing cystinuria. Cystinuria is a common inherited aminoaciduria that leads to recurrent cystine nephrolithiasis. Mutations in a gene encoding a renal amino acid transporter strate the utility of this approach by identifying five mutant alleles including two novel missense mutations. This information will facilitate the identification of other SLC3A I mutations, contribute to our understanding of the molecular basis of cystinuria, and provide the foundation for genotype-phenotype correlations. Methods
Mutations in the SLC3A1 transporter gene in cystinuria
American journal of human genetics, 1995
Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. Guided by the identification of the SLC3A1 amino acid-transport gene on chromosome 2, we recently established genetic linkage of cystinuria to chromosome 2p in 17 families, without evidence for locus heterogeneity. Other authors have independently identified missense mutations in SLC3A1 in cystinuria patients. In this report we describe four additional cystinuria-associated mutations in this gene: a frameshift, a deletion, a transversion inducing a critical amino acid change, and a nonsense mutation. The latter stop codon was found in all of eight Ashkenazi Jewish carrier chromosomes examined. This report brings the number of disease-associated mutations in this gene to 10. We also assess the frequency of these mutations in our 17 cystinuria families.
American Journal of Physiology-Renal Physiology, 2013
Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 ( rBAT) and SLC7A9 ( b 0,+ AT). Gene targeting of the catalytic subunit ( Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b0,+. No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but ...
Five Novel Mutations in Cystinuria Genes SLC3A1 and SLC7A9
Balkan Journal of Medical Genetics - BALK J MED GEN, 2009
Cystinuria is an autosomal recessive disorder that is characterized by impaired transport of cys- tine, lysine, ornithine and arginine in the proximal renal tubule and epithelial cells of the gastrointesti- nal tract. The transport of these amino acids is medi- ated by the rBAT/b0,+AT transporter, the subunits of which are encoded by the genes SLC3A1, located on chromosome 2p16.3-21, and SLC7A9, located on chromosome 19q12-13.1. Based on the urinary cystine excretion patterns of obligate heterozygotes, cystinuria is classified into type I (normal amino acid urinary pattern in heterozygotes) and non type I (a variable degree of urinary hyper excretion of cys- tine and dibasic amino acids in heterozygotes). On the basis of genetic aspects, cystinuria is classified into type A, is caused by mutations in both alleles of SLC3A1; type B, caused by mutations in both alleles of SLC7A9 and type AB, is caused by one mutation in SLC3A1 and one mutation in SLC7A9. Here we present two novel muta...
Human Molecular Genetics, 2001
Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b o,+ AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b o,+ AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in nonconserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.
Genomic Organization ofSLC3A1,a Transporter Gene Mutated in Cystinuria
Genomics, 1996
disorder with an estimated carrier frequency of 1:60 in The SLC3A1 gene encodes a transport protein for the United States and as high as cystine and the dibasic amino acids. Recently muta-1:25 among Libyan Jews living in Israel (Weinberger tions in this gene have been shown to cause cystin- et al., 1974). Calonge et al. (1994) have described six uria. We report the genomic structure and organizamutations in the SLC3A1 gene in cystinuria patients, tion of SLC3A1, which is composed of 10 exons and and we have described four additional mutations (Pras spans nearly 45 kb. Until now screening for mutations et al., 1995). More mutations were described by Gasparin SLC3A1 has been based on RT-PCR amplification ini et al. (1995) and by Miyamoto et al. (1995). Since of illegitimate mRNA transcripts from white blood the genomic structure of this gene was unknown, and cells. In this report we provide primers for amplificasince it is not expressed in readily available tissues tion of exons from genomic DNA, thus simplifying the such as leukocytes, mutation detection has relied upon process of screening for SLC3A1 mutations in cystin-RT-PCR amplification of illegitimate mRNA tranuria. ᭧