Disease relevance of SLC3A1

• Significant contribution of genomic rearrangements in SLC3A1 and SLC7A9 to the etiology of cystinuria [1].
• However, the relative risk for nephrolithiasis and the prevalence of SLC3A1 mutations in these subgroups are unknown [2].
• Herein is presented the case of a 1-year-old girl with cystinuria and recurrent urolithiasis; the genetic basis of the disease was investigated by mutational analysis of the SLC3A1 gene [3].
• The aim of this study was to investigate the distribution of angiotensin converting enzyme (ACE), angiotensinogen (AGT) and angiotensin receptor type 1 (ATR1) genetic polymorphisms in children affected by chronic renal failure due to renal hypodysplasia associated with posterior urethral valves or without urethral abnormalities [4].
• These results suggest that a genetic variant of the ATR1 gene locus influences the risk of essential hypertension in the sex-specific manner in the Serbian population [5].

High impact information on SLC3A1

• Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4) [6].
• Both neutral and dibasic amino acids inhibited the D2H-induced uptake of cystine [7].
• Southern blot analysis of genomic DNA from a panel of mouse-human somatic cell hybrids showed that the human gene for D2H resides on chromosome 2 [7].
• The D2H cDNA is 2284 nucleotides long and encodes a 663 amino acid protein that is 80% identical to the rat D2 amino acid sequence and 86% to that of the rabbit homologue rBAT [7].
• In order to evaluate the role of this protein in human inherited diseases such as cystinuria, we have isolated a human D2 clone (D2H) by low stringency screening of a human kidney cDNA library using the radiolabeled D2 insert as a probe [7].

Chemical compound and disease context of SLC3A1

• Two responsible genes have been identified so far: Mutations in the SLC3A1 gene encoding the heavy chain rbAT of the renal cystine transport system rbAT/b(0,+)AT cause cystinuria type I, while variants in SLC7A9, the gene of its light chain b(0,+)AT, have been demonstrated in non-type I cystinuria [8].

Biological context of SLC3A1

• In the pediatric patients, mutations were found in 54% of type I (SLC3A1) and in 25% of non-type I (SLC7A9) chromosomes [8].
• RESULTS: Two novel mutations were identified in SLC3A1 and three in SLC7A9; three were missense mutations and two frameshift mutations [8].
• The detected duplication in SLC3A1 was analyzed in detail by further real-time assays, reverse transcription (RT)-PCR and direct sequencing [1].
• Molecular genetic analysis of SLC3A1 and SLC7A9 genes in Czech and Slovak cystinuric patients [9].
• Individual exons of the SLC3A1 and SLC7A9 genes were analyzed by direct sequencing [9].

Anatomical context of SLC3A1

• RESULTS: The SLC3A1 gene has been shown to code for a protein that, when expressed in Xenopus oocytes, confers on these cells the ability to transport cystine, arginine, lysine and ornithine [10].
• Until now screening for mutations in SLC3A1 has been based on RT-PCR amplification of illegitimate mRNA transcripts from white blood cells [11].
• We demonstrate its b(0,+)-type amino acid transport kinetics using a heterodimeric fusion construct and show its luminal brush border localization in kidney proximal tubule [12].
• Immunocytochemical studies have indicated that NBAT is primarily localized in the brush border membranes of rat kidney and intestinal epithelial cells, a localization consistent with its proposed role in amino acid transport [13].
• Rabbit kidney brush border membranes and membranes of NBAT cRNA-injected Xenopus oocytes also contain such heterodimers [14].

Associations of SLC3A1 with chemical compounds

• In some patients the disease is caused by mutations in the SLC3A1 gene, which is located on the short arm of chromosome 2 and encodes a renal/intestinal transporter for cystine and the dibasic amino acids [15].
• Mutations of SLC7A9, which encodes the luminal transport channel itself, tend to be dominant and mutations of SLC3A1 (rBAT), which encodes a transporter subunit, are always recessive [16].
• The DNA fragment (317 bp) carrying the point mutation was amplified by polymerase chain reaction (PCR) on the exon 8 of the SLC3A1 gene, which encodes for the transmembrane glycoprotein rBAT, a part of the active cystine and dibasic amino acids transporter [17].
• To determine the role of a neutral and basic amino acid transporter (NBAT) in amino acid transport, we microinjected several COOH-terminal deletion mutants of NBAT cRNA into Xenopus oocytes and measured transport activity for arginine, leucine, and cystine in the presence and absence of sodium [18].
• Although both the WT/NBAT and the truncated mutant, Delta588-683, induce qualitatively similar transport systems, the two forms of the protein exhibit contrasting sensitivities toward a point mutation in which the cysteine residue at position 111 was mutated to serine [19].

Other interactions of SLC3A1

• METHODS: Twenty-one cystinuric children from 16 families were analyzed by mutational analysis of the genes SLC3A1 and the SLC7A9 [8].
• In 1992, rBAT and 4F2hc (genes SLC3A1 and SLC3A2, respectively, in the nomenclature of the Human Genome Organization) were identified as putative heavy subunits of mammalian amino acid transporters [20].
• Type I/I families showed homogeneous linkage to SLC3A1 (Zmax > 3.0 at theta = 0.00; alpha = 1), whereas types I/III and III/III were not linked [21].
• To facilitate systematic screening of this gene for mutations, we have delineated the complete genomic organization of the SLC3A1 coding region using polymerase chain reaction strategies [22].
• Data on SLC3A1 gene expression are available for humans, while data on SLC37A2 are available for mice [23].

Analytical, diagnostic and therapeutic context of SLC3A1

• METHODS: We screened a cohort of 49 cystinurics for copy number deviations in the genes SLC3A1 and SLC7A9 by quantitative real-time PCR assays using fluorogenic 5' nuclease chemistry [1].
• Assignment of the gene for cystinuria (SLC3A1) to human chromosome 2p21 by fluorescence in situ hybridization [24].
• No differences were detected between the patients with mutations in SLC3A1 and those with mutations in SLC7A9 in relation to the age of disease onset, the estimated number of stones, the number of invasive procedures, the number of patients receiving drug therapy, or the patients' urinary pH [25].
• Northern blot analysis demonstrated that D2H, like D2 and rBAT, is expressed strongly in the kidney and intestine [7].
• METHODS: Genotyping was performed in 125 patients who underwent renal transplantation during a 5-year period for the ACE I/D, AGT M235T, ATR1 A1166C, ATR2 C3123A, and ENOS intron 4a/b gene polymorphisms [26].

References