Genomic Organization ofSLC3A1,a Transporter Gene Mutated in Cystinuria

Pras, Elon; Sood, Raman; Raben, Nina; Aksentijevich, Ivona; Chen, Xiang; Kastner, Daniel L.

doi:10.1006/geno.1996.0437

Cited by 28 publications

(17 citation statements)

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“…This normal dog was homozygous for the 7-5 allele of the hexanucleotide repeat area while its affected littermate was homozygous for the 8-5 allele. As expected based on the human SLC3A1 gene structure (Endsley et al 1997;Pras et al 1996;Purroy et al 1996), the canine SLC3A1 gene is divided into ten exons, with the coding region interrupted by introns at places analogous to those in the human gene. The sequences of the exons of the normal Newfoundland dog were identical to the entire open reading frame of the normal cloned cDNA sequence, with the exception of the lengths of the hexanucleotide repeats in exon 1 (6-6 as opposed to 7-5).…”

Section: Isolation and Characterization Of The Canine Slc3a1 Genementioning

confidence: 97%

Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs

et al. 2000

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Cystinuria is an inherited renal and intestinal disease characterized by defective amino acid reabsorption and cystine urolithiasis. Different forms of the disease, designated type I and non-type I in cystinuric humans, can be distinguished clinically and biochemically, and have been associated with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Type I cystinuria is the most common form and is inherited as an autosomal recessive trait in humans. Cystinuria has been recognized in more than 60 breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Here we report the cloning and sequencing of the canine SLC3A1 cDNA and gene, and the identification of a nonsense mutation in exon 2 of the gene in cystinuric Newfoundland dogs. A mutation-specific test was developed for the diagnosis and control of cystinuria in Newfoundland dogs. In cystinuric dogs of six other breeds, either heterozygosity at the SLC3A1 locus or lack of mutations in the coding region of the SLC3A1 gene were observed, indicating that cystinuria is genetically heterogeneous in dogs, as it is in humans. The canine homologue of human type I cystinuria provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases.

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Section: Isolation and Characterization Of The Canine Slc3a1 Genementioning

confidence: 97%

Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs

et al. 2000

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“…The SLC3A1 gene spans ~46 kb and includes 10 coding exons [22,23]. The longest transcript (ENST00000260649) is 2989 bp long, the resulting protein rBAT (ENSP00000260649) consists of 685 amino acids.…”

Section: The Slc3a1 and Slc7a9 Genes And The Amino Acid Transporter Smentioning

confidence: 99%

Cystinuria: an inborn cause of urolithiasis

Eggermann

Venghaus

Zerres

2012

Orphanet J Rare Dis

102

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Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b0,+ transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b0,+AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.

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“…rBAT protein is undetectable in the fetal kidney and is expressed at very low levels even after weaning [96]. Mutations in SLC3A1, the gene encoding rBAT, result in type I cystinuria [97][98][99][100]. B 0+ AT is also a cystine transporter/dibasic amino acid transporter [101,102].…”

Section: Transport Amino Acid: Developmental Featuresmentioning

confidence: 99%

Renal Tubular Development

Baum

2014

Pediatric Nephrology

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The nephron is faced with the enormous task of maintaining a constant composition and volume of the extracellular fluid. The amount of electrolytes and water ingested and absorbed must be eliminated, and the waste products from metabolism must also be excreted. This challenge is all the more complex as our dietary intake is quite variable from day to day. Despite this variable intake, there is virtually no change in the volume or composition of the extracellular fluid volume from day to day.There are two possible ways that our kidney could balance ingestion and excretion. The kidney could be a secretory organ where all the excess solutes and water ingested would be excreted by tubular secretion. This would be very inefficient and require an enormous amount of energy. In addition, in times of a disturbance in the extracellular fluid volume such as a high salt intake or volume loss from diarrhea, the regulatory systems necessary to maintain a constant extracellular fluid volume and composition while excreting waste products would be very complex. On the other hand, the kidney could filter an enormous quantity of extracellular fluid, which would be very efficient in removing waste products, and reclaim the desired salt, organic solutes, and water. With volume depletion, a greater fraction of salt and water could be reabsorbed, and when one has a dietary indiscretion such as the salt intake from a pepperoni pizza, there could be a reduction in sodium reabsorption leading to an increase in excretion to bring us back into balance. The mammalian kidney actually uses both mechanisms to perform its job which is necessary for our survival on land. The adult kidney filters~150 l of isotonic fluid a day and reclaims most of it, leaving the waste produces to be excreted in about 1.5 l of urine. In addition, there are secretory processes for solutes such as organic anions and cations in the proximal tubule and secretory mechanisms to excrete the excess acid generated from metabolism in the distal nephron which aid in maintaining homeostasis.To accomplish the remarkable task of reclamation of the necessary solutes and water to maintain a constant composition of the extracellular fluid volume, the mammalian kidney has evolved into a highly specialized organ with thousands of units called nephrons. Each human kidney has approximately one million nephrons. Each nephron is a tube consisting of epithelial cells and is divided into 12 specialized segments as shown in Fig. 1. The epithelial cells allow for the vectorial transport of solutes. The proximal tubule is responsible for the bulk reclamation of solutes and water and for the secretion of organic cations and anions. Approximately two-thirds of the glomerular filtrate is reabsorbed by the proximal tubule in an isotonic fashion. Virtually all of the organic solutes, as well as the majority of bicarbonate, phosphate, and chloride, are reabsorbed in this segment. The proximal tubule is divided into S 1 , S 2 , and S 3 segments based on the rates of transport of some solutes and mor...

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Genomic Organization ofSLC3A1,a Transporter Gene Mutated in Cystinuria

Cited by 28 publications

References 4 publications

Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs

Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs

Cystinuria: an inborn cause of urolithiasis

Renal Tubular Development

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