Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Clin Invest
2011 Jan 01;1211:446-53. doi: 10.1172/JCI44474.
Show Gene links
Show Anatomy links
Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria.
Bailey CG
,
Ryan RM
,
Thoeng AD
,
Ng C
,
King K
,
Vanslambrouck JM
,
Auray-Blais C
,
Vandenberg RJ
,
Bröer S
,
Rasko JE
.
???displayArticle.abstract???
Solute carrier family 1, member 1 (SLC1A1; also known as EAAT3 and EAAC1) is the major epithelial transporter of glutamate and aspartate in the kidneys and intestines of rodents. Within the brain, SLC1A1 serves as the predominant neuronal glutamate transporter and buffers the synaptic release of the excitatory neurotransmitter glutamate within the interneuronal synaptic cleft. Recent studies have also revealed that polymorphisms in SLC1A1 are associated with obsessive-compulsive disorder (OCD) in early-onset patient cohorts. Here we report that SLC1A1 mutations leading to substitution of arginine to tryptophan at position 445 (R445W) and deletion of isoleucine at position 395 (I395del) cause human dicarboxylic aminoaciduria, an autosomal recessive disorder of urinary glutamate and aspartate transport that can be associated with mental retardation. These mutations of conserved residues impeded or abrogated glutamate and cysteine transport by SLC1A1 and led to near-absent surface expression in a canine kidney cell line. These findings provide evidence that SLC1A1 is the major renal transporter of glutamate and aspartate in humans and implicate SLC1A1 in the pathogenesis of some neurological disorders.
Aoyama,
Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse.
2006, Pubmed
Aoyama,
Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse.
2006,
Pubmed
Arnold,
Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder.
2006,
Pubmed
Arriza,
Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex.
1994,
Pubmed
,
Xenbase
Auray-Blais,
Newborn urine screening programme in the province of Quebec: an update of 30 years' experience.
2003,
Pubmed
Auray-Blais,
Quebec neonatal mass urinary screening programme: from micromolecules to macromolecules.
2007,
Pubmed
Bendahan,
Arginine 447 plays a pivotal role in substrate interactions in a neuronal glutamate transporter.
2000,
Pubmed
,
Xenbase
Borre,
Arginine 445 controls the coupling between glutamate and cations in the neuronal transporter EAAC-1.
2004,
Pubmed
Borsani,
SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance.
1999,
Pubmed
Boudker,
Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter.
2007,
Pubmed
Bröer,
Amino acid transport across mammalian intestinal and renal epithelia.
2008,
Pubmed
Bröer,
Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters.
2008,
Pubmed
Calonge,
Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine.
1994,
Pubmed
,
Xenbase
Camargo,
Aminoacidurias: Clinical and molecular aspects.
2008,
Pubmed
Dickel,
Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder.
2006,
Pubmed
Feliubadaló,
Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.
1999,
Pubmed
Fournier,
Rapid trafficking of the neuronal glutamate transporter, EAAC1: evidence for distinct trafficking pathways differentially regulated by protein kinase C and platelet-derived growth factor.
2004,
Pubmed
Hanna,
Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands.
2002,
Pubmed
Huang,
The role of cation binding in determining substrate selectivity of glutamate transporters.
2009,
Pubmed
,
Xenbase
Kanai,
Primary structure and functional characterization of a high-affinity glutamate transporter.
1992,
Pubmed
,
Xenbase
Kleta,
Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.
2004,
Pubmed
Kowalczuk,
A protein complex in the brush-border membrane explains a Hartnup disorder allele.
2008,
Pubmed
,
Xenbase
Kwon,
Association of the glutamate transporter gene SLC1A1 with atypical antipsychotics-induced obsessive-compulsive symptoms.
2009,
Pubmed
Murphy,
Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake.
1990,
Pubmed
Nieoullon,
The neuronal excitatory amino acid transporter EAAC1/EAAT3: does it represent a major actor at the brain excitatory synapse?
2006,
Pubmed
Peghini,
Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration.
1997,
Pubmed
Rothstein,
Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.
1995,
Pubmed
Ryan,
The position of an arginine residue influences substrate affinity and K+ coupling in the human glutamate transporter, EAAT1.
2010,
Pubmed
,
Xenbase
Ryan,
Site-directed mutagenesis in the study of membrane transporters.
2003,
Pubmed
,
Xenbase
Scimemi,
Neuronal transporters regulate glutamate clearance, NMDA receptor activation, and synaptic plasticity in the hippocampus.
2009,
Pubmed
Seow,
Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19.
2004,
Pubmed
Shanker,
The uptake of cysteine in cultured primary astrocytes and neurons.
2001,
Pubmed
Shayakul,
Localization of the high-affinity glutamate transporter EAAC1 in rat kidney.
1997,
Pubmed
Shugart,
A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families.
2009,
Pubmed
Smith,
Assignment of the gene coding for the human high-affinity glutamate transporter EAAC1 to 9p24: potential role in dicarboxylic aminoaciduria and neurodegenerative disorders.
1994,
Pubmed
Stewart,
Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder.
2007,
Pubmed
Swarna,
Dicarboxylic aminoaciduria associated with mental retardation.
1989,
Pubmed
Teichman,
Aspartate-444 is essential for productive substrate interactions in a neuronal glutamate transporter.
2007,
Pubmed
,
Xenbase
Teijema,
Dicarboxylic aminoaciduria: an inborn error of glutamate and aspartate transport with metabolic implications, in combination with a hyperprolinemia.
1974,
Pubmed
Torrents,
Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.
1999,
Pubmed
,
Xenbase
Wang,
A screen of SLC1A1 for OCD-related alleles.
2010,
Pubmed
Wendland,
A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder.
2009,
Pubmed
Willour,
Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder.
2004,
Pubmed
Wu,
Glutathione metabolism and its implications for health.
2004,
Pubmed
Yernool,
Structure of a glutamate transporter homologue from Pyrococcus horikoshii.
2004,
Pubmed
Zerangue,
Interaction of L-cysteine with a human excitatory amino acid transporter.
1996,
Pubmed
,
Xenbase
