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Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria
Charles G. Bailey, … , Stefan Bröer, John E.J. Rasko
Charles G. Bailey, … , Stefan Bröer, John E.J. Rasko
Published January 4, 2011; First published December 1, 2010
Citation Information: J Clin Invest. 2011;121(1):446-453. https://doi.org/10.1172/JCI44474.
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Categories: Research Article Nephrology

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria

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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.

Authors

Charles G. Bailey, Renae M. Ryan, Annora D. Thoeng, Cynthia Ng, Kara King, Jessica M. Vanslambrouck, Christiane Auray-Blais, Robert J. Vandenberg, Stefan Bröer, John E.J. Rasko

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Figure 2

Mapping of the SLC1A1 mutations.

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Mapping of the SLC1A1 mutations.
(A) Highly conserved regions in ortholo...
(A) Highly conserved regions in orthologs of SLC1A1 (top group) and SLC1 family members (middle group) and the SLC1A1 consensus sequence (bottom). Residues I395 and R445, deleted and mutated, respectively, in DA pedigrees are indicated. Residues known to be functionally important in SLC1A1, aspartate 444 (31) and arginine 447 (30), are indicated (diamonds). Blocks of the same color highlight groups of the same or similar amino acids: yellow, hydrophobic; red, acidic; orange, basic; purple, aromatic; blue, amido; green, hydroxyl; gray, proline; and pink, sulfur containing. (B) Predicted location of mutant residues based on the crystal structure of the prokaryotic glutamate transporter (GltPh). R445 (equivalent to M395 in GltPh) is predicted to be located in transmembrane 8, and I395 (equivalent to I339 in GltPh) is in hairpin loop 2 (HP2) near the hinge region. Blue spheres indicate sodium ions; Asp represents the aspartate substrate.
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