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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 December 1, 2010
Citation Information: J Clin Invest. 2011;121(1):446-453. https://doi.org/10.1172/JCI44474.
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Research Article Nephrology Article has an altmetric score of 7

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 3

Mutations in SLC1A1 from subjects with DA affect its function.

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Mutations in SLC1A1 from subjects with DA affect its function.
(A) Repre...
(A) Representative oocytes expressing WT, R445W, or I395del cRNA or noninjected oocytes (control) were clamped at –60 mV and perfused with ND96 buffer containing 100 μM (for WT and R445W) or 1 mM (for I395del and control) l-glutamate. Black scale bars represent the time (s, x axis) that l-glutamate was applied and the current size (nA, y axis). Scale is shown for time versus current. (B) The l-glutamate dose response for WT (filled circles) and R445W (open circles). Current (Inorm) was normalized to the maximal current, defined as unit Imax (WT, K0.5 = 30 ± 4 μM and Imax = 424 ± 13 nA; R445W, K0.5 = 2 ± 0.3 μM and Imax 53 ± 7 nA). (C) Radiolabeled l-glutamate uptake at K0.5. (D) The l-cysteine dose response for WT (filled circles) and R445W (open circles). Current was normalized to the maximal current (WT, K0.5 = 115 ± 13 μM and Imax = 590 ± 19 nA; R445W, K0.5 = 3.3 ± 0.1 μM and Imax = 54 ± 20 nA). (E) Radiolabeled l-cysteine uptake at K0.5. 3H-l-glutamate and 35S-l-cysteine uptake in noninjected oocytes was subtracted from the data presented (C and E, respectively). All data represent the mean ± SEM of at least 3 oocytes (in B–E). (F–H) Representative oocytes expressing EGFP-tagged SLC1A1 cRNA. (F) WT oocytes. (G) R445W oocytes. (H) Noninjected control oocytes. Scale bar: 200 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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