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

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

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 5

A model of the renal proximal tubule, illustrating the principal epithelial transporters involved in amino acid reabsorption, which are mutated in human aminoacidurias.

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A model of the renal proximal tubule, illustrating the principal epithel...
A nephron is depicted (inset), showing the glomerulus, proximal convoluted tubule (PCT), proximal straight tubule (PST), distal convoluted tubule (DCT), and collecting duct (CD). A cross-section of the proximal convoluted tubule (white square indicated with an arrow) is represented in the main diagram. Four of the aminoacidurias, including DA, iminoglycinuria, Hartnup disorder, and cystinuria manifest at the apical surface of the renal tubule, while lysinuric protein intolerance manifests at the basolateral surface. Mutations in the high-affinity glutamate and aspartate transporter SLC1A1, responsible for DA, were identified in this study. Iminoglycinuria results from complete inactivation of SLC36A2, a proline and glycine transporter, or from additional modifying mutations in the high-affinity proline transporter SLC6A20 when SLC36A2 is not completely inactivated (18). Mutations in the neutral amino acid transporter, SLC6A19, are responsible for Hartnup disorder (16, 17). The neutral amino acid transport defect can also be exacerbated by a kidney-specific loss of heterodimerization of mutant SLC6A19 with TMEM27 (44). Cystinuria has a heterogeneous phenotype and arises from mutations in individual or both subunits of the disulfide bridge-linked heterodimer comprising the type II membrane protein SLC3A1 (12) and the cystine and basic amino acid transporter SLC7A9 (13). Lysinuric protein intolerance (14, 15) results from mutations in the basolaterally expressed basic amino acid transporter SLC7A7, which forms a disulfide bridge-linked heterodimer with type II membrane protein SLC3A2. The major transporters involved in each amino­aciduria are in bold. For a detailed review of renal epithelial amino acid transport systems and their involvement in disease see Bröer (45).