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.
View: Text | PDF
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

×

Figure 1

DA pedigrees with mutations identified in SLC1A1.

Options: View larger image (or click on image) Download as PowerPoint
DA pedigrees with mutations identified in SLC1A1. (A) Pedigrees cons...
(A) Pedigrees consistent with autosomal recessive inheritance are shown. Filled symbols represent individuals with DA, arrows indicate each proband, and the diagonal line represents a deceased subject. Representative chromatograms from control or DA pedigree DNA, with allele genotype (WT, wildtype; Mut, mutant) indicated. Boxes indicate the location of each mutation. (B) RFLP analysis of DA pedigrees. For c.1333C > T RFLP, AgeI digestion releases 252- and 229-bp fragments (shown as control [C]). The c.1333C > T mutation inactivates the AgeI site, leaving a 481-bp product (top panel). For c.1184–1186delTCA RFLP, BsaBI does not cut the 461-bp PCR product (shown as control). The c.1184-1186delTCA mutation results in a 458-bp amplicon, which is cut by BsaBI into 245- and 213-bp fragments (bottom panel). L, 100-bp ladder. (C) The OCD-associated region at 9p24 containing SLC1A1. The 39-kb region identified in early-onset OCD cohorts is represented by the red line; SLC1A1 coding regions are represented by gray bars; untranslated regions are represented by vertical white bars; blue shading indicates a significant association with OCD (P < 0.05); red shading indicates an experimentally validated loss-of-function mutation; stacked boxes represent SNPs; blue triangles represent markers linked to OCD; connected blue circles indicate haplotype blocks significantly associated with OCD (P < 0.05); lower boxes indicate missense mutations (c.490A > G [T164A, ref. 40]), c.1184–1186delTCA [I395del], c.1333C > T [R445W]); red arrow indicates an association with OCD-like features; and coordinates represent telomeric distance (in Mb). Sex-specific association with OCD is indicated (male [M] or female [F]). Roman numerals correlate with individual OCD studies: i (20); ii (21); iii (26); iv (27); v (25); vi (22); vii (23); and viii (24).