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

Bailey, Charles G., Ryan, Renae M., Thoeng, Annora D., Ng, Cynthia, King, Kara, Vanslambrouck, Jessica M., Auray-Blais, Christiane, Vandenberg, Robert J., Broer, Stefan and Rasko, John E. J. (2011) Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. Journal of Clinical Investigation, 121 1: 446-453. doi:10.1172/JCI44474


Author Bailey, Charles G.
Ryan, Renae M.
Thoeng, Annora D.
Ng, Cynthia
King, Kara
Vanslambrouck, Jessica M.
Auray-Blais, Christiane
Vandenberg, Robert J.
Broer, Stefan
Rasko, John E. J.
Title Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria
Journal name Journal of Clinical Investigation   Check publisher's open access policy
ISSN 0021-9738
1558-8238
Publication date 2011-01-04
Year available 2010
Sub-type Article (original research)
DOI 10.1172/JCI44474
Open Access Status DOI
Volume 121
Issue 1
Start page 446
End page 453
Total pages 8
Place of publication Ann Arbor, MI, United States
Publisher American Society for Clinical Investigation
Collection year 2012
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ
Additional Notes First published December 1, 2010

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 07 Mar 2011, 10:16:28 EST by Susan Allen on behalf of Institute for Molecular Bioscience