Glyoxalase I polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity—implications for autism
Article first published online: 12 APR 2011
Copyright © 2011, International Society for Autism Research, Wiley-Liss, Inc.
Volume 4, Issue 4, pages 262–270, August 2011
How to Cite
Barua, M., Jenkins, E. C., Chen, W., Kuizon, S., Pullarkat, R. K. and Junaid, M. A. (2011), Glyoxalase I polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity—implications for autism. Autism Res, 4: 262–270. doi: 10.1002/aur.197
- Issue published online: 5 AUG 2011
- Article first published online: 12 APR 2011
- Manuscript Accepted: 12 MAR 2011
- Manuscript Received: 25 SEP 2009
- National Institutes of Health. Grant Number: NS40691
- New York State Office for People with Developmental Disabilities (formerly the New York State Office of Mental Retardation and Developmental Disabilities); National Alliance for Autism Research (NAAR)
- glyoxalase I;
- advanced glycation endproducts (AGEs);
- receptor for advanced glycation end products (RAGEs);
Autism is a pervasive, heterogeneous, neurodevelopmental disability characterized by impairments in verbal communications, reciprocal social interactions, and restricted repetitive stereotyped behaviors. Evidence suggests the involvement of multiple genetic factors in the etiology of autism, and extensive genome-wide association studies have revealed several candidate genes that bear single nucleotide polymorphisms (SNPs) in non-coding and coding regions. We have shown that a non-conservative, non-synonymous SNP in the glyoxalase I gene, GLOI, may be an autism susceptibility factor. The GLOI rs2736654 SNP is a CA change that causes an Ala111Glu change in the Glo1 enzyme. To identify the significance of the SNP, we have conducted functional assays for Glo1. We now present evidence that the presence of the A-allele at rs2736654 results in reduced enzyme activity. Glo1 activity is decreased in lymphoblastoid cells that are homozygous for the A allele. The Glu-isoform of Glo1 in these cells is hyperphosphorylated. Direct HPLC measurements of the glyoxalase I substrate, methylglyoxal (MG), show an increase in MG in these cells. Western blot analysis revealed elevated levels of the receptor for advanced glycation end products (RAGEs). We also show that MG is toxic to the developing neuronal cells. We suggest that accumulation of MG results in the formation of AGEs, which induce expression of the RAGE that during crucial neuronal development may be a factor in the pathology of autism. Autism Res2011,4:262–270. © 2011 International Society for Autism Research, Wiley Periodicals, Inc.