Original articleGenetic variant of glutathione peroxidase 1 in autism
Introduction
Autism spectrum disorders (ASD) have been associated with alterations of multiple gene variants. Gene-environment interactions may also play a role. Genes of detoxification pathways and oxidative stress have been subjects of research in ASD. Several lines of evidence support an association of oxidative stress with ASD in at least some cases. First, there is evidence of reduced endogenous antioxidant capacity. Specifically, reduced enzymatic activities of glutathione peroxidase (GPX) [1], [2], [3], superoxide dismutase (SOD) [1], [3] and catalase [4], and reduced levels of total glutathione (GSH), GSH/GSSG and cysteine [5] have been reported. Levels of exogenous antioxidants were also reportedly reduced in autism, including vitamin C, vitamin E and vitamin A in plasma, and zinc and selenium in erythrocytes [5].
A second indicator of altered oxidative stress in autism is derived from evidence of impaired energy metabolism. Magnetic resonance spectroscopic study of the brains of autistic individuals showed reduced synthesis of ATP [6]. In addition, higher lactate [7], [8] and pyruvate [9] levels have been reported.
Third, there have been reports of improvement in certain behaviors following antioxidant administration to individuals with autism. In double-blind, placebo-controlled trials, high-dose vitamin C [10] or carnosine [11] improved autistic behavior over baseline observations. Likewise, children with autism, who had decreased blood levels of the antioxidants GSH and cysteine as well as a decreased GSH/GSSG ratio compared with controls, had increases of these following a 3-week supplementation with betaine and folinic acid [5].
Fourth, increased excretion of oxidative stress biomarkers has been reported in children with autism. Specifically, the excretion of a F2 isoprostane, 8-iso-prostaglandin F2α is increased in children with autism spectrum disorders [12]. This isoprostane is a product of nonenzymatic oxidation of arachidonic acid and is widely recognized as a reliable marker of lipid peroxidation [13]. Furthermore, nitric oxide, a free radical that can block energy production, was found to be increased in autism as compared to age and sex-matched controls [2]. In addition, elevated nitrite concentrations have been detected in individuals with autism [14] along with elevations of thiobarbituric acid reactive substances and xanthine oxidase activity in red cells [4]. Consistent with the increased oxidative stress biomarkers, children with ASD were found to have increased body burdens of environmental toxins that may generate oxidative stress [15], [16]. Taken together, these lines of evidence suggest that it is likely that at least some children with autism exhibit enhanced oxidative stress. However, none of these observations suggest how oxidative stress can lead to autism.
Genes of glutathione metabolism have been implicated in ASD. Buyske et al. [17] found that homozygosity of the gene deletion polymorphism of glutathione S-transferase (GST) GSTM1 was associated with autism. Williams et al. [18] reported significant transmission disequilibrium of a GSTP1 haplotype in maternal trios of autistic case families. Further, James et al. [5] reported abnormal metabolism in oxidative stress pathways.
GPX is a major enzyme in the glutathione pathway that catalyzes the reduction of free radicals by glutathione and represents a major enzyme for defense against oxidant molecules [19]. GPX1, a selenium dependent protein, is the predominant and most abundant isoenzyme of GPX. GPX1 is located in cytoplasm and is found in most parenchymal organs and peripheral blood cells, particularly erythrocytes. This enzyme is believed to play an integral role in cellular antioxidant defense mechanisms by catalyzing the reduction of potentially harmful peroxides, thereby contributing to maintenance of health by reducing oxidative stress. Altered GPX enzyme activity was reported in spina bifida [20], another neurodevelopmental disorder, idiosyncratic valproate toxicity [21] and autism [1], [2], [3]. Valproate therapy has been shown to increase serum lipid peroxides and to decrease GPX activity secondary to a valproate-induced decrease in selenium concentrations. Patients with low GPX are at risk for the development of idiosyncratic adverse reaction of valproate [21]. Children with spina bifida had lower erythrocyte GPX activity as compared with their healthy age-matched controls. Parents of these children also demonstrated lower GPX activity [20]. These observations suggest that oxidative stress contributes to valproate toxicity and spina bifida in a genetically susceptible populations. GPX levels were found to be reduced in children with autism [1], [2], [3], and fetal valproate syndrome is associated with autism [22], [23], [24]. Thus, it is possible that oxidative stress contributes to phenotypes of autism spectrum disorders in the presence of a genetic susceptible variant of GPX.
Polymorphisms of GPX1 were reported to be associated with increased risk of breast cancer (Pro198Leu) [25], and cardiovascular disease (GCG repeat) [26]. In addition, mice with a homozygous null mutation for GPX1 show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide [27] and to diquat-induced oxidative stress [28].
The gene for human GPX1 contains a sequence polymorphism in which a short trinucleotide repeat sequence (GCG) codes for a variable length polyalanine stretch close to the N-terminus [29]. The polyalanine repeat polymorphism has three alleles with five (ALA5), six (ALA6) and seven (ALA7) alanine residues [26]. We investigated this common polyalanine repeat polymorphism of human GPX1 in a cohort of trios of autistic disorder family (probands and parents). We report here our finding of disequilibrium in transmission of one of the three polymorphic alleles.
Section snippets
Participants
Families having a child diagnosed with autistic disorder were invited to participate through advertisements in the newsletter of the New Jersey Center for Outreach and Services for the Autism Community (COSAC, Ewing, NJ). A few families were recruited through our Department of Pediatrics. Selection criteria for families were (1) participation of a proband with the clinical diagnosis of non-syndromic autistic disorder by their neurodevelopmental pediatrician as assessed by telephone interview
Results
Of the 103 probands, 101 had the clinical diagnosis of autistic disorder and 2 had the diagnosis PDD-NOS by ADI-R and ADOS-G. Males comprised 86% of the probands. The racial ethnic background of the families was representative of a community-based autistic disorder population. Cognitive levels and comorbidity of the probands were not used as selection criteria.
Sixty-eight case trios (probands and parents) were genotyped for the GPX1 polyalanine repeat polymorphism; three duos consisting of a
Discussion
This study showed that there was overall transmission disequilibrium of the three ALA alleles in autistic disorder. An allele for ALA6 of GPX1 was significantly under transmitted from parents to probands in these trios with autistic disorder, suggesting that possessing this allele may be protective for autistic disorder. GPX is one of the major enzymes participating in reduction of activated oxygen species through the coupled oxidation of reduced glutathione [33]. Reduced GPX function could
Acknowledgement
This study was supported by a grant from The Cure Autism Now Foundation (Autism Speaks) to Ming X.
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