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Published on: August 15, 2019
Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with Cerebral Palsy in Preterm Infants
Shavanthi Rajatileka1, David Odd2,3, Matthew T Robinson4
1Centre for Research in Biosciences, Department of Applied Sciences, Faculty of Health and Applied Sciences, University of the West of England, Bristol, BS16 1QY, UK.
Insights
Genetic variations in the excitatory amino acid transporter 2 (EAAT2) gene are linked to increased risk of cerebral palsy in very preterm infants. These EAAT2 gene variants may serve as early biomarkers for neurodevelopmental disabilities.
Area of Science:
- Neuroscience
- Genetics
- Pediatrics
Background:
- Preterm delivery poses risks for neurodevelopmental impairment due to genetic and environmental factors.
- Excitatory amino acid transporter 2 (EAAT2) dysfunction and impaired glutamate uptake are implicated in neurological disorders.
Purpose of the Study:
- To investigate the role of single nucleotide polymorphisms (SNPs) in the EAAT2 promoter in very preterm infants' susceptibility to brain injury and neurodisability.
- To assess the association between specific EAAT2 genotypes and conditions like cerebral palsy and cystic periventricular leukomalacia.
Main Methods:
- DNA from newborns' dried blood spots was analyzed using pyrosequencing to detect EAAT2 promoter SNPs (g.-200C>A and g.-181A>C).
- Association analyses were performed between identified EAAT2 genotypes and clinical outcomes including cerebral palsy, cystic periventricular leukomalacia, and developmental scores.
Main Results:
- Two common EAAT2 SNPs (g.-200C>A and g.-181A>C) were identified, with concordant genotypes in 89.4% of infants.
- The presence of 'A' alleles at both SNP loci was associated with a significantly increased risk of cerebral palsy (4-6 fold increase per allele).
- These SNPs were found to alter EAAT2 promoter activity and glutamate homeostasis.
Conclusions:
- Glutamate plays a significant role in the pathogenesis of preterm brain injury and subsequent neurodevelopmental disabilities, including cerebral palsy.
- The studied EAAT2 SNPs may serve as early biomarkers for identifying infants at higher risk of neurodisability.
- These findings could inform the development of targeted therapeutic strategies for preterm infants.
Abstract:
Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200C>A and g.-181A>C) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns' dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181 bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies.
