Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with Cerebral Palsy in 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-017-0462-1) contains supplementary material, which is available to authorized users.

The meteorology of cytokine storms, and the clinical usefulness of this knowledge

“…As we have summarized [110], cerebral TNF and consequentially extracellular cerebral glutamate are both chronically increased in Alzheimer’s disease, post-stroke syndromes, traumatic brain injury, and Parkinson’s disease, Huntingdon’s disease, amylotropic lateral sclerosis, septic encephalopathy, poor post-operative cognition, poor post-irradiation cognition, HIV dementia, cerebral malaria and viral encephalitides. Cerebral palsy also fits this pattern [167, 168]. As noted [110], this relationship between TNF and glutamate is consistent with excitotoxicity and synaptic shutdown being major consequences of chronic cerebral cytokine storms, albeit with different anatomical locations, initiators and kinetics.…”

Neonatal Brain Injury and Genetic Causes of Adult-Onset Neurodegenerative Disease in Mice Interact With Effects on Acute and Late Outcomes

“…In term newborns, c atalase gene (21) and interleukin-6 gene (22–24) polymorphisms are associated with higher susceptibility to cerebral palsy after hypoxia-ischemia. In preterm infants, glial glutamate transporter gene EAAT2 polymorphisms associate with greater risk of cerebral palsy (25). The novel information revealed in our study is the demonstration that pathogenic genes causing adult-onset neurodegenerative can have dramatic acute and long-term impacts on neonatal mice with acquired brain injury.…”

“…Catalase gene (21) and interleukin-6 gene (22–24) polymorphisms are associated with higher susceptibility to cerebral palsy after neonatal hypoxia-ischemia. Glial glutamate transporter gene EAAT2 polymorphisms associate with cerebral palsy in preterm infants (25). Indeed, mitochondriopathy, oxidative stress, excitotoxicity, intracellular calcium stress, inflammation, and neuronal cell death are all putative mechanisms in neonatal brain damage (4, 26) and age-related neurodegenerative disease (4).…”

Malectin gene polymorphisms promote cerebral palsy via M2‐like macrophage polarization

“…It implied that MLEC may also play roles in macrophage polarization. Genetic polymorphisms play important roles in the pathogenesis of CP . Therefore, we focused on the potential association of SNPs with the risk of CP.…”