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Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with Cerebral Palsy in Preterm Infants

Rajatileka, Shavanthi; Odd, David; Robinson, Matthew T.; Spittle, Alexandra C.; Dwomoh, Louis; Williams, Maggie; Harding, David; Wagstaff, Miles; Owen, Marie; Crosby, Charlene; Ching, Jared; Molnar, Elek; Luyt, Karen; Varadi, Aniko


Shavanthi Rajatileka

David Odd

Matthew T. Robinson

Alexandra C. Spittle

Louis Dwomoh

Maggie Williams

David Harding

Miles Wagstaff

Marie Owen

Charlene Crosby

Jared Ching

Elek Molnar

Karen Luyt

Aniko Varadi
Professor in Biomedical Research


© 2017, The Author(s). 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.-200CCloseSPigtSPiA and g.-181ACloseSPigtSPiC) 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 -181bp, 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.


Rajatileka, S., Odd, D., Robinson, M. T., Spittle, A. C., Dwomoh, L., Williams, M., …Varadi, A. (2018). Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with Cerebral Palsy in Preterm Infants. Molecular Neurobiology, 55(3), 2013-2024.

Journal Article Type Article
Acceptance Date Feb 16, 2017
Online Publication Date Mar 7, 2017
Publication Date Mar 1, 2018
Journal Molecular Neurobiology
Print ISSN 0893-7648
Electronic ISSN 1559-1182
Publisher Springer (part of Springer Nature)
Peer Reviewed Peer Reviewed
Volume 55
Issue 3
Pages 2013-2024
Keywords brain injury, cerebral palsy, excitatory amino
acid transporter 2 (EAAT2), glutamate, glutamate
transporter, neurodevelopmental disorder, periventricular
Public URL
Publisher URL


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