Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants

Rajatileka, Shavanthi, Odd, David ORCID: https://orcid.org/0000-0002-6416-4966, Robinson, Matthew T., Spittle, Alexandra C., Dwomoh, Louis, Williams, Maggie, Harding, David, Wagstaff, Miles, Owen, Marie, Crosby, Charlene, Ching, Jared, Molnár, Elek, Luyt, Karen and Váradi, Anikó 2018. Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants. Molecular Neurobiology 55 , pp. 2013-2024. 10.1007/s12035-017-0462-1

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer
ISSN:	0893-7648
Date of First Compliant Deposit:	14 July 2020
Date of Acceptance:	16 February 2017
Last Modified:	05 May 2023 16:30
URI:	https://orca.cardiff.ac.uk/id/eprint/133351

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