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

Rajatileka, S. et al. (2018) Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants. Molecular Neurobiology, 55(3), pp. 2013-2024. (doi: 10.1007/s12035-017-0462-1) (PMID:28271401) (PMCID:PMC5840247)

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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:Articles
Additional Information:This work was supported by the University of the West of England, Bristol, UK (AV). EM is supported by the Biotechnology and Biological Sciences Research Council, UK (grants BB/F011326/1 and BB/J015938/1). The blood spot retrieval was funded by the David Telling Charitable Trust (KL).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dwomoh, Dr Louis
Authors: Rajatileka, S., Odd, D., Robinson, M. T., Spittle, A. C., Dwomoh, L., Williams, M., Harding, D., Wagstaff, M., Owen, M., Crosby, C., Ching, J., Molnár, E., Luyt, K., and Váradi, A.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Molecular Neurobiology
Publisher:Springer
ISSN:0893-7648
ISSN (Online):1559-1182
Published Online:07 March 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Molecular Neurobiology 55(3): 2013-2024
Publisher Policy:Reproduced under a Creative Commons License

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