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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)2013-2024
Number of pages12
JournalMolecular Neurobiology
Volume55
Early online date7 Mar 2017
DOIs
DateAccepted/In press - 16 Feb 2017
DateE-pub ahead of print - 7 Mar 2017
DatePublished (current) - Mar 2018

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.

Additional information

16-Feb-17

    Research areas

  • Brain injury, Cerebral palsy, Excitatory amino acid transporter 2 (EAAT2), Glutamate, Glutamate transporter, Neurodevelopmental disorder, Periventricular leukomalacia, Preterm infant, Promoter activity, Pyrosequencing, Single nucleotide polymorphism

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via SpringerLink at https://link.springer.com/article/10.1007%2Fs12035-017-0462-1 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 626 KB, PDF document

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