title: 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.
authors.affiliation: Centre for Research in Biosciences, Department of Applied Sciences, Faculty of Health and Applied Sciences, University of the West of England, Bristol, BS16 1QY, UK.
authors.forename: Shavanthi
authors.initials: S
authors.lastname: Rajatileka
authors.affiliation: Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, St Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK.|Neonatal Intensive Care Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, BS10 5NB, UK.
authors.forename: David
authors.initials: D
authors.lastname: Odd
authors.affiliation: College of Life & Environmental Sciences, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Robinson
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Spittle
authors.affiliation: Centre for Research in Biosciences, Department of Applied Sciences, Faculty of Health and Applied Sciences, University of the West of England, Bristol, BS16 1QY, UK.
authors.forename: Louis
authors.initials: L
authors.lastname: Dwomoh
authors.affiliation: Bristol Genetics Laboratory, Pathology Sciences, Blood Sciences and Bristol Genetics, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Maggie
authors.initials: M
authors.lastname: Williams
authors.affiliation: Regional Neonatal Intensive Care Unit, St Michael's Hospital, University Hospital NHS Trust, Bristol, BS2 8EG, UK.
authors.forename: David
authors.initials: D
authors.lastname: Harding
authors.affiliation: Neonatal Intensive Care Unit, Gloucestershire Royal Hospital, Gloucestershire NHS Trust, Gloucester, GL1 3NN, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Wagstaff
authors.affiliation: Neonatal Intensive Care Unit, Gloucestershire Royal Hospital, Gloucestershire NHS Trust, Gloucester, GL1 3NN, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Owen
authors.affiliation: Bristol Genetics Laboratory, Pathology Sciences, Blood Sciences and Bristol Genetics, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Charlene
authors.initials: C
authors.lastname: Crosby
authors.affiliation: Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, St Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK.
authors.forename: Jared
authors.initials: J
authors.lastname: Ching
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK.
authors.forename: Elek
authors.initials: E
authors.lastname: Molnár
authors.affiliation: Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, St Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK.|Regional Neonatal Intensive Care Unit, St Michael's Hospital, University Hospital NHS Trust, Bristol, BS2 8EG, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Luyt
authors.affiliation: Centre for Research in Biosciences, Department of Applied Sciences, Faculty of Health and Applied Sciences, University of the West of England, Bristol, BS16 1QY, UK. Aniko.Varadi@uwe.ac.uk.
authors.forename: Anikó
authors.identifier: http://orcid.org/0000-0003-3182-5198
authors.initials: A
authors.lastname: Váradi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D002478:Cells, Cultured; D002547:Cerebral Palsy / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D027342:Excitatory Amino Acid Transporter 2; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000502:physiology*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human
keywords: 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