PMID- 28271401
OWN - NLM
STAT- MEDLINE
DCOM- 20190523
LR  - 20220129
IS  - 1559-1182 (Electronic)
IS  - 0893-7648 (Print)
IS  - 0893-7648 (Linking)
VI  - 55
IP  - 3
DP  - 2018 Mar
TI  - Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with 
      Cerebral Palsy in Preterm Infants.
PG  - 2013-2024
LID - 10.1007/s12035-017-0462-1 [doi]
AB  - 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.
FAU - Rajatileka, Shavanthi
AU  - Rajatileka S
AD  - 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.
FAU - Odd, David
AU  - Odd D
AD  - Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, St 
      Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK.
AD  - Neonatal Intensive Care Unit, Southmead Hospital, North Bristol NHS Trust, 
      Bristol, BS10 5NB, UK.
FAU - Robinson, Matthew T
AU  - Robinson MT
AD  - College of Life & Environmental Sciences, University of Exeter, Stocker Road, 
      Exeter, EX4 4QD, UK.
FAU - Spittle, Alexandra C
AU  - Spittle AC
AD  - Centre for Synaptic Plasticity, School of Physiology, Pharmacology and 
      Neuroscience, University of Bristol, Biomedical Sciences Building, University 
      Walk, Bristol, BS8 1TD, UK.
FAU - Dwomoh, Louis
AU  - Dwomoh L
AD  - 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.
FAU - Williams, Maggie
AU  - Williams M
AD  - Bristol Genetics Laboratory, Pathology Sciences, Blood Sciences and Bristol 
      Genetics, Southmead Hospital, Bristol, BS10 5NB, UK.
FAU - Harding, David
AU  - Harding D
AD  - Regional Neonatal Intensive Care Unit, St Michael's Hospital, University Hospital 
      NHS Trust, Bristol, BS2 8EG, UK.
FAU - Wagstaff, Miles
AU  - Wagstaff M
AD  - Neonatal Intensive Care Unit, Gloucestershire Royal Hospital, Gloucestershire NHS 
      Trust, Gloucester, GL1 3NN, UK.
FAU - Owen, Marie
AU  - Owen M
AD  - Neonatal Intensive Care Unit, Gloucestershire Royal Hospital, Gloucestershire NHS 
      Trust, Gloucester, GL1 3NN, UK.
FAU - Crosby, Charlene
AU  - Crosby C
AD  - Bristol Genetics Laboratory, Pathology Sciences, Blood Sciences and Bristol 
      Genetics, Southmead Hospital, Bristol, BS10 5NB, UK.
FAU - Ching, Jared
AU  - Ching J
AD  - Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, St 
      Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK.
FAU - Molnar, Elek
AU  - Molnar E
AD  - Centre for Synaptic Plasticity, School of Physiology, Pharmacology and 
      Neuroscience, University of Bristol, Biomedical Sciences Building, University 
      Walk, Bristol, BS8 1TD, UK.
FAU - Luyt, Karen
AU  - Luyt K
AD  - Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, St 
      Michael's Hospital, Southwell Street, Bristol, BS2 8EG, UK.
AD  - Regional Neonatal Intensive Care Unit, St Michael's Hospital, University Hospital 
      NHS Trust, Bristol, BS2 8EG, UK.
FAU - Varadi, Aniko
AU  - Varadi A
AUID- ORCID: 0000-0003-3182-5198
AD  - 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.
LA  - eng
GR  - BB/F011326/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
GR  - BB/J015938/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170307
PL  - United States
TA  - Mol Neurobiol
JT  - Molecular neurobiology
JID - 8900963
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Glutamate Plasma Membrane Transport Proteins)
RN  - 0 (SLC1A2 protein, human)
SB  - IM
MH  - Animals
MH  - Astrocytes/pathology/physiology
MH  - Cells, Cultured
MH  - Cerebral Palsy/*diagnosis/*genetics
MH  - Child, Preschool
MH  - Excitatory Amino Acid Transporter 2
MH  - Female
MH  - Genetic Variation/*genetics
MH  - Glutamate Plasma Membrane Transport Proteins/*genetics
MH  - Humans
MH  - Infant, Newborn
MH  - Infant, Premature/*physiology
MH  - Male
MH  - Polymorphism, Single Nucleotide/genetics
MH  - Promoter Regions, Genetic/*genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC5840247
OTO - NOTNLM
OT  - Brain injury
OT  - Cerebral palsy
OT  - Excitatory amino acid transporter 2 (EAAT2)
OT  - Glutamate
OT  - Glutamate transporter
OT  - Neurodevelopmental disorder
OT  - Periventricular leukomalacia
OT  - Preterm infant
OT  - Promoter activity
OT  - Pyrosequencing
OT  - Single nucleotide polymorphism
COIS- The study received ethical approval in April 2010 from the National Research 
      Ethics Service, UK (REC reference number 10/H0106/10). CONFLICT OF INTEREST: EM 
      is member of the Scientific Advisory Board of Hello Bio [www.hellobio.com]. 
      FUNDING: 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).
EDAT- 2017/03/09 06:00
MHDA- 2019/05/24 06:00
PMCR- 2017/03/07
CRDT- 2017/03/09 06:00
PHST- 2016/07/08 00:00 [received]
PHST- 2017/02/16 00:00 [accepted]
PHST- 2017/03/09 06:00 [pubmed]
PHST- 2019/05/24 06:00 [medline]
PHST- 2017/03/09 06:00 [entrez]
PHST- 2017/03/07 00:00 [pmc-release]
AID - 10.1007/s12035-017-0462-1 [pii]
AID - 462 [pii]
AID - 10.1007/s12035-017-0462-1 [doi]
PST - ppublish
SO  - Mol Neurobiol. 2018 Mar;55(3):2013-2024. doi: 10.1007/s12035-017-0462-1. Epub 
      2017 Mar 7.