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Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
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ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus

Mayu Shinohara1, Makiko Saitoh, Daisuke Nishizawa

  • 1Department of Developmental Medical Sciences, Graduate School of Medicine, University of Tokyo, Japan.

Neurology
|March 29, 2013
PubMed

Insights

Genetic variations in the adenosine A2A receptor (ADORA2A) are linked to acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). The AA diplotype increases AESD risk by affecting the adenosine/cAMP pathway, potentially causing excitotoxic brain damage.

Area of Science:

  • Neuroscience
  • Genetics
  • Pediatrics

Background:

  • Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe childhood neurological condition with unclear pathogenesis.
  • Neurologic sequelae are common in AESD patients, highlighting the need to understand its underlying mechanisms.

Purpose of the Study:

  • To investigate the potential role of genetic variations in the adenosine A2A receptor (ADORA2A) as a predisposing factor for AESD.
  • To clarify the relationship between ADORA2A genetic variants, receptor expression, and the adenosine/cyclic adenosine monophosphate (cAMP) pathway in AESD.

Main Methods:

  • Analysis of 4 ADORA2A single nucleotide polymorphisms in 85 AESD patients and controls.
  • Comparison of ADORA2A mRNA and protein expression, and cAMP production in lymphoblasts across different ADORA2A diplotypes.

Main Results:

  • Two linked haplotypes (A and B) were identified, with Haplotype A significantly more frequent in AESD patients (p=0.005).
  • The homozygous AA diplotype showed a 2.32-fold increased risk of AESD (p=0.003) and was associated with higher ADORA2A mRNA and protein expression, and elevated cAMP production.

Conclusions:

  • The AA diplotype of ADORA2A is significantly associated with AESD.
  • ADORA2A genetic variations may alter the intracellular adenosine/cAMP cascade, contributing to seizures and excitotoxic brain damage in AESD.
Abstract

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