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Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes
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Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes
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Journal Article
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes
2010
Overview
Kerstin Kutsche and colleagues report that mutations in
GRIN2A
and
GRIN2B
cause variable neurodevelopmental phenotypes including mental retardation and epilepsy.
GRIN2A
and
GRIN2B
encode regulatory subunits of N-methyl-D-aspartate (NMDA) receptors, which mediate excitatory neurotransmission in the brain.
N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca
2+
-permeable cation channels which are blocked by extracellular Mg
2+
in a voltage-dependent manner
1
. Either
GRIN2B
or
GRIN2A
, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of
GRIN2B
in 468 individuals with mental retardation revealed four
de novo
mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a
GRIN2A
nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the
de novo GRIN2A
mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A
N615K
(NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg
2+
block and a decrease in Ca
2+
permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.
Publisher
Nature Publishing Group,Nature Publishing Group US
Subject
/ Adult
/ Animal Genetics and Genomics
/ Biological and medical sciences
/ Biomedical and Life Sciences
/ Brain
/ Child
/ Female
/ Fundamental and applied biological sciences. Psychology
/ Genetics
/ Genetics & genetic processes
/ Genetics of eukaryotes. Biological and molecular evolution
/ Génétique & processus génétiques
/ Humans
/ Intellectual Disability - genetics
/ letter
/ Male
/ Mutation
/ Nervous System Diseases - genetics
/ Pedigree
/ Polymorphism, Single Nucleotide
/ Proteins
