Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy

Hongjie Yuan; Kasper B. Hansen; Jing Zhang; Tyler Mark Pierson; Thomas C. Markello; Karin V.Fuentes Fajardo; Conisha M. Holloman; Gretchen Golas; David R. Adams; Cornelius F. Boerkoel; William A. Gahl; Stephen F. Traynelis

doi:10.1038/ncomms4251

Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy

Hongjie Yuan
, Kasper B. Hansen
, Jing Zhang
, Tyler Mark Pierson
, Thomas C. Markello
, Karin V.Fuentes Fajardo
, Conisha M. Holloman
, Gretchen Golas
, David R. Adams
, Cornelius F. Boerkoel
, William A. Gahl
, Stephen F. Traynelis

Division of Biological and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

125 Scopus citations

Abstract

NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy.

Original language	English
Article number	3251
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4251
State	Published - Feb 7 2014

Funding

We are grateful to Anel Tankovic, Phuong Le and Kevin Ogden for technical assistance. We are also grateful to Eric D. Marsh and Dimitre R. Simeonov for assistance with the clinical and molecular evaluation of the patient. This work was supported by the NINDS (NS036654, S.F.T.), by the NIH Undiagnosed Diseases Program (HSN268201300162P, H.Y.) and by the Intramural Research Program of the National Human Genome Research Institute. TMP was also supported by the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases.

Funder number
HSN268201300162P
R37NS036654

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10.1038/ncomms4251

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Yuan, H., Hansen, K. B., Zhang, J., Mark Pierson, T., Markello, T. C., Fajardo, K. V. F., Holloman, C. M., Golas, G., Adams, D. R., Boerkoel, C. F., Gahl, W. A., & Traynelis, S. F. (2014). Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nature Communications, 5, Article 3251. https://doi.org/10.1038/ncomms4251

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title = "Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy",

abstract = "NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy.",

author = "Hongjie Yuan and Hansen, \{Kasper B.\} and Jing Zhang and \{Mark Pierson\}, Tyler and Markello, \{Thomas C.\} and Fajardo, \{Karin V.Fuentes\} and Holloman, \{Conisha M.\} and Gretchen Golas and Adams, \{David R.\} and Boerkoel, \{Cornelius F.\} and Gahl, \{William A.\} and Traynelis, \{Stephen F.\}",

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AU - Yuan, Hongjie

AU - Hansen, Kasper B.

AU - Zhang, Jing

AU - Mark Pierson, Tyler

AU - Markello, Thomas C.

AU - Fajardo, Karin V.Fuentes

AU - Holloman, Conisha M.

AU - Golas, Gretchen

AU - Adams, David R.

AU - Boerkoel, Cornelius F.

AU - Gahl, William A.

AU - Traynelis, Stephen F.

PY - 2014/2/7

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N2 - NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy.

AB - NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy.

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VL - 5

JO - Nature Communications

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ER -

Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy

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