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Neurology Genetics
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February 2017; 3 (1) ArticleOpen Access

A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits

Yomayra F. Guzmán, Keri Ramsey, Jacob R. Stolz, David W. Craig, Mathew J. Huentelman, Vinodh Narayanan, Geoffrey T. Swanson
First published January 31, 2017, DOI: https://doi.org/10.1212/NXG.0000000000000129
Yomayra F. Guzmán
From the Department of Pharmacology (Y.F.G., J.R.S., G.T.S.), Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Rare Childhood Disorders (K.R., D.W.C., M.J.H., V.N.), and Neurogenomics Division (K.R., D.W.C., M.J.H., V.N.), Translational Genomics Research Institute, Phoenix, AZ.
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Keri Ramsey
From the Department of Pharmacology (Y.F.G., J.R.S., G.T.S.), Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Rare Childhood Disorders (K.R., D.W.C., M.J.H., V.N.), and Neurogenomics Division (K.R., D.W.C., M.J.H., V.N.), Translational Genomics Research Institute, Phoenix, AZ.
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Jacob R. Stolz
From the Department of Pharmacology (Y.F.G., J.R.S., G.T.S.), Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Rare Childhood Disorders (K.R., D.W.C., M.J.H., V.N.), and Neurogenomics Division (K.R., D.W.C., M.J.H., V.N.), Translational Genomics Research Institute, Phoenix, AZ.
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David W. Craig
From the Department of Pharmacology (Y.F.G., J.R.S., G.T.S.), Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Rare Childhood Disorders (K.R., D.W.C., M.J.H., V.N.), and Neurogenomics Division (K.R., D.W.C., M.J.H., V.N.), Translational Genomics Research Institute, Phoenix, AZ.
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Mathew J. Huentelman
From the Department of Pharmacology (Y.F.G., J.R.S., G.T.S.), Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Rare Childhood Disorders (K.R., D.W.C., M.J.H., V.N.), and Neurogenomics Division (K.R., D.W.C., M.J.H., V.N.), Translational Genomics Research Institute, Phoenix, AZ.
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Vinodh Narayanan
From the Department of Pharmacology (Y.F.G., J.R.S., G.T.S.), Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Rare Childhood Disorders (K.R., D.W.C., M.J.H., V.N.), and Neurogenomics Division (K.R., D.W.C., M.J.H., V.N.), Translational Genomics Research Institute, Phoenix, AZ.
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Geoffrey T. Swanson
From the Department of Pharmacology (Y.F.G., J.R.S., G.T.S.), Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Rare Childhood Disorders (K.R., D.W.C., M.J.H., V.N.), and Neurogenomics Division (K.R., D.W.C., M.J.H., V.N.), Translational Genomics Research Institute, Phoenix, AZ.
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Citation
A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits
Yomayra F. Guzmán, Keri Ramsey, Jacob R. Stolz, David W. Craig, Mathew J. Huentelman, Vinodh Narayanan, Geoffrey T. Swanson
Neurol Genet Feb 2017, 3 (1) e129; DOI: 10.1212/NXG.0000000000000129

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    Figure 1 Summary of the clinical picture of the proband

    (A) Clinical and behavioral characteristics of the proband: aonly during the perinatal period; bat 22 months, her head circumference was 43 cm (<second percentile), and at 7 years, it was 47 ½ cm (<second percentile); ctongue thrusting. (B) Facial appearance of the proband. (C) Selected MRIs of the proband (sagittal T1, axial T2, and coronal T2) demonstrating normal anatomy of the cerebrum, cerebellum, and brainstem.

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    Figure 2 Description of the GRIK2 variant

    (A) Location of the single point mutation in the GRIK2 gene responsible for the alanine to threonine amino acid substitution at position 657 within the highly conserved region of the GluK2 protein. (B) Cartoon depiction of a kainate receptor and crystal structure of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) showing the location of the (A657T) mutation within the M3 domain of ionotropic glutamate receptors. NTD and LBD stand for N-terminal domain and ligand-binding domain, respectively. Crystal structure for GluA2 AMPAR was obtained from the Protein Data Bank code 3H5V.

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    Figure 3 Biophysical properties of kainate receptors bearing the GluK2(A657T) subunit

    Representative traces, peak amplitudes, tau of desensitization, and percent desensitization of inward currents evoked by a 1-second 10 mM glutamate (glu) application in (A) homomeric kainate receptors (KARs) bearing the GluK2 (A657T) subunit. (B) Similar traces and data for GluK2(A657T)/Neto2 KARs. (C) Representative traces, peak amplitudes, tau of desensitization, and difference current evoked by a 1-second 10 mM glutamate (glu) application in heteromeric KARs composed of the GluK2(A657T) and GluK5 subunits.

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    Figure 4 Kainate receptors bearing the GluK2 subunit are constitutively active

    (A) Amplitude of holding current at −70 mV for HEK293T/17 cells expressing homomeric GluK2(A567T) kainate receptors (KARs) (left panel), GluK2(A657T)/Neto2 (middle panel), or heteromeric GluK2(A657T)/GluK5 KARs (right panel). (B) Representative traces demonstrating the change in holding current after a 1-second application of 20 μM NASPM in cells expressing homomeric GluK2(A657T) KARs (left panel, n = 4), GluK2(A657T)/Neto2 KARs (middle panel, n = 4), or heteromeric GluK2(A657T)/GluK5 KARs (right panel, n = 4). NASPM = 1-naphthyl acetyl spermine trihydrochloride.

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