Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy

Wenshu XiangWei; Varun Kannan; Yuchen Xu; Gabrielle J Kosobucki; Anthony J Schulien; Hirofumi Kusumoto; Christelle Moufawad El Achkar; Subhrajit Bhattacharya; Gaetan Lesca; Sylvie Nguyen; Katherine L Helbig; Jean-Marie Cuisset; Christina Dühring Fenger; Dragan Marjanovic; Elisabeth Schuler; Ye Wu; Xinhua Bao; Yuehua Zhang; Nina Dirkx; An-Sofie Schoonjans; Steffen Syrbe; Scott J Myers; Annapurna Poduri; Elias Aizenman; Stephen F Traynelis; Johannes R Lemke; Hongjie Yuan; Yuwu Jiang

doi:10.1093/brain/awz232

Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy

Brain. 2019 Oct 1;142(10):3009-3027. doi: 10.1093/brain/awz232.

Authors

Wenshu XiangWei^{1

2}, Varun Kannan², Yuchen Xu^{2

3}, Gabrielle J Kosobucki⁴, Anthony J Schulien⁴, Hirofumi Kusumoto², Christelle Moufawad El Achkar^{5

6}, Subhrajit Bhattacharya², Gaetan Lesca^{7

8}, Sylvie Nguyen⁹, Katherine L Helbig¹⁰, Jean-Marie Cuisset⁹, Christina Dühring Fenger¹¹, Dragan Marjanovic¹¹, Elisabeth Schuler¹², Ye Wu¹, Xinhua Bao¹, Yuehua Zhang¹, Nina Dirkx^{13

14}, An-Sofie Schoonjans¹⁵, Steffen Syrbe¹², Scott J Myers^{2

16}, Annapurna Poduri^{5

6}, Elias Aizenman⁴, Stephen F Traynelis^{2

16}, Johannes R Lemke¹⁷, Hongjie Yuan^{2

16}, Yuwu Jiang¹

Affiliations

¹ Department of Pediatrics and Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
² Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
³ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Department of Neurobiology, University of Pittsburgh School of Medicine and Pittsburgh Institute for Neurodegenerative Diseases, Pittsburgh PA, USA.
⁵ Division of Epilepsy, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁶ Department of Neurology, Harvard Medical School, Boston, MA, USA.
⁷ Service de Genetique, Centre de Reference Anomalies du Developpement, Hospices Civils de Lyon, Bron, France; INSERM U1028, CNRS UMR5292, Paris, France.
⁸ Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Universite Claude Bernard Lyon 1, Bron, France; Claude Bernard Lyon I University, Lyon, France.
⁹ Department of Pediatric Neurology, University Hospital of Lille, and Lille Reference Centre for Rare Epileptic Disorders, Lille, France.
¹⁰ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
¹² Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
¹³ Neurogenetics Group, University of Antwerp, Belgium.
¹⁴ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
¹⁵ Department of Child Neurology, Antwerp University Hospital, Antwerp, Belgium.
¹⁶ Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA.
¹⁷ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.

Abstract

N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.

Keywords: GluN; NMDA receptor; channelopathy; functional genomics; glutamate receptor.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amino Acid Sequence / genetics
Animals
Child
Child, Preschool
Epilepsy, Generalized / genetics*
Epilepsy, Generalized / physiopathology
Female
Gene Expression Regulation / genetics
Glutamic Acid / metabolism
HEK293 Cells
Humans
Male
Neurons / metabolism
Polymorphism, Single Nucleotide / genetics
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / genetics*
Receptors, N-Methyl-D-Aspartate / metabolism
Synaptic Transmission / genetics

Substances

GRIN2D protein, human
NR2D NMDA receptor
Receptors, N-Methyl-D-Aspartate
Glutamic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding