De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities Sonja Martin, Adam Chamberlin, Deepali N. Shinde,

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De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities Sonja Martin, Adam Chamberlin, Deepali N. Shinde, Maja Hempel, Tim M. Strom, Allison Schreiber, Jessika Johannsen, Lilian Bomme Ousager, Martin J. Larsen, Lars Kjaersgaard Hansen, Ali Fatemi, Julie S. Cohen, Johannes Lemke, Kristina P. Sørensen, Katherine L. Helbig, Davor Lessel, Rami Abou Jamra The American Journal of Human Genetics Volume 101, Issue 6, Pages 1013-1020 (December 2017) DOI: 10.1016/j.ajhg.2017.11.004 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Structure of GRIA4 and Variant Location In addition, we show the allele count of genetic variants reported by gnomAD8 for the canonical transcript ENST00000282499 (GenBank: NM_000829.3). At position Arg697, where we describe the variant p.Arg697Pro in proband 5 in this report, another variant (p.Arg697Gln) is reported in gnomAD.8 In the main text, we describe the most likely mild impact of this change on the function of the protein. The figure was made with the help of Protter.64 The American Journal of Human Genetics 2017 101, 1013-1020DOI: (10.1016/j.ajhg.2017.11.004) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Tetrameric Structure of GRIA4 with Variants and Allosteric Movements The structure of GRIA4 was built off the homologous structure of GRIA2 for Rattus norvegicus in the complex with an agonist (PDB: 3KG245). The homology model of Gria4 was built off the homology modeling module of ROSETTA,60 where the sequence alignments were generated with TCOFFEE.61,62 The energy calculations of both and the destabilization of internal structure were calculated with the FoldX program.63 The images were generated with PyMOL (PyMOL Molecular Graphics System, v.1.8, Schrödinger). (A) GRIA4 tetramer with residues in the SYTANLAAF motif of M3. The residue positions of missense variants are indicated by red sticks. (B) GRIA4 tetramer with a variant in the ligand binding domain. The residue position of wild-type Arg697 is indicated by red sticks. (C) Arg697 moves by more than 10 Å from the ligand-bound (green; PDB: 3KG210) to the apo (yellow; PDB: 4U2P62) state. Arg697 interacts with residues on the adjacent monomer (gray), including the repulsive Lys787 and Lys792 (red sticks) in the ligand-bound state and the attractive Glu444 (blue sticks) in the apo state. The American Journal of Human Genetics 2017 101, 1013-1020DOI: (10.1016/j.ajhg.2017.11.004) Copyright © 2017 American Society of Human Genetics Terms and Conditions