De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

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De Novo Mutations in YWHAG Cause Early-Onset Epilepsy Ilaria Guella, Marna B. McKenzie, Daniel M. Evans, Sarah E. Buerki, Eric B. Toyota, Margot I. Van Allen Shelin Adam, Cyrus Boelman, Corneliu Bolbocean, Tara Candido, Patrice Eydoux, Gabriella Horvath, Linda Huh, Tanya N. Nelson, Graham Sinclair, Clara van Karnebeek, Suzanne Vercauteren, Mohnish Suri, Frances Elmslie, Marleen E.H. Simon, Koen L.I. van Gassen, Delphine Héron, Boris Keren, Caroline Nava, Mary B. Connolly, Michelle Demos, Matthew J. Farrer Ilaria Guella, Marna B. McKenzie, Daniel M. Evans, Sarah E. Buerki, Eric B. Toyota, Margot I. Van Allen Shelin Adam, Cyrus Boelman, Corneliu Bolbocean, Tara Candido, Patrice Eydoux, Gabriella Horvath, Linda Huh, Tanya N. Nelson, Graham Sinclair, Clara van Karnebeek, Suzanne Vercauteren, Mohnish Suri, Frances Elmslie, Marleen E.H. Simon, Koen L.I. van Gassen, Delphine Héron, Boris Keren, Caroline Nava, Mary B. Connolly, Michelle Demos, Matthew J. Farrer The American Journal of Human Genetics Volume 101, Issue 2, Pages 300-310 (August 2017) DOI: 10.1016/j.ajhg.2017.07.004 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 De Novo SLC1A2 and YWHAG Mutations in Individuals with Early-Onset Epilepsy (A) Top: transmembrane topology of EAAT2 (adapted from Yernool et al.30) and localization of the variants identified in this study (green) or previously reported (black) (the asterisk indicates a recurrent variant). Bottom: partial sequence alignment of EAAT2 orthologs and different human EAAT proteins surrounding p.Pro289Arg (indicated by an arrow). Identical residues across all proteins are shown in black, and residues identical to the human EAAT2 are in gray. GenBank accession numbers are as follows: Homo sapiens, NP_004162.2; Macaca mulatta, NP_001248598.1; Mus musculus, NP_001070982.1; Gallus gallus, NP_001012917.1; Xenopus tropicalis, XP_002937340.1; Dario rerio, NP_956273.1; Caenorhabditis elegans, NP_001024393.1; human EAAT1, NP_004163.3; human EAAT3, NP_004161.4; human EAAT4, NP_005062.1; and human EAAT5, NP_006662.3. (B) Top: crystal structure of 14-3-3γ (PDB: 5D3E). Left: dimeric 14-3-3γ is shown as green ribbons, and the phosphopeptide ligand is shown as an orange stick. Right: close-up view of the binding groove, side chains of the residues crucial for the phosphopeptide binding, and hydrogen bonds (green dashed lines). Images were generated with Swiss-Pdb Viewer v.4.10.31 Bottom: partial sequence alignment of 14-3-3γ orthologs and different human 14-3-3 proteins surrounding the mutated residues identified in this study (green) or previously reported (black). Identical residues across all proteins are shown in black, and residues identical to the human 14-3-3γ are in gray. GenBank accession numbers are as follows: Homo sapiens, NP_036611.2; Macaca mulatta, NP_001181365.1; Mus musculus, NP_061359.2; Gallus gallus, NP_001026648.1; Xenopus tropicalis, NP_001072309.1; Dario rerio, NP_998187.1; Caenorhabditis elegans, AAA61872.1; human 14-3-3β, NP_003395.1; human 14-3-3ε, NP_006752.1; human 14-3-3 ζ, NP_001129174.1; human 14-3-3 η, NP_003396.1; human 14-3-3 θ, NP_006817.1; and human 14-3-3 NP_006133.1. Sequences were aligned with CLUSTAL Omega.32 Asterisks indicate positions with a single fully conserved residue, colons indicate conservation between groups with strongly similar properties, and periods indicate conservation between groups with weakly similar properties. The American Journal of Human Genetics 2017 101, 300-310DOI: (10.1016/j.ajhg.2017.07.004) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 MRI Findings in Individuals with SLC1A2 Mutations (A–G) Subject A. Sagittal T1 (A) and axial T2 (B) at 6 weeks revealed a thin corpus callosum but within normal limits for age. Axial T2 (C and D) and sagittal T1 (E) at 2 years revealed volume loss and a thin corpus callosum, increased T2 white-matter signal intensity, delayed myelination, decreased T2 signal of thalami, and increased T2 signal of putamen and caudate. At 4 years, axial T2 (F) and sagittal T1 (G) showed progressive volume loss; persistent abnormal signal in thalami, putamen, and caudate; a focal area of increased T2 signal in the left lentiform nucleus; and a thin corpus callosum. (H–J) Subject C. Axial T2 (H) and sagittal T1 (I) at 2 months were normal. At 2.5 years, axial T2 (J) revealed atrophy, delayed myelination, and bilateral T2 prolongation in caudate heads and putamina. The American Journal of Human Genetics 2017 101, 300-310DOI: (10.1016/j.ajhg.2017.07.004) Copyright © 2017 American Society of Human Genetics Terms and Conditions