Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly Hasan Tawamie, Igor Martianov,

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Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly Hasan Tawamie, Igor Martianov, Natalie Wohlfahrt, Rebecca Buchert, Gabrielle Mengus, Steffen Uebe, Luigi Janiri, Franz Wolfgang Hirsch, Johannes Schumacher, Fulvia Ferrazzi, Heinrich Sticht, André Reis, Irwin Davidson, Roberto Colombo, Rami Abou Jamra The American Journal of Human Genetics Volume 100, Issue 3, Pages 555-561 (March 2017) DOI: 10.1016/j.ajhg.2017.01.032 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of Affected Individuals and MRI of Individual IV-6 from Family 1 (A and B) Pedigrees of families 1 (A) and 2 (B). (C) MRI of individual IV-6 at 10 months of age shows mild delayed myelinization (I), discrete frontal pachygyria (II), and deep sulci of the cerebrum (III). The American Journal of Human Genetics 2017 100, 555-561DOI: (10.1016/j.ajhg.2017.01.032) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Pathogenicity of TAF13 Variants on the Formation of the TAF13-TAF11 Complex (A) I: structure of TAF13 (dark blue) in complex with TAF11 (cyan). Residues Leu31 and Met40 are shown in space-filled presentation and colored according to their atom types. The interacting residues Leu57 and IIe62 are colored in red and orange, respectively. II: the p.Met40Lys pathogenic variant results in unfavorable interactions between the Lys40 amide group and the hydrophobic Leu62 side chain (black arrow) and additionally causes steric clashes because the lysine side chain is longer than the methionine (red arrow). III: the p.Leu31His pathogenic variant results in a loss of the hydrophobic contacts with Ile62 (black arrow). In summary, the structural effects described above for the p.Leu31His and p.Met40Lys pathogenic variants destabilize the bent TAF13 conformation required for TAF11 binding and are therefore expected to hamper formation of the TAF13-TAF11 complex. The investigation of the structural effects of the p.Leu31His and p.Met40Lys variants was based on the crystal structure of the TAF13-TAF11 complex (PDB: 1BH8).3 We modeled mutations with SWISS-Model18 by selecting the lowest-energy sidechain rotamer for each mutated residue. Structure analysis and visualization was performed with RasMol.19 (B) Western blots of coIP experiments of the HeLa cells transfected with TAF11 and either wild-type or mutant TAF13. The anti-B10 antibody (3010F12, provided by the laboratory of Irwin Davidson) was to precipitate TAF11, and TAF13 levels were assessed with an anti-HA antibody (H6908, Sigma). The American Journal of Human Genetics 2017 100, 555-561DOI: (10.1016/j.ajhg.2017.01.032) Copyright © 2017 American Society of Human Genetics Terms and Conditions