Fig. 1: De novo CLTC variants.

(a) Distribution of de novo variants in the CLTC gene in a schematic representation of the structure of the CLTC gene (NM_004859.3. 2; NP_004850.1; Uniprot: https://www.uniprot.org/uniprot/Q00610). Indicated are the globular terminal domain (TD) (residues 2–479), the flexible linker (residues 480–523), and the heavy chain arm (residues 524–1675) with clathrin heavy chain repeats (CHCR), which is involved in binding a clathrin light chain (CLC binding; residues 1213–1522) and contains the trimerization domain (TD; residues 1550–1675). Variants identified in this study are indicated in bold and variants located in a splice site are indicated in italics. (b) 3D structure of the clathrin coat complex (PDB file 3iyv) showing one centrally located CLTC protein (in gray) with the abovementioned domains and with the position of de novo in-frame CLTC variants in the protein (red points). Eight additional clathrin heavy chains, interacting with the centrally located CLTC protein, are shown in different colors (blue, green, and purple). Note the interaction of the C-terminal helix (trimerization domain) with two other heavy chains (blue/green). Smaller clathrin light chains, which are located close to the proximal domain of the heavy chain, are shown in yellow. (c) 3D structure close-ups of the clathrin complex displayed in (b), showing specific domains of the centrally located protein encoded by the CLTC gene (in gray) with de novo in-frame CLTC variants (in red), surrounded by clathrin heavy chains (in blue, green, and purple) and clathrin light chains (in yellow). (c1) Close-up of the distal segment of the heavy chain arm, showing that in-frame variants occur in an area that is in close interaction with the other heavy chains. An abnormal or loss of interaction with other heavy chains is predicted to affect the local structure of the clathrin coat complex. (c2) Close-up of the proximal segment of the heavy chain arm, showing that variants occur nearby a clathrin light chain and/or the KR-loop residues 1161–1165 (shown in orange), which is considered relevant for the regulation of the interactions with the light chain (Wilbur et al.¹⁶ Dev Cell 2010;18(5):841–848), likely resulting in an abnormal or loss of interactions with both heavy and light chains. Panels (c1) and (c2) were made using PDB file 3iyv.