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Fig. 3 | Acta Neuropathologica Communications

Fig. 3

From: Core-rod myopathy due to a novel mutation in BTB/POZ domain of KBTBD13 manifesting as late onset LGMD

Fig. 3

Schematic view of KBTBD13 and functional essays. Schematic view of KBTBD13 transcript (a) showing BTB and Kelch-repeat domains. Kelch domain is composed by five repeats. First and last aminoacidic residues of both domains are also reported. The novel G67R mutation (bold red) in BTB domain and the three previously described mutations (dark blue) in Kelch domain. WB of KBTBD13 (b) showing the reduced protein expression in patient’s muscle biopsy (pt) compared to healthy controls (ctrl). Representative confocal microscopy images of HeLa cells transfected with KBTBD13WT and KBTBD13G67R pCMV6-AC-GFP plasmids. Nuclei were counterstained with 4,6-diamidino-2-phenylindole (DAPI). Scale bars: 10 μm. No difference between wild type-KBTBD13 and G67R-KBTBD13 expression and localization in HeLa transfected cells (c). Molecular models (D) of WT and mutated KBTBD13. In the upper left panel, interaction of two homodimer BTB domains (light blue and green, respectively) of two KBTBD13 molecules (not shown) as obtained by molecular modelling. The protein backbone atoms are represented as ribbons, while the two Gly67 side chains are shown as Van der Waals spheres and circled in red. The upper right panel displays the calculated model of the complex between the BTB (green) and Cul3 (red). The protein backbone is represented as ribbons, and Gly67 side chain are shown as Van der Waals spheres and circled in red. The calculated model suggests that the mutated residue lies far from the interaction interface with Cul3. The lower panel on the left shows the structure of the predicted homodimer BTB-BTB (with the same size and orientation of the upper left panel) which is coloured according to its calculated surface electrostatic potential. Regions of positive and negative electrostatic potential are shown in blue and red, respectively, and the yellow asterisks indicate the position of residue 67 in both BTB domains forming the dimer. The lower panels on the right depict the changes in the surface electrostatic potential of BTB domain when Gly67 (WT) is mutated in silico into Arg67 (G67R). Note the surface electrostatic potential showing a marked loss of the surface negative potential (red colour) surrounding residue 67 in G67R mutant with respect to the WT

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