Fig. 2
TrIdx-phenotype landscape and TrIdx-structure in the absence and presence of SAHA. a NPC1 variants are positioned by their variant sequence position (VarSeqP) (x-axis) normalized to the full-length sequence and measured Chol values of NPC1 variants (y-axis normalized to I1061T) in the absence (left panel) or presence (right panel) of SAHA. The projected z-axis (color gradient) is defined by the absolute measured TrIdx of each variant. The spatial relationships of pairwise comparisons of variants are illustrated as black lines. b The molecular variogram illustrating the spatial variance of measured TrIdx for distance values defined by VarSeqP and Chol in the absence (black line) or presence (red line) of SAHA (see Methods; Supplementary Fig. 6a). c VSP predicted TrIdx-phenotype landscape is shown as a heatmap in the absence (left panel) or presence (right panel) of SAHA. Confidence relationships (see Supplementary Fig. 6b) within the molecular variogram range are plotted as contour lines and the top 25% confidence quartile is shown as a bold line. Color-scale values: defective trafficking (red); ~50% WT trafficking (yellow); WT trafficking (green). I1061T ER-restricted variant is bolded. Dashed ovals 1 and 2 highlight two SCV clusters found in the top 25% confidence quartiles that have defective trafficking in the absence of SAHA. d Mapping the TrIdx-phenotype landscape on the NPC1 structure25,29. The highest confident prediction of the TrIdx value and the corresponding Chol value is assigned for each residue with ball color representing TrIdx, ball size representing Chol, and transparency representing prediction confidence. SCV cluster 1 and 2 are selectively highlighted as balls in cartoon presentation of the structure
