Fig. 4: Scrutiny of individual variants: example for INPP5E variants.

A Schematic of INPP5E protein showing the phosphatase domain. On top are displayed missense variants described in individuals with Joubert syndrome from the literature, at the bottom are the variants identified in the healthy individuals in our cohort. Note the clustering of missense variants in the phosphatase domain in affected individuals. The two missense variants identified in our cohort localize just next to previously described disease alleles. B–C” Protein modeling using HOPE software [34] for the two INPP5E missense variants identified in the healthy individuals in our cohort. B, C Overview of the protein in ribbon-presentation. The protein is colored grey, the mutated residue is colored magenta. B’–B”, C’–C” Close-ups of the mutations. The protein is colored in grey, the side chains of wild-type and mutant residues are colored green and red, respectively. B D438H: The HOPE report indicates that the wild-type Aspartic acid residue forms a hydrogen bond with Threonines at positions 395 and 426. The size difference between wild-type and mutant residues makes that the new residue is not in the correct position to make the same hydrogen bond as the original wild-type residue did. In addition, the wild-type residue forms a salt bridge with Arginines at position 396, 435, and 441. The difference in charge will disturb the ionic interaction made by the original, wild-type residue. C R486C: The HOPE report indicates that the wild-type Arginine residue forms hydrogen bonds with Aspartic Acid at position 544, Arginine at position 550 and Tyrosine at position 543. The size difference between wild-type and mutant residues makes that the new residue is not in the correct position to make the same hydrogen bonds as the original wild-type residue did. The difference in hydrophobicity will affect hydrogen bond formation. In addition, the wild-type residue forms a salt bridge with Aspartic Acid at positions 490, 537 and 544. The difference in charge will disturb the ionic interaction made by the original, wild-type residue.