Fig. 1
Identification of compound heterozygous variants in ITPR3 in two patients with immunodeficiency or immune dysregulation. A Pedigrees of two unrelated families illustrating the genotype of the tested individuals. B Schematic domain structure of IP3R3 with positions of the variants indicated by red lines. C PopViz plot showing the mean allelic frequency (MAF) and the Combined Annotation Dependent Deletion (CADD) score with the identified variants in red. The dashed line indicates the gene-specific mutation significance cutoff (MSC). D Cryo-EM structure of homotetrameric IP3R3 (6DQJ) depicted in a ribbon diagram with different subunits in different colors. Two orthogonal views are shown: a side view along the membrane plane (left) and a view from the cytosol (right). E Illustration of the identified variants mapped onto the 3D structure of IP3R3 (6DQJ). Two opposing subunits are shown in side view. Unresolved sequences are indicated by dashed lines. The red dashed line spans a known phosphorylation region including the R1850 residue. Putative residues involving Ca2+ binding to the receptor are rendered as pink spheres. F Slices through the space-filled model of the IP3R3 TM region perpendicular to the 4-fold axis as seen from the cytosol. Surfaces are color-coded according to electrostatic charges calculated for the model (red: negative; blue: positive)
