PSMB10 variants with biological and histological features. (A) Liver histology of PII. Left upper part: Partial phlebosclerosis of central vein (arrow) and sinusoidal dilatation with aggregation of erythrocytes and lymphocytes, trichrome staining, ×13. Right upper part: Chronic disease, with shrunken other central vein and fibrous occlusion (arrow), binucleation and hepatocyte anisonucleosis, HES staining, ×20. Left lower part: Zone 3 perisinusoidal fibrosis (arrow) with loss or atrophy of hepatocytes, associated with areas of hepatocyte regeneration (plump hepatocytes with pale cytoplasm), no nodular regenerative hyperplasia, Sirius red staining, ×22. Right lower part: Very mild portal inflammation (arrow) and moderate lobular inflammation with CD3⁺, CD8⁺ in sinusoids, CD3 immunostaining, ×16. Inset on the right lower part. Detail of a near normal portal tract in the insert, cytokeratin 7 immunostaining, ×25. (B) Radiosensitivity testing of PBMC of PI, PI’s mother and father (PI_M and PI_F), and PIII compared to healthy controls (C, green), ataxia telangiectasia (AT, brown), and DNA-ligaseIV (Lig4, purple) radiosensitive patients. No fibroblast available for all patients. (C) PROMIDISα signature clustering of PI (red arrow), PI’s mother and father (PI_M and PI_F, red dotted arrows), PIII (green arrow), and group of V(D)J/DNA repair-deficient patients (grey), patients with ataxia telangiectasia (blue), and healthy control individuals (yellow). (D) Family pedigrees for PI, PII and PIII. (E) Schematic representation of PSMB10 intron–exon organization (intron in lines and coding regions in boxes, lower part) with corresponding protein (upper part), respectively, and noncoding exon sequences (in dashed boxes). Variants of the three patients are colored; the PRAAS biallelic mutation, other PSMB10 heterozygous mutations involved in inborn errors of immunity, and the TUB6 mouse mutation are represented in black. (F) Cryo-EM 3D structure of human PSMB10 within the immunoproteasome complex, with positions of mutated amino acids labeled in red (this study) and pink (Protein Data Bank accession no. 6AVO [8]). H-bonds are shown with broken lines. WT, wild-type.