Fig. 1: Pedigrees and genetics of families with SOCS1 mutations.

a Pedigrees of families with SOCS1 mutations. Squares: males; circles: females; black: affected mutation carriers; gray: unaffected mutation carriers. WT: wild-type SOCS1 allele. b Clinical manifestations in patients with SOCS1 mutations. Discoid lupus erythematosus (D1, upper left), active lupus nephritis (E1, lower left) with segmental cellular crescent associated with mesangial hypercellularity (Masson’s trichrome × 400) and glomerular capillary wall and mesangial C1q deposition by immunofluorescence microscopy, abdominal MRI showing splenomegaly (C1, middle), and plaque, intertrigous and guttata psoriasis (E4, right). c SOCS1 protein domains and locations of the mutations (upper panel, black arrows). The kinase inhibitory region (KIR) functions as a pseudosubstrate that can inhibit the tyrosine kinase activity of Janus kinase (JAK) proteins. The SRC-homology 2 (SH2) domain binds the activation loop of the JAK proteins’ catalytic domain. The SOCS box recruits the ubiquitin-transferase system and initiates the proteasomal degradation of JAK proteins. The SOCS1 M161Afs*46 mutant leads to a predicted 46-residue neopeptide in the SOCS box domain three amino acids shorter than the wild-type protein (lower panel). d Top panel: position of the P123 and Y154 in human SOCS1 within a 3D model of the JAK1/SOCS1 complex. Bottom panel: a model of the human SOCS1’s SH2 domain. The two mutated amino acids (P123R and Y154H) are highlighted in the phosphotyrosine peptide binding groove (the pY and pY+3 pockets). The possible location of a phosphotyrosine peptide is shown in purple. e SOCS1 protein expression in patient-derived cells and transfected cells. Top: Western blot (WB) analysis of lysates from Epstein-Barr-virus (EBV)-tranformed B cells from patients A1, B2, and D1 and from two healthy controls (CT1 and CT2), following incubation with anti-SOCS1 antibodies (upper panel) or anti-actin antibodies as a loading control (lower panel). Bottom: HEK293T cells transiently transfected with an empty vector (EV), a vector coding for hemagglutinin (HA)-tagged wild-type (WT) SOCS1 protein, or vectors coding for the five HA-tagged mutant SOCS1 proteins. Lysates were incubated with anti-HA antibodies (upper panel) or anti-actin antibodies as a loading control (lower panel). Data are representative of two independent experiments.