Figure 1.

Mutations in OTULIN in Patients with a Systemic Autoinflammatory Syndrome

(A) Segregation of the inflammatory symptoms (filled symbols) and the c.815T>C substitution in OTULIN in the affected kindred. ○, females; □, males; double lines, consanguineous relationship; crossed symbols, deceased individuals; Δ, miscarriage; ◊, stillbirths. Roman numerals indicate generations.

(B and C) Lifetime measurements of (B) C-reactive protein (CRP) serum concentrations and (C) white blood cell (WBC, black line) and neutrophil numbers (cyan line) in blood from patients IV:3, IV:4, and V:2. Reference ranges (dotted lines) are indicated on the graphs. Patient V:2 was treated with Infliximab as indicated (orange shade).

(D) OTULIN DNA sequence chromatograms identifying the homozygous single-base substitution (c.815 T>C, p.Leu272Pro, arrowhead).

(E) Schematic of the cardinal symptoms of OTULIN-related autoinflammatory syndrome (ORAS). The efficacy of trialed treatments are indicated in the table.

(F) Superimposed structures of OTULIN’s catalytic domain (blue) without substrate and bound to Met1 diUb (green [only distal Ub shown]; PDB: 3znv and PDB: 3znz [Keusekotten et al., 2013]), showing the position of Leu272 in the distal Ub binding site.

(G) Met1-linked diUb hydrolysis by OTULIN^WT and OTULIN^L272P.

(H) Immunoblot showing the levels of Met1-linked polyUb, total Ub, OTULIN, and LUBAC in buffy coat cells from patient V:2.

See also Figure S1 and Document S1. Tables S1 and S3–S8, Table S2. Rare Homozygous Variants in ORAS Patients, Related to Figure 1.