A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome

• DOI: 10.1084/jem.20231941
• Publication Date: 2024-04-23T14:08:39Z
• Authors: Yukiko Takeda; Masahiro Ueki; Junpei Matsuhiro; Erik Walinda; Takayuki Tanaka; Masafumi Yamada; Hiroaki Fujita; Shunichiro Takezaki; Ichiro Kobayashi; Sakura Tamaki; Sanae Nagata; Noriko Miyake; Naomichi Matsumoto; Mitsujiro Osawa; Takahiro Yasumi; Toshio Heike; Fumiaki Ohtake; Megumu K. Saito; Junya Toguchida; Junko Takita; Tadashi Ariga; Kazuhiro Iwai
• Keywords: Male; 0303 health sciences; Tumor Necrosis Factor-alpha; Ubiquitin; Hereditary Autoinflammatory Diseases; Induced Pluripotent Stem Cells; Ubiquitination; Mesenchymal Stem Cells; Article; Pedigree; 03 medical and health sciences; Endopeptidases; Mutation; Humans; Female

OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis.