Sophia Davidson, Yuri Shibata, Sophie Collard, Hongyu Zheng, Klara Kong, June M Sun, Pawat Laohamonthonkul, Anthony Cerra, Tobias Kratina, Margaret W Y Li, Carolyn Russell, Anna van Beek, Edwin P Kirk, Rebecca Walsh, Jubran Alqanatish, Abdullah Almojali, Wafaa Alsuwairi, Abdulrahman Alrasheed, Najoua Lalaoui, Paul E Gray, David Komander, Seth L Masters
OTU deubiquitinase with linear linkage specificity (OTULIN) regulates inflammation and cell death by deubiquitinating linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC). Biallelic loss-of-function mutations causes OTULIN-related autoinflammatory syndrome (ORAS), while OTULIN haploinsuffiency has not been associated with spontaneous inflammation. However, herein, we identify two patients with the heterozygous mutation p.Cys129Ser in OTULIN. Consistent with ORAS, we observed accumulation of linear ubiquitin chains, increased sensitivity to TNF-induced death, and dysregulation of inflammatory signaling in patient cells...
June 3, 2024: Journal of Experimental Medicine