Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor.

Abstract Background Type I interferonopathies are a recently established subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA and DNA sensing pathways. Objective This study aimed to unveil the molecular pathogenesis of a patient with novel type I interferonopathy, for which no known genetic mutations have been identified. Methods We performed the whole exome sequencing (WES) of a 1-month-old boy with novel type I interferonopathy. We also investigated proteasome activities using patient-derived B lymphoblastoid cell lines (LCLs) and normal LCLs transduced with the mutant gene. Results WES identified a de novo proteasome 20S subunit beta 9 (PSMB9) p.G156D mutation in the patient who developed fever, a chilblain-like skin rash, myositis, and severe pulmonary hypertension due to the hyperactivation of interferon-alpha. Patient-derived LCLs revealed reduced proteasome activities, and exogenous transduction of mutant PSMB9 p.G156D into normal LCLs significantly suppressed proteasome activities, and the endogenous PSMB9 protein was lost along with the reduction of other immunoproteasome subunits, PSMB8 and PSMB10 proteins. He responded to the administration of a Janus kinase (JAK) inhibitor, tofacitinib, and he was successfully withdrawn from veno-arterial extracorporeal membranous oxygenation. At 7 months of age, he received an unrelated cord blood transplantation. At 2 years post transplantation, he no longer required tofacitinib and experienced no disease recurrence. Conclusion We present the case of a patient with a novel type I interferonopathy caused by a de novo PSMB9 p.G156D mutation which suppressed the wild-type PSMB9 protein expression. JAK inhibitor and stem cell transplantation could be curative therapies in patients with severe interferonopathies.