Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor - 04/08/21

Doi : 10.1016/j.jaci.2021.03.010

Shinsuke Kataoka, MD ^a,^{^{∗
These authors contributed equally to this work.}}, Nozomu Kawashima, MD, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Yusuke Okuno, MD, PhD ^b, Hideki Muramatsu, MD, PhD ^a, Shunsuke Miwata, MD ^a, Kotaro Narita, MD ^a, Motoharu Hamada, MD, PhD ^a, Norihiro Murakami, MD, PhD ^a, Rieko Taniguchi, MD, PhD ^a, Daisuke Ichikawa, MD ^a, Hironobu Kitazawa, MD ^a, Kyogo Suzuki, MD, PhD ^a, Eri Nishikawa, MD, PhD ^a, Atsushi Narita, MD, PhD ^a, Nobuhiro Nishio, MD, PhD ^a,^c, Hidenori Yamamoto, MD ^a, Yoshie Fukasawa, MD ^a, Taichi Kato, MD, PhD ^a, Hiroyuki Yamamoto, MD, PhD ^a, Jun Natsume, MD, PhD ^a, Seiji Kojima, MD, PhD ^a, Ichizo Nishino, MD, PhD ^d, Takeshi Taketani, MD, PhD ^e, Hidenori Ohnishi, MD, PhD ^f, Yoshiyuki Takahashi, MD, PhD ^a,^⁎
^a Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
^b Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan
^c Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
^d Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
^e Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan
^f Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan

^∗Corresponding author: Yoshiyuki Takahashi, MD, PhD, Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.Department of PediatricsNagoya University Graduate School of Medicine65 Tsurumai-choShowa-kuNagoyaAichi466-8550Japan

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 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

Whole-exome sequencing 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 IFN-α. 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 inhibitor, tofacitinib, and he was successfully withdrawn from venoarterial extracorporeal membranous oxygenation. At age 7 months, he received an unrelated cord blood transplantation. At 2 years posttransplantation, he no longer required tofacitinib and experienced no disease recurrence.

Conclusions

We present the case of a patient with a novel type I interferonopathy caused by a de novo PSMB9 p.G156D mutation that suppressed the wild-type PSMB9 protein expression. Janus kinase inhibitor and stem cell transplantation could be curative therapies in patients with severe interferonopathies.

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Key words : JAK inhibitor, interferonopathy, pulmonary hypertension, proteasome 20S subunit beta 9 (PSMB9)

Abbreviations used : CPK, IB, JAK, LCL, PSMB9, STAT1, VA-ECMO, WT

Plan

Introduction

Methods

Results and discussion

	This work was supported by “Research on Measures for Intractable diseases” Project from the Ministry of Health, Labour and Welfare of Japan, and partly by Intramural Research Grant for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry.
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 148 - N° 2

P. 639-644 - août 2021 Retour au numéro

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Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor - 04/08/21

Abstract

Background

Objective

Methods

Results

Conclusions

Plan

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