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

Kataoka, Shinsuke; Kawashima, Nozomu; Muramatsu, Hideki; Miwata, Shunsuke; Narita, Kentaro; Hamada, Masanori; Murakami, Norihiro; Taniguchi, Rieko; Ichikawa, Daisuke; Kitazawa, Hironobu; Suzuki, Kyogo; Nishikawa, Eri; Narita, Atsushi; Nishio, Naomichi; Yamamoto, Hidenori; Fukasawa, Yoshie; Kato, Taichi; Yamamoto, Hiroyuki; Natsume, Jun; Kojima, Seiji; Nishino, Ichizo; Taketani, Takeshi; Ohnishi, Hiroyuki; Takahashi, Yoshiyuki

doi:10.1016/j.jaci.2021.03.010

Cited by 26 publications

(20 citation statements)

References 7 publications

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“…Although cognitive impairment is found in both syndromes, 23 most of the individuals with STISS only rarely develop typical clinical signs of autoinflammation, including skin lesions and recurrent fever, which are the hallmarks of CANDLE/PRAAS. [20][21][22][23][24][25][26][27] The lack of inflammatory manifestations in individuals with STISS is surprising but does not contradict the type I IFN gene signature detected in these patients. Indeed, interferonopathies are not necessarily associated with the development of clinical inflammatory symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…Given that loss-of-function variants in genes encoding 20S core particle subunits and/or proteasome assembly chaperones typically trigger a type I IFN response in individuals with chronic atypical neurophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)/ proteasome-associated autoinflammatory syndrome (PRAAS), [20][21][22][23][24][25][26][27] we next sought to determine whether PSMD12 loss-of-function variants would induce type I ISG as well. To answer this question, whole-blood samples stored in PAXgene RNA tubes from patients and healthy controls were assessed for their ISG mRNA contents (ie, IFI44L, IFIT1, IFI27, ISG15, RSAD2, and SIGLEC1) by qPCR before calculating a type I IFN score following the procedure of Rice et al 9 As shown in Figure 4A, the type I IFN scores of patient with STISS were significantly higher than those of the controls with IFIT1, IFI44L, RSAD2, and SIGLEC1 being the most prominently upregulated ISGs (Supplemental Figure 3A).…”

Section: Psmd12 Haploinsufficiency Causes a Type I Ifn Gene Signature...mentioning

confidence: 99%

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Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Isidor

Ebstein

Hurst

et al. 2022

Genetics in Medicine

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Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion:We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.

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Section: Discussionmentioning

confidence: 99%

Section: Psmd12 Haploinsufficiency Causes a Type I Ifn Gene Signature...mentioning

confidence: 99%

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Isidor

Ebstein

Hurst

et al. 2022

Genetics in Medicine

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“…Inherited or de novo loss-of-function mutations in genes encoding for proteasome subunits of the 20S core particle (as PSMB8, PSMB9, PSMB7, PSMA3, PSMB10), or proteasome chaperone factors (as Proteasome Maturation Protein or POMP and proteasome assembly chaperone 2 PSMG2) are the genetic substrates of a heterogeneous class of IFNopathies, named PRAAS [172][173][174][175][176][177][178]. The main diseases that can be included in this group are the joint contractures, muscle atrophy, microcytic anaemia and panniculitis-induced lipodystrophy syndrome (JMP), the Nakajo-Nishimura syndrome and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CAN-DLE) [119].…”

Section: Proteasome Associated Autoinflammatory Syndromes (Praas)mentioning

confidence: 99%

Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives

Donato¹,

d’Angelo²,

Breda³

et al. 2021

IJMS

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Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.

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“…Like most of the NDD due to genomic alterations of UPS genes, these syndromes are seemingly devoid of systemic signs of immune dysregulation. This observation is even more surprising considering the fact that proteasome loss-of-function mutations have been described to cause autoinflammatory diseases referred to as proteasome-associated autoinflammatory syndromes (PRAAS) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) ( Agarwal et al, 2010 ; Arima et al, 2011 ; Kitamura et al, 2011 ; Liu et al, 2012 ; Brehm et al, 2015 ; Poli et al, 2018 ; de Jesus et al, 2019 ; Sarrabay et al, 2019 ; Kataoka et al, 2021 ). In contrast to the NDD alterations that may affect 20S or 19S proteasome complexes, the CANDLE/PRAAS mutations are exclusively located in the 20S core particle and/or proteasome assembly chaperones ( Ebstein et al, 2019 ).…”

Section: Ndd-associated E3 Ubiquitin Ligases and Their Roles In The Immune Responsementioning

confidence: 99%

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Ebstein

Küry

Papendorf

et al. 2021

Front. Mol. Neurosci.

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Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

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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

Cited by 26 publications

References 7 publications

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

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