Somatic mosaicism of <i>CIAS1</i> in a patient with chronic infantile neurologic, cutaneous, articular syndrome

Saito, Megumu K.; Fujisawa, Akihiro; Nishikomori, Ryuta; Kambe, Naotomo; Nakata-Hizume, Mami; Yoshimoto, Momoko; Ohmori, Katsuyuki; Okafuji, Ikuo; Yoshioka, Takakazu; Kusunoki, Takashi; Miyachi, Yoshiki; Heike, Toshio; Nakahata, Tatsutoshi

doi:10.1002/art.21404

Cited by 125 publications

(24 citation statements)

References 24 publications

(23 reference statements)

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“…Finally, this study is among the first to demonstrate somatic mosaicism underlying immunologic disease (Holzelova et al, 2004;Saito et al, 2005;Wolach et al, 2005;Tanaka et al, 2011;Liu et al, 2014;de Inocencio et al, 2015). Mosaicism remains an underappreciated feature of monogenic disorders.…”

Section: Discussionmentioning

confidence: 59%

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Transcriptional and Biochemical Function

Gruber

Calis

Buta

et al. 2019

Preprint

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Autoinflammatory disease can result from monogenic errors of immunity. We describe herein the first example of a patient with early-onset widespread autoinflammation resulting from a mosaic, heterozygous, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of over twenty-five cytokines. By first-ofits-kind custom single-cell RNA sequencing, we examine mosaicism with single cell resolution. We uncover that JAK1 transcription is predominantly restricted to a single allele across different immune cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the S703I mutation not only increased JAK1 kinase activity, but also resulted in transactivation of partnering JAKs, independently of its catalytic domain. Further, S703I JAK1 was not solely hypermorphic for cytokine signaling, but neomorphic as well, as it enabled downstream signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, which led to rapid resolution of her clinical disease. Together, these findings represent an unprecedented degree of personalized medicine with the concurrent discovery of fundamental biological principles.Herein, we identify a novel mutation (S703I) of JAK1 in a patient with a severe, early-onset immunodysregulatory syndrome identified in our undiagnosed disease program. Using extensive nextgeneration genomic, molecular and multi-parametric immunological tools, we probe the effects of S703I JAK1 in vitro and ex vivo in order to investigate clinical dysfunction in vivo.

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Section: Discussionmentioning

confidence: 59%

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Transcriptional and Biochemical Function

Gruber

Calis

Buta

et al. 2019

Preprint

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“…Recently, 70% of these Sanger sequencing “mutation negative” NOMID patients were found to have somatic mosaicism in NLRP3 . In the majority of cases, the disease severity seems to be milder than in patients with germline mutations (99-102). …”

Section: Syndromes Presenting With Neutrophilic Urticaria (The Crymentioning

confidence: 99%

“…However, subcloning or deep sequencing are required to establish a genetic diagnosis. Thus making a genetic diagnosis is currently not clinically established and would unnecessarily hold up a therapeutic intervention (99-102). …”

Section: Syndromes Presenting With Neutrophilic Urticaria (The Crymentioning

confidence: 99%

Monogenic autoinflammatory diseases: Concept and clinical manifestations

Jesús¹,

Goldbach‐Mansky²

2013

Clinical Immunology

181

132

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The objectives of this review are to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary “periodic fever syndromes”, familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) 6. very rare conditions presenting with autoinflammation and immunodeficiency.

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“…Somatic mosaicism in NLRP3 causing disease was first described in 2005 in an individual with a p.Tyr507Cys variant occurring at a frequency of 16.7% detected using Sanger sequencing [108]. Somatic mosaicism in NLRP3 has since been reported by multiple groups with a mutation frequency as low as 2.7% noted [109–116].…”

Section: Genetic Sequencing Of Autoinflammatory Disordersmentioning

confidence: 99%

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Moghaddas

Masters

2018

Clinical Science

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Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be ‘autoinflammatory’, but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term ‘autoinflammatory’ is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype–phenotype correlations, with the aim of identifying areas of future research.

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Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome

Cited by 125 publications

References 24 publications

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Transcriptional and Biochemical Function

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Transcriptional and Biochemical Function

Monogenic autoinflammatory diseases: Concept and clinical manifestations

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

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