JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome

Bel, Kate L. Del; Ragotte, Robert J.; Saferali, Aabida; Lee, Susan; Vercauteren, Suzanne; Mostafavi, Sara; Schreiber, Richard A.; Prendiville, Julie S.; Phang, Min S.; Halparin, Jessica; Au, Nicholas; Dean, John Mark; Priatel, John J.; Jewels, Emily; Junker, Anne; Rogers, Paul C.; Seear, Michael; McKinnon, Margaret L.; Turvey, Stuart E.

doi:10.1016/j.jaci.2016.12.957

Cited by 109 publications

(62 citation statements)

References 16 publications

(4 reference statements)

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“…More broadly, this case implicates JAK1 dysfunction in common forms of multifactorial diseases, including dermatitis, enteritis, colitis and eosinophilic disorders. These features align with the other reported JAK1 GoF mutation recently published (Del Bel et al, 2017), and together, provide strong justification for the expanding use of JAK inhibitors in these disorders (O'Shea et al, 2015;O'Shea and Gadina, 2019). Yet, to date, MN has not been recognized to involve JAK-STAT dysregulation.…”

Section: Discussionsupporting

confidence: 80%

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: Discussionsupporting

confidence: 80%

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

Gruber

Calis

Buta

et al. 2019

Preprint

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“…The S703I mutation localizes to the pseudokinase domain of JAK1, a putative regulatory domain ( Figure 2 A). Although S703I is located between the germline JAK1 mutations identified to date, these other mutations diverged in their downstream consequences (LoF and GoF), making functional predictions for S703I difficult ( Del Bel et al., 2017 , Eletto et al., 2016 ). To assess the possible pathogenicity of the mutation and its impact on JAK1 function, we transduced WT JAK1 , S703I JAK1 , and empty vector lentiviruses into U4C cells, a fibrosarcoma cell line previously selected to lack endogenous JAK1 ( Pellegrini et al., 1989 ).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1 , encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational “transcriptotype” that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

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“…Further evidence for a role of altered JAK–STAT signaling in allergic disease can be found in a family with a gain-of-function mutation in JAK1 ( JAK1 GOF ) which can facilitate STAT5B phosphorylation ( Del Bel et al, 2017 ). Affected family members had severe atopic dermatitis, marked peripheral and tissue eosinophilia on a scale similar to that seen in the somatic STAT5B GOF patients, and allergic asthma.…”

Section: Altered Cytokine Signalingmentioning

confidence: 99%

Primary atopic disorders

Lyons

Milner

2018

Journal of Experimental Medicine

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JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome

Cited by 109 publications

References 16 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

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

Primary atopic disorders

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