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Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation.

ABSTRACT: Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1 ^{H595D/+;I596I/+;Y597Y/+} mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1 ^{H595D/+;I596I/+;Y597Y/+} mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1 ^{H595D/+;I596I/+;Y597Y/+} mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.

SUBMITTER: Takeichi T

PROVIDER: S-EPMC8761858 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation.

Takeichi Takuya T Lee John Y W JYW Okuno Yusuke Y Miyasaka Yuki Y Murase Yuya Y Yoshikawa Takenori T Tanahashi Kana K Nishida Emi E Okamoto Tatsuya T Ito Komei K Muro Yoshinao Y Sugiura Kazumitsu K Ohno Tamio T McGrath John A JA Akiyama Masashi M

Frontiers in immunology 20220103

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock- ...[more]

PMID: 35046931

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Project description:BackgroundMonogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.MethodsBetween October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.ResultsEighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.ConclusionUpon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.Trial registrationClinicalTrials.gov NCT01724580 and NCT02974595.FundingThis research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Dataset Information

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation.

Publications

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation.

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