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

Authors :
Takuya Takeichi
John Y. W. Lee
Yusuke Okuno
Yuki Miyasaka
Yuya Murase
Takenori Yoshikawa
Kana Tanahashi
Emi Nishida
Tatsuya Okamoto
Komei Ito
Yoshinao Muro
Kazumitsu Sugiura
Tamio Ohno
John A. McGrath
Masashi Akiyama
Source :
Frontiers in Immunology, Vol 12 (2022), Frontiers in Immunology
Publication Year :
2022
Publisher :
Frontiers Media SA, 2022.

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 (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;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 Jak1H595D/+;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.

Details

ISSN :
16643224
Volume :
12
Database :
OpenAIRE
Journal :
Frontiers in Immunology
Accession number :
edsair.doi.dedup.....203d25dfc51ef88fd183c606241d1b2a