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 (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.

Dysregulated ceramide metabolism in mouse progressive dermatitis resulting from constitutive activation of Jak1

“…JAK inhibitors have already been approved as human AD drugs, and many JAK inhibitors have advanced to clinical studies ( 44 ). Two reports have indicated that increased Jak1 activity led to an inflammatory skin phenotype in mice ( 45 , 46 ). Therefore, it is suggested that Jak1 is important for maintaining skin homeostasis.…”

The role of JAK/STAT signaling pathway in cerebral ischemia-reperfusion injury and the therapeutic effect of traditional Chinese medicine: A narrative review

“…[17] In the brain of mice with 22q11.2 deletion syndrome, activation of JAK1 leads to auto-inflammation and may cause neurological dysfunction. [18] 2.1.2. The function of JAK2.…”

Autoinflammatory Keratinization Diseases—The Concept, Pathophysiology, and Clinical Implications

“…JAK1 -activating mutations were detected in hematologic malignancies, such as acute lymphoblastic leukemia [ 91 ]. Based on a recent report, heterozygous JAK1 mutations were also implicated in triggering superficial cutaneous inflammation and aberrant keratosis [ 92 ].…”

“…Recently, a case report of a child with early-onset ichthyotic eczema coexisting with eosinophilia, liver abnormalities, growth retardation, and autism was published [ 92 ]. Quickly progressing hepatic cirrhosis produced the necessity to perform liver transplantation at the age of 3 years.…”