Project Details


Project Summary Albeit rare, monogenic causes of complex disorders provide unique opportunities for a deeper understanding of common diseases. In this application, we seek to study the molecular pathogenesis of novel, rare, monogenic autoinflammatory disorders. Central clinical presentations of these syndromic patients include severe skin inflammation, non-specific gastrointestinal inflammation, and aberrant neurologic features. Using whole exome sequencing (WES) we have identified fourteen novel, exceedingly rare, inborn genetic variations in genes with primary functions in innate immunity, specifically cytokine production, transduction or regulation. These inborn errors of immunity are putative molecular drivers of autoinflammation, the mechanisms of which we propose to explore in detail. Type I Interferons (IFNs) are cytokines that signal through the JAK-STAT pathway. Beneficial effects of IFNs largely concern antiviral defense, but profound detrimental effects to human health can manifest if this pathway is overactive. Mendelian type I Interferonopathy disorders best exemplify how constitutive upregulation of IFN-I activity can lead to aberrant immune and neurologic features. We have recently identified and reported children presenting type I Interferonopathy features due to complete loss-of-function mutations in either ISG15 or USP18, which are essential for shutting off the IFN-I response at the IFN-I receptor. These deficiencies are the first genetic defects affecting the negative regulation of the IFN-I response. In this proposal we seek to characterize patients with novel, complete or hypomorphic, mutations in these two genes, but also patients who present with alike syndromes with mutations in genes that either induce IFN-I or convey the signal downstream of IFN-I and other JAK-STAT engaging cytokines. We propose to study these rare patients in vitro, ex vivo, and in vivo to determine the molecular, immunological, and clinical significance of these genes in JAK-STAT pathway regulation, and, by extension, their function in severe autoinflammatory immune regulation. A deeper understanding of the molecular pathophysiology governing these disorders will lay the groundwork for the development of medicines to better manage persistent inflammatory disorders, rare or common.
Effective start/end date1/07/2030/06/23


  • National Institute of Allergy and Infectious Diseases: $493,107.00
  • National Institute of Allergy and Infectious Diseases: $502,255.00
  • National Institute of Allergy and Infectious Diseases: $501,657.00


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