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Project

Gene discovery and development of targeted treatment in severe early-onset autoinflammatory diseases.

The field of IEI is evolving at a rapid pace with the introduction of next generation sequencing (NGS) in 2010, close collaboration between clinicians and researchers, availability of new tools and model organisms and identification of novel clinical phenotypes. The historical view on IEI limited to a predisposition to infection has been abandoned for a comprehensive view on disease with classification based on the primary immune subset disturbed and increased recognition of autoimmunity and immune dysregulation.

In the first chapter we reported on a novel mutation in IKZF1, encoding a hematopoietic transcription factor, in a patient with a phenotype predominated by systemic lupus erythematosus. There were 4 prior reports on loss-of-function IKZF1 mutations in patients with CVID and autoimmunity and the clinical spectrum attributed to mutant IKAROS has expanded since to include ALL and early onset CID. Our group demonstrated mutant IKAROS B cells are reprogrammed to a hyperresponsive state with depressed CD22 expression and reduced IKAROS DNA binding to the CD22 locus, contributing to a lower threshold for activation. Collectively these patient studies have revealed novel biological functions of IKZF1, including B cell development and signaling, T cell development and activation, and dendritic cell development and function. However, a thorough understanding of the mechanism leading to autoimmunity is still lacking with both arguments for defects in central tolerance studied in mice and peripheral tolerance as demonstrated by our group.

In the second chapter, we expand the spectrum of SEC61A1-related Mendelian disease to include severe congenital neutropenia (SCN) through identification of a novel de novo mutation in SEC61A1. The Sec61 complex is responsible for transport of newly synthesized proteins into the ER and passive leakage of calcium. There were only 2 prior reports on SEC61A1 mutations, including AD tubulo-interstitial kidney disease and primary antibody deficiency. Our study provided definitive proof of causality through mutation-specific induction of the UPR leading to cellular arrest of myeloid precursors. However, protein instability, dysregulated calcium homeostasis and defective protein translocation with induction of ER stress have been implicated in the pathogenesis of all five SEC61A1 mutations, regardless of the phenotype, indicating there are genotype-specific effects that remain to be elucidated.

The third and final chapter reveals novel clinical phenotypes attributable to mutations in OTULIN. Two consecutive papers reported on hypomorphic homozygous OTULIN mutations in patients with a potentially life-threatening, very early-onset autoinflammatory condition coined OTULIN-related autoinflammatory syndrome (ORAS). Here, we presented a patient harboring a private heterozygous variant with incomplete penetrance and a clearly distinct clinical phenotype, with episodic inflammation and recurrent sterile neutrophilic abscesses in his lungs in the absence of any skin manifestations. While his asymptomatic mother harbors the same pathogenic mutation, monocytes from mother and patient are equally hyperresponsive in vitro. This is another example of how unidentified environmental triggers or genetic modifiers may influence the penetrance of a particular allele.

Date:1 Oct 2015 →  1 Oct 2020
Keywords:severe, early-onset, autoinflammatory diseases, targeted treatment, Gene discovery
Disciplines:Genetics, Systems biology, Molecular and cell biology
Project type:PhD project