Whole Exome Sequencing Revealed a Novel Sequence Variant in The OTULIN Underlying Auto-Inflammatory Syndrome

Abstract

Purpose Systemic auto-inflammatory diseases are a diverse group of heterogeneous disorders resulting in development of the systemic inflammation in absence of the inflammatory induction. Sequence variants in the OTULIN gene, which disrupts its ubiquitination activity lead to auto-inflammation, panniculitis, and dermatosis syndrome. To date, only few disease-causing variants in the OTULIN have been reported.In the study, presented here, sequence analysis of the OTULIN gene in a patient, exhibiting features of OTULIN-related auto-inflammatory syndrome (ORAS), revealed a novel disease-causing missense variant p.(Thr312Met). Further, effect of the variant on structure and function of the OTULIN protein has been examined using in silico OTULINWT and OTULINT312M. Methods Cells, collected from the patient blood, were examined by flow cytometry. Search for the disease-causing variants was carried out using exome followed by Sanger sequencing. Effect of the sequence variant on structure of the mutated protein was studied using in-silico analyses. Results Flow cytometry analysis revealed slightly reduced number of lymphocytes, marked leukocytosis, and mildly increased levels of IgG. Whole exome sequencing coupled with Sanger sequencing revealed a homozygous missense variant [c.935C>T; p.(Thr312Met)] in the OTULIN gene. In-silico analyses revealed that the missense variant reduces OTULIN’s expression and promotes accumulation of LUBAC-linked UB chains leading to auto-inflammation.Conclusion Taken together, OTULIN may act as a novel therapeutic target for the development of immunomodulatory drugs that may potentially increase or stabilize their expression. Targeting more components of the Ub-proteasome pathway may provide new opportunities for therapeutic exploitation and drug discovery.

OTULIN deficiency: focus on innate immune system impairment

“…According to the 2022 Update of the IUIS Phenotypical Classification, OTULIN deficiency is classified among auto-immunodeficiency disorders of sterile inflammation, predominant at skin and joint ( 41 ). To date, 10 patients with ORAS from seven families have been identified ( 29 – 31 , 40 , 42 , 43 ). The clinical landscapes of humans with biallelic hypomorphic mutations of OTULIN deficiency are complex and multifaceted ( Figure 2 ) and dominated by premature birth at gestation from 28 + 6 weeks to 36 weeks, recurrent episodes of neonatal-onset fever, and rashes.…”