Rare Inflammatory Disease Identified in Children

A rare, deadly inflammatory disease among young children, known as otulipenia has been discovered, and it is caused by the malfunction of OTULIN, a gene on chromosome 5 that regulates the development of new blood vessels and the mobilization of infection-fighting cells and proteins.

Four children from Pakistani and Turkish families have been identified with the disease, which is characterized by a problem processing the small protein ubiquitin and is accompanied by inflammation that leads to skin rashes and inflamed joints. The abnormal OTULIN gene is part of the innate immune system, which is present at birth with cells and proteins to fight infections.


An international team of scientists in collaboration with those at the US National Human Genome Research Institute (Bethesda, MD, USA) identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency.

The scientists performed whole-exome sequencing in two patients and their family members, candidate-gene sequencing in the third patient and her parents, and mutation-specific genotyping in 1,630 DNA samples from the Turkish population. To study protein function, they used short hairpin ribonucleic acid (shRNA) knockdowns in Human Embryonic Kidney 293 (HEK293) cells and NF-κB luciferase assay, and Met1-linked linear polyubiquitin deubiquitination assay in the same cells. Immunoprecipitation and immunoblotting, flow cytometry, Nanostring, intracellular cytokine staining, and cytokine profiling were performed on samples from the patients and healthy controls. Gene expression analysis was conducted using the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA).

The investigators found that HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with wild-type (WT) OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. They effectively used anti-tumor necrosis factor drugs (TNF inhibitors), which are used to treat other chronic inflammatory diseases such as rheumatoid arthritis, to treat the children with otulipenia.

Daniel L Kastner, MD, PhD, a senior author of the study, said, “The results have been amazing and life changing for these children and their families. We have achieved the important goal of helping these young patients and made progress in understanding the biological pathways and proteins that are important for the regulation of the immune system’s responses.” The study was published on August 22, 2016, in the journal Proceedings of the National Academy of Sciences.

Related Links:
US National Human Genome Research Institute
NanoString Technologies