Rare, potentially lethal inflammatory disease recently discovered by NIH researchers

Otulipenia is a newly discovered, rare, inflammatory disease caused by malfunction of a gene—OTULIN—located on chromosome 5, that affects primarily young children, according to findings published online in the journal Proceedings of the National Academy of Sciences. Symptoms include fever, skin rashes, diarrhea, joint pain, and overall failure to grow or thrive.

“We describe a recessively inherited autoinflammatory disease caused by excessive linear ubiquitination in innate immune signaling pathways, which we denote as ‘otulipenia.’ We show that OTULIN deficiency leads to increased linear ubiquitination of target proteins, which is associated with enhanced NF-κB activity, increased TNFR1 signaling, and NLRP3 inflammasome activity. The phenotype is very severe and potentially lethal if left untreated,” wrote these authors, who included researchers from the National Human Genome Research Institute (NHGRI), the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, and the NIH Clinical Center, all part of NIH, along with their colleagues in Turkey and the United Kingdom.

They identified four children from Pakistani and Turkish families who presented with unexplained skin rashes and inflamed joints. Using whole-exome sequencing in the first two patients and their family members, candidate-gene sequencing in the third patient and parents, and mutation-specific genotyping in 1,630 DNA samples from the Turkish population, they conducted genetic and functional analyses.

For studies of protein function, they used short hairpin RNA (shRNA) knockdowns in 293 cells and NF-κB luciferase assay and Met1-linked linear polyubiquitin deubiquitination assay in 293 cells. In both patients and healthy controls, they performed immunoprecipitation and immunoblotting, flow cytometry, Nanostring intracellular cytokine staining, and cytokine profiling.

Researchers identified three homozygous mutations in the OUTLIN/FAM105B gene in unrelated families of Pakistani and Turkish descent. Parents and siblings who were unaffected were carriers for the mutations. No mutations were found in the 1,630 healthy Turkish controls or in public databases.

Children with these OTULIN gene abnormalities had difficulty processing ubiquitin, which is a regulator of many proteins in the body, including immune molecules. They demonstrated an inability to remove ubiquitin proteins from various molecules, which increased production of inflammatory cytokines that led to inflammation.

Children responded to treatment with anti-tumor necrosis factor (TNF) inhibitors, which are used in the treatment of chronic inflammatory diseases including rheumatoid arthritis. After TNF inhibitor treatment, their inflammation subsided.

“The malfunction in this protein has not been previously linked to clinical disorders of the human immune system,” said co-author Ivona Aksentijevich, MD, staff scientist, NHGRI's Medical Genetics Branch. “This discovery suggests a direction that can be explored for development of new therapies for patients with a wide range of inflammatory diseases.”

“The results have been amazing and life changing for these children and their families,” said Daniel Kastner, MD, PhD, co-author and NHGRI scientific director and head, NHGRI’s Inflammatory Disease Section. “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.”