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NIH researchers discover new inflammatory disease among children
NIH researchers have discovered a new, potentially lethal inflammatory disease that primarily affects young children, according to a press release.
Called otulipenia, the rare condition is caused by the malfunction of OTULIN, a single gene on chromosome 5. When functioning properly, the gene regulates the development of new blood vessels and the mobilization of cells and proteins to fight infections, according to the press release. Symptoms of otulipenia include fever, skin rashes, diarrhea, joint pain and overall failure to grow and thrive. The researchers have also identified anti-inflammatory treatments that ease some of those symptoms.
“The results have been amazing and life changing for these children and their families,” Daniel Kastner, MD, PhD, scientific director of the National Human Genome Research Institute (NHGRI) and study co-author, said in the press release. “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.”
According to NIH, an international network of researchers — from the 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, along with colleagues in Turkey and the United Kingdom — identified four children from Pakistani and Turkish families with unexplained skin rashes and inflamed joints. They then searched for disease-causing genes using DNA sequencing, discovering that the OTULIN gene was abnormal in the sick children.
To understand the mechanisms of the disease, the researchers studied the immune pathway, and found a problem in the processing of the ubiquitin protein, which is critical to the regulation of many other proteins in the body, including immune molecules. The inability to remove the ubiquitin proteins from various molecules resulted in increased production of chemical messengers that lead to inflammatory cytokines.
The researchers then determined that the affected children may respond to drugs that turned off tumor necrosis factor, a chemical messenger involved in systemic inflammation. The inflammation subsided in the 2 children who had been treated with TNF inhibitors.
According to NIH officials, the researchers’ findings, published in the Proceedings of the National Academy of Sciences, along with the 2016 identification of haploinsufficiency of A20, “suggests a new category of human inflammatory diseases caused by impaired ubiquitination.
“The malfunction in this protein has not been previously linked to clinical disorders of the human immune system,” Ivona Aksentijevich, MD, staff scientist at the NHGRI and study co-author, said in the press release. “This discovery suggests a direction that can be explored for development of new therapies for patients with a wide range of inflammatory diseases.”
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