Mutation in OTULIN gene causes rare childhood skin disease

An international team of researchers has identified a genetic cause for a rare inflammatory skin condition. 

The investigators report in the journal Nature Immunology that a mutation in the gene OTULIN causes pediatric-onset pyoderma gangrenosum characterized by recurrent ulcerating skin sores. They classify the condition as a new inborn error of immunity (IEI) - one of a group of more than 500 genetic disorders that impair the development or function of the immune system. 

The discovery of novel IEIs creates opportunities to dissect the molecular and cellular basis of human immune pathology and can reveal potential therapeutic targets."

Janet Markle, Assistant Professor of Pathology, Microbiology and Immunology, Vanderbilt Health 

Pyoderma gangrenosum is poorly understood and has no curative treatments. Familial clustering has been reported, but the genetic basis has not been deeply explored, Markle said. Her research group and a team in the Netherlands led by András Spaan, MD, PhD, Associate Professor of Medical Microbiology at University Medical Center Utrecht, were studying patients from different parts of the world with pediatric-onset pyoderma gangrenosum. 

"We were independently investigating whether this condition might represent an unrecognized IEI," Markle said. Using whole exome sequencing, the groups identified the same mutation in OTULIN, an enzyme with broad roles regulating inflammation, cell death, and immune responses. 

They learned of each other's work through a shared former mentor and decided to join forces. Graduate students from each team, Barathram Swaminathan at UMC Utrecht and Hwi Gil at Vanderbilt Health, co-led the experimental work using different, complementary approaches. 

"The international IEI research community is highly interconnected and collaborative," said Spaan, co-corresponding senior author of the Nature Immunology report. "This study is the product of a highly productive scientific collaboration with a direct clinical impact." 

To investigate the effect of the OTULIN mutation, the researchers performed functional studies in cell lines and patient-derived samples, examining protein interactions, ubiquitination dynamics (this process has roles in multiple immune signaling pathways and is regulated by the OTULIN enzyme), and cellular responses. 

Highlights of their findings: 

• At the molecular level, the mutation uncouples two important OTULIN functions: its enzymatic activity, which is preserved, and its interaction with a ubiquitination complex, which is impaired. 

• At the immunological level, patient samples showed high levels of the pro-inflammatory molecules interleukin-1beta and TNF (tumor necrosis factor), and increased inflammasome activation. 

• At the cellular level, patient skin cells showed accumulation of linear ubiquitin and heightened sensitivity to TNF-dependent cell death. 

The study pointed to TNF blockade as a potential therapeutic option for patients with OTULIN-related pyoderma gangrenosum. The investigators noted that one patient, whose painful skin sores were resistant to years of treatment with nonspecific anti-inflammatory therapy, was successfully treated with TNF blockade. 

"This study adds to a growing body of work showcasing the critical role of highly regulated linear ubiquitin signaling in human health and highlights the value of studying rare genetic diseases to uncover fundamental immunological mechanisms," Markle said. 

Swaminathan and Gil, the graduate students who led experimental work, and Sagar Bhattad, MD, from the Department of Pediatrics at Aster CMI Hospital in Bengalaru, India, are equal contributors and co-first authors of the Nature Immunology report. The research was supported in part by the Dutch Research Council and U.S. National Institutes of Health (grants R35GM155339 and F31AR082264).