A rare childhood disorder that mimics inflammatory bowel disease termed “Deficiency in ELF4, X-linked,” or DEX for short, has been recently identified. Using genome sequencing, Yale researchers reported they have uncovered the underlying genetic cause of the disorder. Their work may help identify the roots of a host of other inflammatory and autoimmune disorders.

The findings were published in the journal Nature Immunology, in a paper titled, “Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation.”

“Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined,” wrote the researchers. “We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade.”

“It is very exciting to start with patients who are sick and discover an unexpected new gene with a fundamental role in regulating inflammation,” explained Carrie Lucas, PhD, an assistant professor of immunobiology at Yale School of Medicine and senior author. The study was headed by Paul Tyler, Molly Bucklin, and Mengting Zhao, all of whom are members of Lucas’s lab.

The researchers observed that the symptoms experienced by the children in the study were similar to those associated with other inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease.

After identifying the ELF4 variant, the researchers studied its effects in cultured cells from patients, as well as in mice using CRISPR gene-editing to introduce patient-derived ELF4 mutations. They confirmed that the variant disrupted ELF4 function, and resulted in elevated inflammatory responses of a variety of immune cell types.

The widespread effects of the variant suggest ELF4 and its target genes likely play a role in regulating inflammation in multiple diseases, Lucas said.

“This gives us the opportunity to identify and study the effects not only of ELF4 but also the genes it regulates across immune cell types and inflammatory disease phenotypes,” she said. “This will help us create a new molecular roadmap relevant to understanding and treating human disease.”

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