New inflammatory disease discovered

Instead of looking at similarities in symptoms, the team examined genomes to discover a new disease. AnnaStills / iStock / Getty Images Plus

Nearly 125 million people in the U.S. live with some form of chronic inflammatory disease. Chronic inflammation can have many underlying causes: infections that don’t go away, abnormal immune reactions to normal tissues, certain diseases or conditions, or changes in certain genes. Chronic inflammatory diseases often have similar symptoms, which makes it difficult for doctors to diagnose the specific disease.

Genes related to ubiquitylation have been shown to play a role in some inflammatory diseases. This process alters proteins to regulate their function or tag them for degradation.

To investigate whether genes related to ubiquitylation play a role in patients with undiagnosed inflammatory disease, a research team led by NIH researchers Drs. Peter Grayson at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Daniel Kastner at the National Human Genome Research Institute (NHGRI), and Achim Werner at the National Institute of Dental and Craniofacial Research (NIDCR) studied the genomes of more than 2,500 patients. Over 1,400 of these individuals had undiagnosed recurrent fevers and body-wide inflammation. The rest, part of the NIH Undiagnosed Diseases Program, had unusual and unclassified disorders.

The study was funded by several NIH Institutes. Results were published on October 27, 2020 in the New England Journal of Medicine.

The team focused on a set of about 840 genes related to ubiquitylation. Out of those, one stood out: the UBA1 gene. Three middle-aged males had rare and potentially damaging genomic mutations in the gene. UBA1 holds the instructions to make the E1 enzyme, which is needed to initiate ubiquitin signaling in cells.

Men normally carry only one copy of this gene since it resides in the X chromosome. (Males have only one X chromosome and one Y chromosome). However, DNA-sequencing revealed that each of the men appeared to carry two different versions of the gene. Further investigation showed that that some cells in their bodies carried the UBA1 gene in its normal form while others carried the gene in a mutated form. This phenomenon is known as mosaicism, where a cell picks up a genetic mutation at some time during early development.

The mutated gene was found in the patients’ myeloid cells, which are responsible for systemic inflammation and act as the first line of defense against infections.

The researchers then discovered an additional 22 adult males, most of them participants in other NIH studies, with the UBA1 gene mutations. Symptoms of the 25 patients included blood clots in veins, recurrent fevers, lung abnormalities, and unusual vacuoles (cavity-like structures) in myeloid cells. The team called the new disease VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome).

“By using this genomic approach, we have managed to find a thread that ties together patients carrying all of these seemingly unrelated, disparate diagnoses,” Kastner says.

The severe condition has devastating consequences. So far, 40% of VEXAS patients who the team studied have died. The researchers hope that this new genomic strategy will help health care professionals improve disease assessments and treatments for various inflammation-related conditions.