Researchers from National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Human Genome Research Institute (NHGRI), and National Institute of Dental and Craniofacial Research (NIDCR) have found a new inflammatory disease.
Approximately 125 million people in the United States live with some form of chronic inflammatory disease. It can have many underlying causes: abnormal immune reactions to normal tissues, infections that don’t go away, 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.
In a bid 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, Daniel Kastner at the National Human Genome Research Institute, and Achim Werner at the National Institute of Dental and Craniofacial Research studied the genomes of more than 2,500 patients.
More than 1,400 of these individuals had undiagnosed recurrent fevers and body-wide inflammation. The remaining, part of the NIH Undiagnosed Diseases Program, had unusual and unclassified disorders.
The research was funded by several NIH Institutes. They were published in the New England Journal of Medicine.
The group 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.
X & Y Chromosome
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).
According to Kastner, “By using this genomic approach, we have managed to find a thread that ties together patients carrying all of these seemingly unrelated, disparate diagnoses.”
The severe condition has devastating effects. Till now, 40 per cent 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.
(With inputs from The OnLook News Research Bureau)