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'Genotype-First' Study Leads to Blood Cell Mutations Underlying Severe Autoinflammatory Disease

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NEW YORK – A genotype-driven study has implicated somatic mutations in a gene involved in protein ubiquitylation in a severe adult-onset male autoinflammatory disorder. Since the mutations are only found in a subset of patients' blood cells, the disorder, which currently has no cure, might be treatable with a bone marrow transplant.

The results also highlight that somatic mutations not only play a role in cancer but can also cause other disorders, in particular inflammatory diseases.

The study, conducted by a team at the National Human Genome Research Institute, was published in the New England Journal of Medicine on Tuesday and presented on the same day by lead author and NHGRI clinical fellow David Beck during a plenary session at the American Society of Human Genetics 2020 Virtual Meeting.

"Our genotype-first strategy has helped define a new molecular taxonomy of rheumatic diseases, which we think will be important for the management and treatment of these patients going forward," he said.

Beck explained that his lab is interested in the causes of inflammatory diseases, which traditionally involves studying patients with a similar phenotype and looking for a common mutation in their exomes or genomes that could explain it. However, more recently his team has taken a different approach, starting with genetic data for a large group of patients and looking for a mutation that several of them share that correlates with clinical traits. This genotype-first approach has the advantage that no family members are needed and that it can be used to study diseases with heterogeneous presentations.

For this particular study, Beck and his team decided to focus on mutations in genes involved in protein ubiquitylation, which have been implicated in a number of other inflammatory diseases in the past. Specifically, they searched for novel variants that occurred in genes that are intolerant to haploinsufficiency and were shared across cases.

Their patient data consisted of exomes and genomes from almost 1,500 individuals with undiagnosed autoinflammatory disorders and from about 1,100 patients with atypical disorders from the NIH's Undiagnosed Diseases Program. In three male patients, they discovered novel variants in the UBA1 gene, which resides on the X chromosome and encodes the E1 enzyme that initiates protein ubiquitylation. Remarkably, the same codon, methionine-41, was affected in all three cases.

"What was initially confusing about this identification was that UBA1 is an X-chromosomal gene and these patients seemed to have heterozygous variants at these locations," Beck explained, "and men should only have one variant in an X-chromosomal gene."

It turned out that the variants were somatic and only occurred in a subset of patients' peripheral blood cells, and not in their skin. Looking at bone marrow biopsies from the three patients, the researchers found that the earliest hematopoietic stem cells had a mixture of wildtype and mutant UBA1 alleles, whereas differentiated myeloid cells — neutrophils and monocytes — mostly had the mutant allele. Lymphocytes, on the other hand, were mostly wild type and were decreased in number.

In addition, the three patients had unusual vacuoles in their erythroid and myeloid precursor cells, which Beck said are not found in other types of inflammatory diseases and seem to be a hallmark of disease with these types of UBA1 mutations.

He noted that UBA1 has previously been implicated in another disease— X-linked spinal muscular atrophy — but in those cases, mutations in the gene are clustered around the catalytic domain of the enzyme instead of in methionine-41.

The researchers decided to name the new UBA1-associated disease VEXAS for "Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic" syndrome.

Based on clinical similarities, they identified an additional 25 patients, all male, with somatic mutations that affect the methionine-41 codon of UBA1. In all of them, the disease started after age 45 and came with symptoms such as fevers, inflammation of the skin, lung, and cartilage, and hematologic problems such as thromboembolism, anemia, and bone marrow vacuoles. Forty percent of the patients have already died and most of them only respond to high doses of steroids or glucocorticoids, Beck said.

Interestingly, prior to their discovery, these patients had met the diagnostic criteria for a variety of other disorders, such as relapsing polychondritis, Sweet syndrome, myelodysplastic syndrome, or multiple myeloma. "Before our work, there was very little evidence that these diseases were connected," Beck said. "Using this genotype-first approach, we were able to link these seemingly disparate diagnoses, which we think will have important ramifications for treatment and management of patients and understanding the underlying mechanism of disease."

To characterize VEXAS further, the team took a closer look at the mutant neutrophils of patients and found that many of them were undergoing cell death. Also, patient myeloid cells were found to have highly activated inflammatory pathways, whereas lymphocytes without the mutation did not.

The UBA1 enzyme is usually expressed as two isoforms, one residing in the cytoplasm, the other in the nucleus. Mutant patient cells had lost the cytoplasmic isoform, the researchers found, and instead expressed a catalytically inactive, new isoform.

They confirmed these results in a zebrafish model, where fish lacking all UBA1 isoforms and those lacking just the cytoplasmic isoform both had a drastic reduction in neutrophils and activated inflammatory profiles.

While disease-causing somatic mutations are usually associated with cancer, the study showed that they can also play a role in other types of diseases. "Somatic mutations may account for a significant fraction of adult-onset inflammatory diseases," Beck said. "Similar to neoplasia, where mutations cause sustained growth, in severe inflammatory diseases, somatic mutations may be driving sustained inflammation, like in VEXAS."

Also, somatic variants in genes that reside on the X chromosome, like UBA1, "are an under-recognized cause of diseases," he added.

Finally, the study offered some suggestions for a possible treatment. The fact that the UBA1 patient mutations were only found in myeloid cells and not in fibroblasts could mean that VEXAS might be treatable with a bone marrow transplant, and Beck said he and his NIH colleagues are currently developing a protocol for a clinical trial to test this. "It does make sense, from a mechanistic standpoint, to get rid of the mutated cells and improve the clinical manifestations, and it's something that we're pursuing," he said. Such an option would be especially helpful, he added, because there are currently not effective treatments to manage the inflammation of VEXAS patients.

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