Not all broken genes stop functioning in the same way. Some simply stop working, while others interfere with those that are still working.
Researchers at Hiroshima University have identified a key boundary within an immunoregulatory gene called RELA that can help predict how deleterious mutations cause disease. Their findings could improve diagnosis and treatment of patients with rare genetic inflammatory diseases.
This research Journal of Allergy and Clinical Immunology March 13, 2026.
RELA produces proteins that play important roles in immune responses, cell survival, and inflammation. Mutations in one copy of the RELA gene can cause a condition known as autosomal dominant RELA deficiency. Patients may experience recurrent oral and genital ulcers, intestinal inflammation, and in some cases, a wide range of autoinflammatory symptoms. So far, only 45 people in 17 families have been confirmed to have this deficiency worldwide.
In autosomal dominant RELA deficiency, clinical symptoms vary depending on the nature of the mutation. ”
Satoshi Okada Lead author, Professor, Graduate School of Biomedical and Health Sciences, Hiroshima University
Some mutations cause haploinsufficiency, where the body does not produce enough functional protein. Some cause dominant-negative effects, where abnormal proteins interfere with normal proteins.
Seeking a way to accurately predict which types of mutations cause which effects, the research team studied eight patients from five families with autosomal dominant RELA deficiency. Their results identified the amino acid proline at position 290 (P290) as a critical dividing line in the RELA protein.
“RELA mutants with a stop codon located at the N-terminus of amino acid P290 exhibit haploinsufficiency, whereas RELA mutants with a stop codon located at the C-terminus of P290 exhibit a dominant-negative effect,” Okada said.
A stop codon, like a period at the end of a sentence, is a nucleotide sequence in an mRNA that signals the cell to stop protein synthesis. If the stop codon occurs early, before P290 (or near the N-terminus of the protein), the defective gene copy is often unable to produce usable protein, leaving only one functional copy and resulting in a shortage of RELA protein. If the stop codon occurs after P290 (or near the C-terminus), cells can produce truncated proteins that interfere with normal proteins and cause more severe inflammation.
Understanding this difference may have direct clinical value. Patients with dominant-negative mutations were less responsive to corticosteroids and more often required biologic therapy, particularly anti-tumor necrosis factor (anti-TNF) drugs.
“Our findings provide indicators that may help clinicians more quickly interpret newly discovered RELA mutations and select more appropriate treatments earlier in the disease course,” Professor Okada said.
However, not all variants are easy to classify. Missense mutations that change a single amino acid rather than producing a premature stop signal still require clinical testing, as their effect cannot be predicted from position alone.
“Reliably determining the functional impact of RELA missense variants remains an open challenge and is an important priority for future research,” said Dr. Okada.
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Reference magazines:
Hiroshi Hayakawa others (2026). Discovery of patterns in the pathological significance of non-missense deleterious mutations in RELA. Journal of Allergy and Clinical Immunology. DOI: 10.1016/j.jaci.2026.01.020. https://www.jacionline.org/article/S0091-6749(26)00074-6/fulltext.
