To explore this further, they isolated B cells from the cousins carrying the mutation, as well as healthy controls, then sorted B cells based on calcium flux, a functional outcome measure. They found that the B cells with negative calcium flux were only expressing the mutant allele, and the cousin with normal IgG levels expressed both alleles. This was the second example of monoallelic expression correlating with phenotypic output.
In Sum
Monoallelic expression occurs naturally in all humans and explains some instances of incomplete penetrance in inborn errors of immunity. Why this occurs remains an unanswered question; however, Dr. Bogunovic closed by framing MAE in the broader context of human evolution: genes deemed bad get kicked out, and those that are good are passed down over generations. MAE, he proposed, allows for a form of personal evolution, allowing genetic flexibility and tonality to the genome.
Dr. Bogunovic speculated that patients with rheumatic disease may have skewed biallelic expression during an active disease flare—a question that his laboratory continues to investigate. He also highlighted the invaluable contributions of his colleagues, including Conor Gruber, O’Jay Stewart and Haley Randolph, PhD, whose work was instrumental in advancing their research.
Michael Cammarata, MD, RhMSUS, is an assistant professor of medicine at the Johns Hopkins University School of Medicine in Baltimore.
