Characterization of an immunodeficiency-associated EZH2 variant

Epigenetic gene regulation is central to the development and function of immune cells. For example, B cell differentiation and function require high levels of EZH2, the catalytic subunit of epigenetic regulator Polycomb Repressive Complex 2 (PRC2). Our clinical evaluation identified two sisters with adult-onset recurrent infections and memory B cell deficiency who share a heterozygous variant (Leu50Ser, L50S) in a conserved region of EZH2. Most EZH2-catalyzed histone H3 lysine 27 methylation (H3K27me) was maintained with EZH2-L50S, in patient samples and cell lines expressing EZH2-L50S. However, gene promoters that normally have the highest H3K27me3 levels are deficient with L50S, despite high EZH2-L50S recruitment. EZH2-L50S stably forms PRC2, but the variant affects methylation of nucleosomes and disrupts allosteric stimulation that normally amplifies H3K27me3, consistent with the location of L50 in the PRC2 allosteric regulatory region. Our molecular characterization supports a role for EZH2-L50S in contributing to the observed adult B cell immunodeficiency through epigenetic mis-regulation. Given our findings, at a frequency of approximately 1 in 10-20,000 in the human population, EZH2-L50S may more broadly contribute to adult immunodeficiency.