Characterization of an immunodeficiency-associated EZH2 variant

Abstract

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 ~1 in 10–20 000 in the human population, EZH2-L50S may more broadly contribute to adult immunodeficiency.

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BibTeX RIS

BibTeX

@article{santos2026characterization,
  title = {{Characterization of an immunodeficiency-associated EZH2 variant}},
  author = {Francisco Perez de los Santos and Lily Beck and Emily DeCurtis and April M Griffin and Maggie M Balas and Charlotte Marchioni and Attila Kumanovics and Matthew R G Taylor and Kimberly R Jordan and Charles H Kirkpatrick and Aaron M Johnson},
  journal = {NAR Molecular Medicine},
  year = {2026},
  month = oct,
  doi = {10.1093/narmme/ugag045},
  url = {https://doi.org/10.1093/narmme/ugag045},
  note = {CC BY-NC 4.0},
}

RIS

TY  - JOUR
TI  - Characterization of an immunodeficiency-associated EZH2 variant
AU  - Francisco Perez de los Santos
AU  - Lily Beck
AU  - Emily DeCurtis
AU  - April M Griffin
AU  - Maggie M Balas
AU  - Charlotte Marchioni
AU  - Attila Kumanovics
AU  - Matthew R G Taylor
AU  - Kimberly R Jordan
AU  - Charles H Kirkpatrick
AU  - Aaron M Johnson
PY  - 2026
DA  - 2026/10/15
JO  - NAR Molecular Medicine
DO  - 10.1093/narmme/ugag045
UR  - https://doi.org/10.1093/narmme/ugag045
AB  - 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 ~1 in 10–20 000 in the human population, EZH2-L50S may more broadly contribute to adult immunodeficiency.
SN  - 2976-856X
ER  -

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