A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)

Abstract

Activation-induced cytidine deaminase (AID), encoded by AICDA, facilitates class-switch recombination (CSR) and somatic hypermutation (SHM) in activated B cells. Loss of AID function causes hyper-IgM syndrome type 2 (HIGM2). While typically autosomal recessive, three C-terminal truncation variants have been reported to act in autosomal dominant manner. We describe a novel heterozygous AICDA nonsense variant, c.589G>T (p.G197*), that truncates the final two C-terminal residues of AID and results in adult-onset HIGM2. Single-cell sequencing of primary patient B cells revealed a complete block in CSR and a [~]10-fold reduction in SHM. AICDA mRNA expression was balanced between wild-type and variant alleles, yet AID protein abundance was reduced to [~]56% with normal subcellular localization. Remarkably, inducible germinal center (iGB) cultures restored CSR in purified naive patient B cells. CRISPR-Cas9 editing of healthy donor B cells confirmed that the iGB platform can rescue B cells harboring heterozygous, but not homozygous, AICDA variants. These results demonstrate that even a two-amino-acid truncation at the AID C-terminus is sufficient to disrupt its function and cause HIGM2.

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BibTeX

@misc{green2026minimal,
  title = {{A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)}},
  author = {K. Green and A. B. Rovsing and E. Terczynska-Dyla and L. Jensen and K. Machalica and J. H. Wolff and L. Westerberg and C. S. Larsen and L. Lin and J. G. Mikkelsen and J. M. B. Jensen and S. E. Degn},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.27.762264},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762264v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)
AU  - K. Green
AU  - A. B. Rovsing
AU  - E. Terczynska-Dyla
AU  - L. Jensen
AU  - K. Machalica
AU  - J. H. Wolff
AU  - L. Westerberg
AU  - C. S. Larsen
AU  - L. Lin
AU  - J. G. Mikkelsen
AU  - J. M. B. Jensen
AU  - S. E. Degn
PY  - 2026
DA  - 2026/10/27
PB  - bioRxiv
DO  - 10.64898/2026.10.27.762264
UR  - https://www.biorxiv.org/content/10.64898/2026.10.27.762264v1
AB  - Activation-induced cytidine deaminase (AID), encoded by AICDA, facilitates class-switch recombination (CSR) and somatic hypermutation (SHM) in activated B cells. Loss of AID function causes hyper-IgM syndrome type 2 (HIGM2). While typically autosomal recessive, three C-terminal truncation variants have been reported to act in autosomal dominant manner. We describe a novel heterozygous AICDA nonsense variant, c.589G>T (p.G197*), that truncates the final two C-terminal residues of AID and results in adult-onset HIGM2. Single-cell sequencing of primary patient B cells revealed a complete block in CSR and a [~]10-fold reduction in SHM. AICDA mRNA expression was balanced between wild-type and variant alleles, yet AID protein abundance was reduced to [~]56% with normal subcellular localization. Remarkably, inducible germinal center (iGB) cultures restored CSR in purified naive patient B cells. CRISPR-Cas9 editing of healthy donor B cells confirmed that the iGB platform can rescue B cells harboring heterozygous, but not homozygous, AICDA variants. These results demonstrate that even a two-amino-acid truncation at the AID C-terminus is sufficient to disrupt its function and cause HIGM2.
ER  -

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