Agammaglobulinemia due to p.E555K TCF3 Dominant-Negative Variant

Takanori Utsumi, Miyuki Tsumura, Masato Yashiro, Makiko Yamazaki, Zenichiro Kato, Kosuke Noma, Fumiaki Sakura, Reiko Kagawa, Yoko Mizoguchi, Shuhei Karakawa, Hidenori Ohnishi, Charlotte Cunningham-Rundles, Peter Arkwright, Ariharan Anantharachagan, Masao Kobayashi, Hirokazu Kanegane, Dusan Bogunovic, Bertrand Boisson, Jean-Laurent Casanova, Takaki AsanoSatoshi Okada

Research output: Contribution to journalArticlepeer-review


Transcription factor 3 (TCF3) dominant negative (DN) variant causes autosomal dominant (AD) E47 transcription factor deficiency. AD E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the p.E555K variant has been reported as the causative variant in this disease. In this study, we describe the first Asian patient with wide phenotypes due to the p.E555K variant and highlight the unique features that contribute to the exclusivity of this variant. The patient was a 25-year-old male presenting with B-cell deficiency, agammaglobulinemia, and mild facial dysmorphic features. We confirmed the diagnosis of AD E47 transcription factor deficiency by the identification of a heterozygous missense variant c.1663G >A; p.E555K in the TCF3 gene. Alanine scanning of the E47 basic region revealed the structural Utsumi T, et al.3 significance of position 555. In addition, a comprehensive mutational analysis centered on position 555 found that only the amino acid substitution for lysine has a potent DN effect. Structurally the change from glutamic acid to lysine at position 555 not only abolished hydrogen bonds related to the protein-DNA interaction but also inverted the charge in the E47 protein surface. Our study reveals a partial aspect of the exclusivity of the E555K in the TCF3 DN variant.
Original languageEnglish
JournalJournal of Clinical Immunology
Publication statusAccepted/In press - 21 Jun 2024


  • TCF3
  • E47
  • E555K
  • Dominant-negative
  • B-cell deficiency
  • Agammaglobulinemia


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