Advanced computational analysis of CD40LG variants in atypical X-linked hyper-IgM syndrome

Amudha Pazhanisamy, Salomao Doria Jorge, Michael T. Zimmermann, Maleewan Kitcharoensakkul, Manar Abdalgani, Amer Khojah, Christian Victor, Cesar Rueda, Raul Urrutia, Roshini S. Abraham

Research output: Contribution to journalArticlepeer-review


X-Linked Hyper-IgM Syndrome is caused by pathogenic variants in CD40LG. Three patients with atypical clinical and immunological features were identified with variants in CD40LG requiring further characterization. Flow cytometry was used to evaluate CD40L protein expression and binding capacity to a surrogate receptor, CD40-muIg. Though functional anomalies were observed, there was still a lack of clarity regarding the underlying mechanism. We developed structural models for wild-type and the three variants of CD40L protein observed in these patients (p. Lys143Asn, Leu225Ser and Met36Arg) to evaluate structural alterations by molecular mechanic calculations, and assess protein movement by molecular dynamic simulations. These studies demonstrate that functional analysis of variants of unknown significance in CD40LG can be supplemented by advanced computational analysis in atypical clinical contexts. These studies in combination identify the deleterious effects of these variants and potential mechanisms for protein dysfunction.

Original languageEnglish
Article number109692
JournalClinical Immunology
StatePublished - Aug 2023


  • B cell lymphoma
  • CD4+ T cells
  • CD40, CD40 ligand
  • CD40L deficiency
  • Flow cytometry
  • Hypogammaglobulinemia
  • Molecular dynamics
  • Neutropenia
  • Protein modeling
  • X-linked hyper IgM syndrome


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