Advanced computational analysis of CD40LG variants in atypical X-linked hyper-IgM syndrome. Clin Immunol 2023 Aug;253:109692
Date
07/12/2023Pubmed ID
37433422DOI
10.1016/j.clim.2023.109692Scopus ID
2-s2.0-85164736502 (requires institutional sign-in at Scopus site)Abstract
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.
Author List
Pazhanisamy A, Jorge SD, Zimmermann MT, Kitcharoensakkul M, Abdalgani M, Khojah A, Victor C, Rueda C, Urrutia R, Abraham RSAuthors
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of WisconsinMichael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
CD40 AntigensCD40 Ligand
Humans
Hyper-IgM Immunodeficiency Syndrome
Hyper-IgM Immunodeficiency Syndrome, Type 1
Immunoglobulin M
Mutation
