Department of Pediatrics, Nationwide Children's Hospital, OH, USA; The Ohio State University Wexner Medical Center, OH, USA.
Medical College of Wisconsin, WI, USA.
Clin Immunol. 2023 Aug;253:109692. doi: 10.1016/j.clim.2023.109692. Epub 2023 Jul 9.
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.
X 连锁高免疫球蛋白 M 综合征是由 CD40LG 的致病变异引起的。鉴定出三例具有非典型临床和免疫学特征的患者，他们的 CD40LG 变异需要进一步表征。使用流式细胞术评估 CD40L 蛋白表达和与替代受体 CD40-muIg 的结合能力。尽管观察到功能异常，但潜在机制仍不明确。我们为在这些患者中观察到的 CD40L 蛋白的三种野生型和变体（p.Lys143Asn、Leu225Ser 和 Met36Arg）构建了结构模型，通过分子力学计算评估结构改变，并通过分子动力学模拟评估蛋白质运动。这些研究表明，在非典型临床情况下，对 CD40LG 中意义不明的变异进行功能分析可以通过先进的计算分析来补充。这些研究结合起来确定了这些变体的有害影响和蛋白质功能障碍的潜在机制。
