Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
Genes (Basel). 2023 Sep 24;14(10):1855. doi: 10.3390/genes14101855.
(1) Background: Mutations in , a transcriptional regulator of immunomodulating proteins, are a known cause of inborn errors of immunity. Our proband is a 22-year-old male with a diagnosis of common variable immunodeficiency (CVID), cytopenias with massive splenomegaly, and nodular regenerative hyperplasia of the liver. Genetic studies identified a novel, single-point mutation variant in , c. T638A p. V213E. (2) Methods: Next-generation panel sequencing of the patient uncovered a novel single-point mutation in the gene that was modeled using the I-TASSER homology-modeling software, and molecular dynamics were assessed using the YASARA2 software (version 20.14.24). (3) Results: This variant replaces valine with glutamic acid at position 213 in the NFκB1 sequence. Molecular modeling and molecular dynamic studies showed altered dynamics in and around the rel homology domain, ankyrin regions, and death domain of the protein. We postulate that these changes alter overall protein function. (4) Conclusions: This case suggests the pathogenicity of a novel variant using protein-modeling techniques and molecular dynamic simulations.
(1) 背景：免疫调节蛋白转录调节剂 的突变是先天性免疫缺陷的已知原因。我们的先证者是一名 22 岁男性，患有普通可变免疫缺陷（CVID）、血细胞减少症伴巨脾和肝结节性再生性增生。遗传研究在 基因中发现了一种新的单点突变变体，c. T638A p. V213E。(2) 方法：对患者进行下一代靶向测序，发现 基因中的一个新的单点突变，使用 I-TASSER 同源建模软件对其进行建模，并使用 YASARA2 软件（版本 20.14.24）对分子动力学进行评估。(3) 结果：该变体在 NFκB1 序列中的第 213 位将缬氨酸替换为谷氨酸。分子建模和分子动力学研究表明，蛋白质的 rel 同源结构域、锚蛋白区域和死亡结构域及其周围的动力学发生改变。我们推测这些变化会改变整体蛋白质功能。(4) 结论：本病例通过蛋白质建模技术和分子动力学模拟提示了一种新变异体的致病性。
