Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA; Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA.
Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA.
Exp Neurol. 2025 Jan;383:115025. doi: 10.1016/j.expneurol.2024.115025. Epub 2024 Oct 24.
Mutations in the Immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene result in two distinct diseases, SMA with Respiratory Distress Type I (SMARD1) and Charcot Marie Tooth Type 2S (CMT2S). To understand the phenotypic and molecular differences between SMARD1 and CMT2S, and the role of IGHMBP2 in disease development, we generated mouse models based on six IGHMBP2 patient mutations. Previously, we reported the development and characterization of Ighmbp2 mice and in this manuscript, we examine two mutations: D565N (D564N in mice) and H924Y (H922Y in mice) in the Ighmbp2 and Ighmbp2 contexts. We found significant differences between these mouse models, providing critical insight into the role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S. Importantly, these studies also demonstrate how disease pathogenesis is significantly altered in the context of Ighmbp2 D564N and H922Y homozygous recessive and compound heterozygous mutations. Notably, there were short-lived and long-lived lifespan cohorts within Ighmbp2 mice with early (P12/P16) respiratory pathology serving as a key predictor of lifespan. Despite differences in lifespan, motor function deficits initiated early and progressively worsened in all Ighmbp2 mice. There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in Ighmbp2 mice. Consistent with CMT2S, Ighmbp2 mice did not have altered lifespans nor respiratory pathology. Interestingly, Ighmbp2 limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180. This is the first study that demonstrates differences associated with IGHMBP2 function within respiration with those within limb motor function. Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these IGHMBP2 patient mutations and IGHMBP2 biochemical activity. Importantly, these studies reveal the dynamic differences that are presented when either a single mutant protein is present (IGHMBP2-D564N or IGHMBP2-H922Y) or two mutant proteins are present (IGHMBP2-D564N and IGHMBP2-H922Y) within cells.
IGHMBP2 基因中的突变导致两种不同的疾病，即具有呼吸窘迫型 I 型（SMARD1）的 SMA 和 Charcot-Marie-Tooth 型 2S（CMT2S）。为了了解 SMARD1 和 CMT2S 之间的表型和分子差异，以及 IGHMBP2 在疾病发展中的作用，我们基于 6 种 IGHMBP2 患者突变生成了小鼠模型。此前，我们曾报道过 Ighmbp2 小鼠的开发和特性，在本文中，我们研究了 Ighmbp2 和 Ighmbp2 背景下的两种突变：D565N（小鼠中的 D564N）和 H924Y（小鼠中的 H922Y）。我们发现这些小鼠模型之间存在显著差异，为 IGHMBP2 在 SMARD1 和 CMT2S 发病机制中的作用提供了重要的见解。重要的是，这些研究还表明，IGHMBP2 基因 D564N 和 H922Y 纯合隐性和复合杂合突变的背景下，疾病发病机制发生了显著改变。值得注意的是，在 Ighmbp2 小鼠中存在寿命较短和寿命较长的两个群体，出生后 12/16 天（P12/P16）的呼吸病理是预测寿命的关键指标。尽管存在寿命差异，但所有 Ighmbp2 小鼠的运动功能缺陷都在早期出现，并逐渐恶化。Ighmbp2 小鼠的肢体骨骼肌肉纤维面积减少，神经肌肉接头（NMJ）去神经支配增加。与 CMT2S 一致，Ighmbp2 小鼠的寿命和呼吸病理均无改变。有趣的是，Ighmbp2 肢体肌肉纤维的面积增加，随后减少，而 NMJ 神经支配的变化即使在 P180 时也很小。这是第一项研究，表明 IGHMBP2 功能与呼吸相关的差异与与肢体运动功能相关的差异。对我们理解 IGHMBP2 功能具有重要意义的是，我们证明了与这些 IGHMBP2 患者突变相关的疾病发病机制与 IGHMBP2 生化活性之间存在直接相关性。重要的是，这些研究揭示了当单个突变蛋白（IGHMBP2-D564N 或 IGHMBP2-H922Y）或两个突变蛋白（IGHMBP2-D564N 和 IGHMBP2-H922Y）存在于细胞中时呈现的动态差异。
