Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
Department of Pediatrics and Clinical Genomics, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, 350-0495, Japan.
Sci Rep. 2023 May 15;13(1):7865. doi: 10.1038/s41598-023-34541-w.
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder characterized by an accumulation of glycosaminoglycans (GAGs), including heparan sulfate, in the body. Major manifestations involve the central nerve system (CNS), skeletal deformation, and visceral manifestations. About 30% of MPS II is linked with an attenuated type of disease subtype with visceral involvement. In contrast, 70% of MPS II is associated with a severe type of disease subtype with CNS manifestations that are caused by the human iduronate-2-sulfatase (IDS)-Pro86Leu (P86L) mutation, a common missense mutation in MPS II. In this study, we reported a novel Ids-P88L MPS II mouse model, an analogous mutation to human IDS-P86L. In this mouse model, a significant impairment of IDS enzyme activity in the blood with a short lifespan was observed. Consistently, the IDS enzyme activity of the body, as assessed in the liver, kidney, spleen, lung, and heart, was significantly impaired. Conversely, the level of GAG was elevated in the body. A putative biomarker with unestablished nature termed UA-HNAc(1S) (late retention time), one of two UA-HNAc(1S) species with late retention time on reversed-phase separation,is a recently reported MPS II-specific biomarker derived from heparan sulfate with uncharacterized mechanism. Thus, we asked whether this biomarker might be elevated in our mouse model. We found a significant accumulation of this biomarker in the liver, suggesting that hepatic formation could be predominant. Finally, to examine whether gene therapy could enhance IDS enzyme activity in this model, the efficacy of the nuclease-mediated genome correction system was tested. We found a marginal elevation of IDS enzyme activity in the treated group, raising the possibility that the effect of gene correction could be assessed in this mouse model. In conclusion, we established a novel Ids-P88L MPS II mouse model that consistently recapitulates the previously reported phenotype in several mouse models.
黏多糖贮积症 II 型（MPS II）是一种溶酶体贮积病，其特征是体内糖胺聚糖（GAG）积聚，包括硫酸乙酰肝素。主要表现涉及中枢神经系统（CNS）、骨骼变形和内脏表现。大约 30%的 MPS II 与内脏受累的疾病亚型的衰减型有关。相比之下，70%的 MPS II 与中枢神经系统表现的严重疾病亚型有关，这是由人类艾杜糖-2-硫酸酯酶（IDS）Pro86Leu（P86L）突变引起的，这是 MPS II 的一种常见错义突变。在这项研究中，我们报告了一种新型的 Ids-P88L MPS II 小鼠模型，这是一种类似于人类 IDS-P86L 的突变。在这种小鼠模型中，观察到血液中 IDS 酶活性显著受损，寿命较短。一致地，肝脏、肾脏、脾脏、肺和心脏中身体的 IDS 酶活性也显著受损。相反，身体中的 GAG 水平升高。一种尚未确定的潜在生物标志物 UA-HNAc(1S)（延迟保留时间），是反相分离中两种具有延迟保留时间的 UA-HNAc(1S) 物种之一，是最近报道的源自硫酸乙酰肝素的 MPS II 特异性生物标志物，其机制尚不清楚。因此，我们询问这种生物标志物是否可能在我们的小鼠模型中升高。我们发现这种生物标志物在肝脏中的显著积累，表明肝脏形成可能占主导地位。最后，为了检查基因治疗是否可以提高这种模型中的 IDS 酶活性，我们测试了核酸酶介导的基因组校正系统的疗效。我们发现治疗组 IDS 酶活性略有升高，这表明可以在这种小鼠模型中评估基因校正的效果。总之，我们建立了一种新型的 Ids-P88L MPS II 小鼠模型，该模型在几种小鼠模型中一致地再现了先前报道的表型。
