Nguyen Khue Vu
Department of Medicine, Biochemical Genetics and Metabolism, The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California, San Diego, Building CTF, Room C-103, 214 Dickinson Street, San Diego, CA 92103-8467, USA.
Department of Pediatrics, University of California, San Diego, School of Medicine, San Diego, La Jolla, CA 92093-0830, USA.
AIMS Neurosci. 2021 Oct 28;8(4):548-557. doi: 10.3934/Neuroscience.2021030. eCollection 2021.
Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorders of purine metabolic in which the cytoplasmic enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. Despite having been characterized over 60 years ago, however, up to now, there is no satisfactory explanation of how deficits in enzyme HGprt can lead to LND with the development of the persistent and severe self-injurious behavior. Recently, a role for epistasis between the mutated hypoxanthine phosphoribosyltransferase 1 () and the β-amyloid precursor protein (APP) genes affecting the regulation of alternative APP pre-mRNA splicing in LND has been demonstrated. Furthermore, there were also some reported cases of LND developing thrombosis while APP is an important regulator of vein thrombosis and controls coagulation. Otherwise, the surface expression of HGprt enzyme was also observed in several somatic tissue cancers while APP and the APP-like protein-2 (APLP2) are deregulated in cancer cells and linked to increased tumor cell proliferation, migration, and invasion. The present review provides a discussion about these findings and suggests a potential molecular link between APP and HGprt via epistasis between and genes affecting the regulation of alternative APP pre-mRNA splicing. As a perspective, expression vectors for HGprt enzyme and APP are constructed as described in Ref. # 24 (Nguyen KV, Naviaux RK, Nyhan WL (2020) Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). 39: 905-922), and they could be used as tools for clarification of these issues. In addition, these expression vectors, especially the one with the glycosyl-phosphatidylinositol (GPI) anchor can be used as a model for the construction of expression vectors for any protein targeting to the cell plasma membrane for studying intermolecular interactions and could be therefore useful in the vaccines as well as antiviral drugs development (studying intermolecular interactions between the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as well as its variants and the angiotensin-converting enzyme 2, ACE2, in coronavirus disease 2019 (COVID-19) [43],[44], for example).
莱施-奈恩病（LND）是一种罕见的X连锁遗传性嘌呤代谢神经遗传疾病，其细胞质酶次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGprt）存在缺陷。然而，尽管早在60多年前就已对其进行了特征描述，但直到现在，对于HGprt酶的缺陷如何导致LND并伴有持续且严重的自伤行为的发展，仍没有令人满意的解释。最近，已证明突变的次黄嘌呤磷酸核糖转移酶1（）与β-淀粉样前体蛋白（APP）基因之间的上位性作用影响了LND中APP前体mRNA可变剪接的调控。此外，也有一些LND并发血栓形成的报道病例，而APP是静脉血栓形成的重要调节因子并控制凝血。另外，在几种体细胞组织癌症中也观察到了HGprt酶的表面表达，而APP和类APP蛋白-2（APLP2）在癌细胞中失调并与肿瘤细胞增殖、迁移和侵袭增加有关。本综述对这些发现进行了讨论，并提出通过影响APP前体mRNA可变剪接调控的和基因之间的上位性作用，APP与HGprt之间可能存在分子联系。从这个角度来看，如参考文献#24（Nguyen KV，Naviaux RK，Nyhan WL（2020）莱施-奈恩病：I.次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGprt）酶和淀粉样前体蛋白（APP）表达载体的构建。39：905 - 922）所述构建了HGprt酶和APP的表达载体，它们可作为阐明这些问题的工具。此外，这些表达载体尤其是带有糖基磷脂酰肌醇（GPI）锚的表达载体，可作为构建靶向细胞质膜的任何蛋白质表达载体的模型，用于研究分子间相互作用，因此在疫苗以及抗病毒药物开发中可能有用（例如，研究严重急性呼吸综合征冠状病毒2（SARS-CoV-2）及其变体的刺突糖蛋白与2019冠状病毒病（COVID-19）中的血管紧张素转换酶2（ACE2）之间的分子间相互作用[43]，[44]）。
