Wiśniewska Karolina, Żabińska Magdalena, Szulc Aneta, Gaffke Lidia, Węgrzyn Grzegorz, Pierzynowska Karolina
Department of Molecular Biology, Faculty of Biology, University of Gdansk, Wita Stwosza 59, 80-308 Gdansk, Poland.
Int J Mol Sci. 2024 Dec 15;25(24):13447. doi: 10.3390/ijms252413447.
Mucopolysaccharidosis (MPS) comprises a group of inherited metabolic diseases. Each MPS type is caused by a deficiency in the activity of one kind of enzymes involved in glycosaminoglycan (GAG) degradation, resulting from the presence of pathogenic variant(s) of the corresponding gene. All types/subtypes of MPS, which are classified on the basis of all kinds of defective enzymes and accumulated GAG(s), are severe diseases. However, neuronopathy only occurs in some MPS types/subtypes (specifically severe forms of MPS I and MPS II, all subtypes of MPS III, and MPS VII), while in others, the symptoms related to central nervous system dysfunctions are either mild or absent. The early diagnosis of neuronopathy is important for the proper treatment and/or management of the disease; however, there are no specific markers that could be easily used for this in a clinical practice. Therefore, in this work, a comparative analysis of shared and specific gene expression alterations in neuronopathic and non-neuronopathic MPS types was performed using cultures of cells derived from patients. Using transcriptomic analyses (based on the RNA-seq method, confirmed by measuring the levels of a selected gene product), we identified genes (including , , and ) with dysregulated expression that are common for all, or almost all, types of MPS, suggesting their roles in MPS pathogenesis. Moreover, a distinct set of genes (including and ) exhibited expression changes only in neuronopathic MPS types/subtypes, but not in non-neuronopathic ones, suggesting their possible applications as biomarkers for neurodegeneration in MPS. These findings provide new insights into both the molecular mechanisms of MPS pathogenesis and the development of differentiation method(s) between neuronopathic and non-neuronopathic courses of the disease.
黏多糖贮积症（MPS）是一组遗传性代谢疾病。每种MPS类型都是由参与糖胺聚糖（GAG）降解的一种酶的活性缺乏引起的，这是由于相应基因存在致病性变异所致。根据各种缺陷酶和积累的GAG对MPS的所有类型/亚型进行分类，它们都是严重疾病。然而，神经病变仅发生在某些MPS类型/亚型中（特别是MPS I和MPS II的严重形式、MPS III的所有亚型以及MPS VII），而在其他类型中，与中枢神经系统功能障碍相关的症状要么轻微要么不存在。神经病变的早期诊断对于疾病的适当治疗和/或管理很重要；然而，在临床实践中没有可轻易用于此目的的特异性标志物。因此，在这项工作中，使用来自患者的细胞培养物对神经病变型和非神经病变型MPS类型中共享和特定的基因表达改变进行了比较分析。通过转录组分析（基于RNA测序方法，并通过测量选定基因产物的水平进行确认），我们鉴定出了表达失调的基因（包括 、 和 ），这些基因在所有或几乎所有MPS类型中都很常见，表明它们在MPS发病机制中的作用。此外，一组独特的基因（包括 和 ）仅在神经病变型MPS类型/亚型中表现出表达变化，而在非神经病变型中则没有，这表明它们可能作为MPS神经退行性变的生物标志物。这些发现为MPS发病机制的分子机制以及疾病神经病变型和非神经病变型病程之间的鉴别方法的发展提供了新的见解。
