Scholarlink

<p>Mucopolysaccharidosis-plus syndrome (MPSPS) is an ultrarare inherited metabolic disease (a few dozen patients diagnosed to date) which is characterised by accumulation of undegraded glycosaminoglycans (GAGs). Despite GAG storage occurs also in the groups of diseases classified as mucopolysaccharidoses (MPS), contrary to MPS, no dysfunctions of lysosomal enzymes is detected in MPSPS which is caused by mutations in the <i>VPS33A</i> gene. The c.1492C &gt; T (p.Arg498Trp) variant, associated with a severe course of the disease, was found in most MPSPS patients. There are only two patients described to date with a homozygous c.599G &gt; C (p.Arg200Pro) variant and a milder (juvenile) form. Until now, the molecular mechanism of MPSPS remained largely unknown, especially for the juvenile form. Here, a battery of cellular and molecular assays, performed using fibroblasts derived from a patient bearing the c.599G &gt; C (p.Arg200Pro) variant of the <i>VPS33A</i> gene, indicated specific changes in cellular vacuoles, elevated levels of the EEA1 protein (required at the stages of the fusions of early and late endosomes, and early endosome sorting), changes in Golgi apparatus morphology, decreased levels of F-actin, and increased levels of α- and β-tubulins, as well as elevated levels of the LC3-II and p62 proteins (autophagy markers). Results of experiments presented here might suggest that severely decreased levels the p.Arg200Pro variant of VSP33A could cause defective endosomal trafficking, possibly resulting in inefficient delivery of GAGs to lysosomes, and their subsequent accumulation in cells. This might induce a cascade of secondary and tertiary disorders, finally expressing as the disease symptoms.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Cellular and molecular changes in mucopolysaccharidosis-plus syndrome caused by a homozygous c.599G > C (p.Arg200Pro) variant of the VPS33A gene

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月4日

查看全文
  • Zuzanna Cyske,
  • Estera Rintz,
  • Magdalena Narajczyk,
  • Natalia Świątek,
  • Lidia Gaffke,
  • Karolina Pierzynowska,
  • Grzegorz Węgrzyn

摘要

Mucopolysaccharidosis-plus syndrome (MPSPS) is an ultrarare inherited metabolic disease (a few dozen patients diagnosed to date) which is characterised by accumulation of undegraded glycosaminoglycans (GAGs). Despite GAG storage occurs also in the groups of diseases classified as mucopolysaccharidoses (MPS), contrary to MPS, no dysfunctions of lysosomal enzymes is detected in MPSPS which is caused by mutations in the VPS33A gene. The c.1492C > T (p.Arg498Trp) variant, associated with a severe course of the disease, was found in most MPSPS patients. There are only two patients described to date with a homozygous c.599G > C (p.Arg200Pro) variant and a milder (juvenile) form. Until now, the molecular mechanism of MPSPS remained largely unknown, especially for the juvenile form. Here, a battery of cellular and molecular assays, performed using fibroblasts derived from a patient bearing the c.599G > C (p.Arg200Pro) variant of the VPS33A gene, indicated specific changes in cellular vacuoles, elevated levels of the EEA1 protein (required at the stages of the fusions of early and late endosomes, and early endosome sorting), changes in Golgi apparatus morphology, decreased levels of F-actin, and increased levels of α- and β-tubulins, as well as elevated levels of the LC3-II and p62 proteins (autophagy markers). Results of experiments presented here might suggest that severely decreased levels the p.Arg200Pro variant of VSP33A could cause defective endosomal trafficking, possibly resulting in inefficient delivery of GAGs to lysosomes, and their subsequent accumulation in cells. This might induce a cascade of secondary and tertiary disorders, finally expressing as the disease symptoms.