Sulfatases catalyze essential cellular reactions, including degradation of glycosaminoglycans (GAGs). All sulfatases are post-translationally activated by the formylglycine generating enzyme (FGE) which is deficient in multiple sulfatase deficiency (MSD), a neurodegenerative lysosomal storage disease. Historically, patients were presumed to be deficient of all sulfatase activities; however, a more nuanced relationship is emerging. Each sulfatase may differ in their degree of post-translational modification by FGE, which may influence the phenotypic spectrum of MSD. Here, we evaluate if residual sulfatase activity and accumulating GAG patterns distinguish cases from controls and stratify clinical severity groups in MSD. We quantify sulfatase activities and GAG accumulation using three complementary methods in MSD participants. Sulfatases differed greatly in their tolerance of reduction in FGE-mediated activation. Enzymes that degrade heparan sulfate (HS) demonstrated lower residual activities than those that act on other GAGs. Similarly, HS-derived urinary GAG subspecies preferentially accumulated, distinguished cases from controls, and correlated with disease severity. Accumulation patterns of specific sulfatase substrates in MSD provide fundamental insights into sulfatase regulation and will serve as much-needed biomakers for upcoming clinical trials. This work highlights that biomarker investigation of an ultra-rare disease can simultaneously inform our understanding of fundamental biology and advance clinical trial readiness efforts.

中文翻译：

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多种硫酸酯酶缺乏症疾病严重程度的生化特征

硫酸酯酶催化重要的细胞反应，包括糖胺聚糖 (GAG) 的降解。所有硫酸酯酶均由甲酰甘氨酸生成酶 (FGE) 进行翻译后激活，该酶在多种硫酸酯酶缺乏症 (MSD)（一种神经退行性溶酶体贮积病）中存在缺陷。从历史上看，患者被认为缺乏所有硫酸酯酶活性。然而，一种更加微妙的关系正在出现。每种硫酸酯酶的 FGE 翻译后修饰程度可能有所不同，这可能会影响 MSD 的表型谱。在这里，我们评估残余硫酸酯酶活性和累积的 GAG 模式是否能够区分病例和对照，并对 MSD 的临床严重程度进行分层。我们使用三种互补方法对 MSD 参与者的硫酸酯酶活性和 GAG 积累进行量化。硫酸酯酶对 FGE 介导的激活减少的耐受性差异很大。降解硫酸乙酰肝素 (HS) 的酶比作用于其他 GAG 的酶表现出较低的残留活性。同样，HS 衍生的尿 GAG 亚种优先积累，将病例与对照区分开来，并与疾病严重程度相关。MSD 中特定硫酸酯酶底物的积累模式为硫酸酯酶调节提供了基本见解，并将作为即将进行的临床试验急需的生物制造者。这项工作强调，对一种极其罕见疾病的生物标志物研究可以同时增进我们对基础生物学的理解，并推进临床试验准备工作。