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Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate
Biochemical Journal ( IF 4.4 ) Pub Date : 2020-09-18 , DOI: 10.1042/bcj20200546
Christof Trabszo 1 , Bastian Ramms 1, 2 , Pradeep Chopra 3 , Renate Lüllmann-Rauch 4 , Stijn Stroobants 5 , Jens Sproß 6 , Anke Jeschke 7 , Thorsten Schinke 7 , Geert-Jan Boons 3, 8, 9 , Jeffrey D. Esko 2 , Torben Lübke 1 , Thomas Dierks 1
Affiliation  

Mucopolysaccharidoses comprise a group of rare metabolic diseases, in which the lysosomal degradation of glycosaminoglycans (GAGs) is impaired due to genetically inherited defects of lysosomal enzymes involved in GAG catabolism. The resulting intralysosomal accumulation of GAG-derived metabolites consequently manifests in neurological symptoms and also peripheral abnormalities in various tissues like liver, kidney, spleen and bone. As each GAG consists of differently sulfated disaccharide units, it needs a specific, but also partly overlapping set of lysosomal enzymes to accomplish their complete degradation. Recently, we identified and characterized the lysosomal enzyme arylsulfatase K (Arsk) exhibiting glucuronate-2-sulfatase activity as needed for the degradation of heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS). In the present study, we investigated the physiological relevance of Arsk by means of a constitutive Arsk knockout mouse model. A complete lack of glucuronate desulfation was demonstrated by a specific enzyme activity assay. Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of HS and CS metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends. Pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology like bone abnormalities were detected. Our results from the Arsk mouse model suggest a new although mild form of mucopolysacharidose (MPS), which we designate MPS type IIB.

中文翻译:

由于乙酰肝素和硫酸软骨素的葡萄糖醛酸脱硫不足,芳基硫酸酯酶K失活会引起粘多糖贮积症

粘多糖酶包括一组罕见的代谢疾病,其中由于与GAG分解代谢有关的溶酶体酶的遗传遗传缺陷,糖胺聚糖(GAG)的溶酶体降解受到损害。因此,GAG衍生代谢产物的溶酶体内累积表现为神经系统症状,以及肝,肾,脾和骨等各种组织的周围异常。由于每个GAG由不同的硫酸化二糖单元组成,因此需要特定的溶酶体酶,但也要部分重叠以完成其完全降解。最近,我们鉴定并表征了降解硫酸乙酰肝素(HS),硫酸软骨素(CS)和硫酸皮肤素(DS)所需的溶酶体酶芳基硫酸酯酶K(Arsk),其表现出葡萄糖醛酸-2-硫酸酯酶的活性。在本研究中,我们通过构成性Arsk基因敲除小鼠模型调查了Arsk的生理相关性。通过特异性酶活性测定法证实了葡萄糖醛酸脱硫的完全缺乏。缺乏Arsk的小鼠以器官特异性的方式显示出中等积累的HS和CS代谢产物,其特征是在其非还原性末端被2-O-硫酸化的葡萄糖醛酸部分。病理生理学研究反映了相当轻微的表型,包括行为改变。有趣的是,未检测到明显的溶酶体贮藏病理,如骨骼异常。我们从Arsk小鼠模型获得的结果表明,粘多糖型(MPS)是一种新的但温和的形式,我们将其命名为IIB型MPS。通过特异性酶活性测定法证明完全缺乏葡萄糖醛酸脱硫。缺乏Arsk的小鼠以器官特异性的方式显示出中等积累的HS和CS代谢产物,其特征是在其非还原性末端被2-O-硫酸化的葡萄糖醛酸部分。病理生理学研究反映了相当轻微的表型,包括行为改变。有趣的是,未检测到明显的溶酶体贮藏病理,如骨骼异常。我们从Arsk小鼠模型获得的结果表明,粘多糖型(MPS)是一种新的但温和的形式,我们将其命名为IIB型MPS。通过特异性酶活性测定法证实了葡萄糖醛酸脱硫的完全缺乏。缺乏Arsk的小鼠以器官特异性的方式显示出中等积累的HS和CS代谢产物,其特征是在其非还原性末端被2-O-硫酸化的葡萄糖醛酸部分。病理生理学研究反映了相当轻微的表型,包括行为改变。有趣的是,未检测到明显的溶酶体贮藏病理,如骨骼异常。我们从Arsk小鼠模型获得的结果表明,粘多糖型(MPS)是一种新的但温和的形式,我们将其命名为IIB型MPS。HS和CS代谢产物的中等积累,其特征是在其非还原末端为2-O-硫酸葡萄糖醛酸酸酯部分。病理生理学研究反映了相当轻微的表型,包括行为改变。有趣的是,未检测到明显的溶酶体贮藏病理,如骨骼异常。我们从Arsk小鼠模型获得的结果表明,粘多糖型(MPS)是一种新的但温和的形式,我们将其命名为IIB型MPS。HS和CS代谢产物的适度积累,其特征是在其非还原端的2-O-硫酸葡萄糖醛酸酯部分。病理生理学研究反映了相当轻微的表型,包括行为改变。有趣的是,未检测到明显的溶酶体贮藏病理,如骨骼异常。我们从Arsk小鼠模型获得的结果表明,粘多糖型(MPS)是一种新的但温和的形式,我们将其命名为IIB型MPS。
更新日期:2020-09-18
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