Strauch Oliver F, Stypmann Jörg, Reinheckel Thomas, Martinez Elke, Haverkamp Wilhelm, Peters Christoph
Institut für Molekulare Medizin und Zellforschung, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
Pediatr Res. 2003 Nov;54(5):701-8. doi: 10.1203/01.PDR.0000084085.65972.3F. Epub 2003 Aug 6.
Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of arylsulfatase B (ASB) which has its function in the sequential degradation of glycosaminoglycans (GAG). Targeted disruption of the ASB gene resulted in a mouse model of MPS VI that has been closely investigated for skeletal and chondral dysplasia. As ocular and cardiac impairment are also clinically important manifestations of the MPS VI syndrome, the present study was initiated for detailed biochemical, histologic and functional analysis of cornea, optic nerve and heart in ASB-deficient mice. Biochemical evidence for GAG-storage could be obtained for liver, kidney, spleen and myocardium as well as for heart valves, cornea and optic nerve from ASB-deficient mice. In MPS VI mice, histology revealed structural impairment of corneal stroma and epithelium as well as a thickening of the heart valves. According to histologic investigations, the optic nerve appeared not to be altered. However, GAG-storage in the dura mater could be demonstrated in MPS VI mice. Heart function was assessed by echocardiography. While the dimensions of MPS VI hearts were not altered, these hearts clearly showed decreased myocardial contraction and a 50% reduction of cardiac output. In addition, insufficiencies in the mitral and aortic valves were detected. Thus, ASB-deficient mice resemble the phenotype of human MPS VI not only in the skeletal but also in the ocular and cardiac symptoms. To our knowledge, these in vivo evaluations of heart function represent the first respective investigation of a MPS VI animal model and should provide a valuable measure for therapy studies in the MPS VI mouse.
VI型黏多糖贮积症（MPS VI）是一种溶酶体贮积病，由芳基硫酸酯酶B（ASB）缺乏引起，ASB在糖胺聚糖（GAG）的顺序降解中发挥作用。ASB基因的靶向破坏导致了MPS VI小鼠模型，该模型已针对骨骼和软骨发育异常进行了深入研究。由于眼部和心脏损害也是MPS VI综合征的重要临床症状，因此开展了本研究，以对ASB缺陷小鼠的角膜、视神经和心脏进行详细的生化、组织学和功能分析。在ASB缺陷小鼠的肝脏、肾脏、脾脏、心肌以及心脏瓣膜、角膜和视神经中均获得了GAG贮积的生化证据。在MPS VI小鼠中，组织学检查显示角膜基质和上皮结构受损，心脏瓣膜增厚。根据组织学研究，视神经似乎未发生改变。然而，在MPS VI小鼠中可证实硬脑膜中有GAG贮积。通过超声心动图评估心脏功能。虽然MPS VI小鼠心脏的尺寸未改变，但这些心脏明显显示心肌收缩力下降，心输出量减少50%。此外，还检测到二尖瓣和主动脉瓣功能不全。因此，ASB缺陷小鼠不仅在骨骼方面，而且在眼部和心脏症状方面都与人类MPS VI的表型相似。据我们所知，这些对心脏功能的体内评估是对MPS VI动物模型的首次相关研究，应为MPS VI小鼠治疗研究提供有价值的衡量标准。
