Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
Orphan Technologies Ltd., Rapperswil, Switzerland.
Hum Mutat. 2018 Feb;39(2):210-218. doi: 10.1002/humu.23360. Epub 2017 Nov 13.
Skeletal and connective tissue defects are the most striking symptoms in patients suffering from classical homocystinuria (HCU). Here, we determined body composition and bone mass in three mouse models of HCU and assessed whether a long-term administration of enzyme replacement therapy (ERT) corrected the phenotype. The mouse models of HCU were analyzed using dual-energy X-ray absorptiometry and the data were complemented by plasma biochemical profiles. Both the mouse model lacking CBS (KO) and the one expressing human CBS mutant transgene on a mouse CBS null background (I278T) showed marked bone loss and decreased weight mostly due to a lower fat content compared with negative controls. In contrast, the HO mouse expressing the human CBS WT transgene on a mouse CBS null background showed no such phenotype despite similar plasma biochemical profile to the KO and I278T mice. More importantly, administration of ERT rescued bone mass and changes in body composition in the KO mice treated since birth and reversed bone loss and improved fat content in the I278T mice injected after the development of clinical symptoms. Our study suggests that ERT for HCU may represent an effective way of preventing the skeletal problems in patients without a restricted dietary regime.
骨骼和结缔组织缺陷是经典同型胱氨酸尿症（HCU）患者最明显的症状。在这里，我们确定了三种 HCU 小鼠模型的身体成分和骨量，并评估了长期酶替代疗法（ERT）是否纠正了表型。使用双能 X 射线吸收法分析 HCU 小鼠模型，并通过血浆生化谱补充数据。缺乏 CBS 的小鼠模型（KO）和在 CBS 缺失背景下表达人类 CBS 突变体转基因的小鼠模型（I278T）均表现出明显的骨丢失和体重下降，主要是由于与阴性对照相比，脂肪含量较低。相比之下，在 CBS 缺失背景下表达人类 CBS WT 转基因的 HO 小鼠尽管与 KO 和 I278T 小鼠具有相似的血浆生化谱，但没有表现出这种表型。更重要的是，ERT 的给药挽救了从出生开始治疗的 KO 小鼠的骨量和身体成分变化，并逆转了 I278T 小鼠在出现临床症状后注射的骨丢失和改善脂肪含量。我们的研究表明，ERT 治疗 HCU 可能是一种预防无饮食限制患者骨骼问题的有效方法。
