Varied mechanisms underlie the free sialic acid storage disorders
Varied mechanisms underlie the free sialic acid storage disorders
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DOI：
10.1074/jbc.m411295200
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发表时间：
2005-01-14
影响因子：
4.8
通讯作者：
Reimer, RJ
中科院分区：
文献类型：
--
作者：
Wreden, CC;Wlizla, M;Reimer, RJ
萨拉病和婴儿唾液酸贮积症是常染色体隐性神经退行性疾病，其特征在于溶酶体唾液酸转运活性的丧失和由此导致的游离唾液酸在溶酶体中的积累。这些疾病的遗传分析已经在编码称为唾液酸蛋白的蛋白质的单个基因中鉴定了几个独特的突变（Verheijen，F. W.，Verbeek，E.，Aula，N.，贝伦角E、Havelaar，A. C.的方法，Joosse，M.，佩尔托宁湖Aula，P.，Galjaard，H.，货车德斯佩克，P. J.，Mancini，G. M.等人（1999）Nat.Genet. 23，462-465; Aula，N.，Salomaki，P.，蒂莫宁河Verheijen，F.，Mancini，G.，Mansson，J. E.，Aula，P.，和Peltonen，L.（2000年）美国J. Genet. 67，832-840）。从疾病的生化表型和蛋白质的预测多面体结构，它已被建议，唾液酸作为溶酶体唾液酸转运蛋白的功能。在这里，我们直接证明，这种活性是由唾液酸蛋白介导的，重组蛋白具有类似于天然溶酶体唾液酸转运系统的功能特性。此外，我们描述了致病突变对蛋白质的影响。我们发现，大多数突变与活动的完全丧失有关，而与疾病的轻度形式相关的突变导致功能降低，但仍有残留。因此，唾液酸蛋白功能与疾病状态之间存在直接相关性。此外，我们发现有一个突变，蛋白质保留在内质网，表明改变运输唾液酸也与疾病。唾液酸储存障碍的分子机制的分析是确定这些疾病的治疗方法的进一步步骤。
Salla disease and infantile sialic acid storage disorder are autosomal recessive neurodegenerative diseases characterized by loss of a lysosomal sialic acid transport activity and the resultant accumulation of free sialic acid in lysosomes. Genetic analysis of these diseases has identified several unique mutations in a single gene encoding a protein designated sialin (Verheijen, F. W., Verbeek, E., Aula, N., Beerens, C. E., Havelaar, A. C., Joosse, M., Peltonen, L., Aula, P., Galjaard, H., van der Spek, P. J., and Mancini, G. M. (1999) Nat. Genet. 23, 462-465; Aula, N., Salomaki, P., Timonen, R., Verheijen, F., Mancini, G., Mansson, J. E., Aula, P., and Peltonen, L. ( 2000) Am. J. Hum. Genet. 67, 832-840). From the biochemical phenotype of the diseases and the predicted polytopic structure of the protein, it has been suggested that sialin functions as a lysosomal sialic acid transporter. Here we directly demonstrate that this activity is mediated by sialin and that the recombinant protein has functional characteristics similar to the native lysosomal sialic acid transport system. Furthermore, we describe the effect of disease-causing mutations on the protein. We find that the majority of the mutations are associated with a complete loss of activity, while the mutations associated with the milder forms of the disease lead to reduced, but residual, function. Thus, there is a direct correlation between sialin function and the disease state. In addition, we find with one mutation that the protein is retained in the endoplasmic reticulum, indicating that altered trafficking of sialin is also associated with disease. This analysis of the molecular mechanism of sialic acid storage disorders is a further step in identifying therapeutic approaches to these diseases.