Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis
Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis
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DOI：
10.1093/hmg/9.18.2715
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发表时间：
2000-11-01
影响因子：
3.5
通讯作者：
d'Azzo, A
中科院分区：
文献类型：
--
作者：
Bonten, EJ;Arts, WF;d'Azzo, A
溶酶体神经氨酸酶是唾液酸化糖缀合物的溶酶体内催化的关键酶，并且在两种神经退行性溶酶体疾病唾液酸沉积症和半乳糖唾液酸沉积症中缺乏。在这里，我们报告了11例不同程度的唾液酸中毒患者的神经氨酸酶基因的8个新突变的鉴定。人神经氨酸酶的一级结构与细菌唾液酸酶的一级和三级结构的比较表明，大多数的单个氨基酸取代发生在功能基序或保守残基。基于突变神经氨酸苷酶的亚细胞分布和残余催化活性，我们将突变蛋白分为三组：（i）无催化活性而非溶酶体;（ii）无催化活性，但定位于溶酶体中;和（iii）有催化活性和溶酶体。一般而言，突变酶的残留活性与疾病的临床严重程度密切相关。患有严重婴儿II型疾病的患者具有来自I组的突变，而患有轻度I型疾病的患者具有来自III组的至少一个突变。来自第二组的突变主要在具有中等临床严重程度的青少年II型患者中发现。总的来说，我们的研究结果解释了在唾液酸中毒中观察到的临床异质性，并可能有助于将现有或新的等位基因组合分配给特定的表型。
Lysosomal neuraminidase is the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates and is deficient in two neurodegenerative lysosomal disorders, sialidosis and galactosialidosis. Here we report the identification of eight novel mutations in the neuraminidase gene of 11 sialidosis patients with various degrees of disease penetrance. Comparison of the primary structure of human neuraminidase with the primary and tertiary structures of bacterial sialidases indicated that most of the single amino acid substitutions occurred in functional motifs or conserved residues. On the basis of the subcellular distribution and residual catalytic activity of the mutant neuraminidases we assigned the mutant proteins to three groups: (i) catalytically inactive and not lysosomal; (ii) catalytically inactive, but localized in lysosome; and (iii) catalytically active and lysosomal. In general, there was a close correlation between the residual activity of the mutant enzymes and the clinical severity of disease. Patients with the severe infantile type II disease had mutations from group I, whereas patients with a mild form of type I disease had at least one mutation from group III. Mutations from the second group were mainly found in juvenile type II patients with intermediate clinical severity. Overall, our findings explain the clinical heterogeneity observed in sialidosis and may help in the assignment of existing or new allelic combinations to specific phenotypes.