Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-l-fucosidase (FUCA1) activity, leading to the accumulation of fucose-containing glycolipids and glycoproteins in various tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex. All exons and flanking intron regions of FUCA1 were screened by direct sequencing to identify mutations and polymorphisms in three unrelated families with fucosidosis. Bioinformatics tools were then used to predict the impacts of novel alterations on the structure and function of proteins. Furthermore, the identified mutations were localized onto a 3D structure model using the DeepView Swiss-PdbViewer 4.1 software, which established a function-structure relationship of the FUCA1 proteins. Four novel mutations were identified in this study. Two patients (P1 and P2) in Families 1 and 2 who had the severe phenotype were homoallelic for the two identified frameshift mutations p.K57Sfs*75 and p.F77Sfs*55, respectively. The affected patient (P3) from Family 3, who had the milder phenotype, was heterozygous for the novel missense mutation p.G332E and the novel splice site mutation c.662+5g>c. We verified that this sequence variation did not correspond to a polymorphism by testing 50 unrelated individuals. Additionally, 16 FUCA1 polymorphisms were identified. The structure prediction analysis showed that the missense mutation p.G332E would probably lead to a significant conformational change, thereby preventing the expression of the FUCA1 protein indeed; the 3D structural model of the FUCA1 protein reveals that the glycine at position 332 is located near a catalytic nucleophilic residue. This makes it likely that the enzymatic function of the protein with p.G332E is severely impaired. These are the first FUCA1 mutations identified in Tunisia that cause the fucosidosis disease. Bioinformatics analysis allowed us to establish an approximate structure–function relationship for the FUCA1 protein, thereby providing better genotype/phenotype correlation knowledge.

中文翻译：

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突尼斯患者的岩藻糖苷沉积症：FUCA1 酶的突变分析和基于同源性的建模


岩藻糖苷贮积症是一种常染色体隐性遗传性溶酶体贮积病，由α-L-岩藻糖苷酶（FUCA1）活性缺陷引起，导致含岩藻糖的糖脂和糖蛋白在各种组织中积聚。临床特征包括血管角化瘤、进行性精神运动迟缓、神经系统体征、粗糙的面部特征和多发性骨发育不全。通过直接测序筛选 FUCA1 的所有外显子和侧翼内含子区域，以鉴定三个不相关的岩藻糖苷沉积症家族的突变和多态性。然后使用生物信息学工具来预测新的改变对蛋白质结构和功能的影响。此外，使用 DeepView Swiss-PdbViewer 4.1 软件将识别出的突变定位到 3D 结构模型上，从而建立了 FUCA1 蛋白的功能-结构关系。这项研究发现了四种新的突变。家系 1 和家系 2 中具有严重表型的两名患者（P1 和 P2）分别与两个已确定的移码突变 p.K57Sfs*75 和 p.F77Sfs*55 具有同等位基因。来自家族3的受影响患者（P3）具有较温和的表型，其为新错义突变p.G332E和新剪接位点突变c.662+5g>c的杂合子。我们通过测试 50 个不相关的个​​体来验证该序列变异并不对应于多态性。此外，还鉴定出 16 个 FUCA1 多态性。结构预测分析表明，错义突变p.G332E可能会导致显着的构象变化，从而确实阻止FUCA1蛋白的表达； FUCA1 蛋白的 3D 结构模型表明，第 332 位的甘氨酸位于催化亲核残基附近。 这使得 p.G332E 蛋白的酶功能可能受到严重损害。这是在突尼斯发现的第一个导致岩藻糖苷沉积症的 FUCA1 突变。生物信息学分析使我们能够建立 FUCA1 蛋白的近似结构-功能关系，从而提供更好的基因型/表型相关知识。