Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene.
Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene.
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DOI：
10.1002/humu.9504
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发表时间：
2007-09-01
期刊：
影响因子：
3.9
通讯作者：
Ballabio, Andrea
中科院分区：
文献类型：
--
作者：
Annunziata, Ida;Bouche, Valentina;Ballabio, Andrea
硫酸酯酶催化来自多种底物的硫酸酯键的水解，并且与几种人类遗传性疾病有关。多发性硫酸酯酶缺乏症（MSD）是一种罕见的常染色体隐性遗传疾病，其特征是所有已知的硫酸酯酶同时缺乏。MSD由编码α-甲酰甘氨酸生成酶（FGE）的硫酸酯酶修饰因子1（SUMF 1）基因突变引起，该酶负责硫酸酯酶的翻译后修饰。在所有MSD患者中，可检测到不同水平的残余硫酸酯酶活性。为了将在MSD患者中检测到的残余硫酸酯酶活性的性质与残余FGE活性相关联，分析了在MSD患者中纯合性中发现的四种FGE突变体（即p.S155P、p.R224W、p.R345C、p.R349W）。使用病毒介导的基因传递，这些突变体在小鼠胚胎成纤维细胞（MEFs）从最近开发的Sumf 1 KO小鼠系，这是完全没有所有硫酸酯酶的活动过度表达。所获得的结果表明，突变体SUMF 1 cDNA编码稳定的SUMF 1蛋白，其具有适当的分子量，并适当地定位于内质网中。这些cDNA在Sumf 1-/- MEFs中的表达导致硫酸酯酶活性的部分拯救。这些数据表明，MSD是由于亚型SUMF 1突变，并表明SUMF 1功能的完全丧失可能是致命的人类。
Sulfatases catalyze the hydrolysis of sulfate ester bonds from a wide variety of substrates and are implicated in several human inherited diseases. Multiple sulfatase deficiency (MSD) is a rare autosomal recessive disorder characterized by the simultaneous deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the alpha-formylglycine generating enzyme (FGE), which is responsible for the post-translational modification of sulfatases. In all MSD patients, residual sulfatase activities are detectable, at variable levels. To correlate the nature of the residual sulfatase activities detected in MSD patients with residual FGE activity, four FGE mutants (i.e. p.S155P, p.R224W, p.R345C, p.R349W) found in homozygosis in MSD patients were analyzed. Using viral-mediated gene delivery, these mutants were over-expressed in mouse embryonic fibroblasts (MEFs) from a recently developed Sumf1 KO mouse line which is completely devoid of all sulfatase activities. The results obtained indicate that mutant SUMF1 cDNAs encode stable SUMF1 proteins which are of the appropriate molecular weight and are properly localized in the endoplasmic reticulum. Expression of these cDNAs in Sumf1-/- MEFs results in partial rescue of sulfatase activities. These data indicate that MSD is due to hypomorphic SUMF1 mutations and suggest that complete loss of SUMF1 function is likely to be lethal in humans.