Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency
Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency
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DOI：
10.1038/ejhg.2012.291
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发表时间：
2013-09-01
影响因子：
5.2
通讯作者：
Gaertner, Jutta
中科院分区：
文献类型：
--
作者：
Schlotawa, Lars;Radhakrishnan, Karthikeyan;Gaertner, Jutta
多发性硫酸酯酶缺乏症（MSD）是一种罕见的先天性代谢缺陷，影响甲酰基甘氨酸生成酶（FGE）对硫酸酯酶的翻译后激活。由于编码SUMF 1基因的突变，FGE的催化能力受损，导致细胞硫酸酯酶活性降低。FGE蛋白稳定性和残留活性两者都决定疾病的严重程度，并且先前已与临床MSD表型相关。在这里，我们报告一个病人与晚期婴儿严重的病程。该患者是两个迄今未描述的SUMF 1突变的复合杂合子，c.156delC（p.C52fsX57）和c.390A>T（p.E130D）。在患者成纤维细胞中，移码等位基因的mRNA不可检测。相反，表达编码FGE-E130 D的等位基因。FGE-E130 D正确定位于内质网，并在体外具有非常高的残留分子活性（野生型FGE的55%）;然而，它会迅速降解。因此，尽管有大量的残留酶活性，蛋白质的不稳定性决定了疾病的严重程度，这突出表明，潜在的MSD治疗方法应该靶向蛋白质折叠和稳定机制。
Multiple sulfatase deficiency (MSD) is a rare inborn error of metabolism affecting posttranslational activation of sulfatases by the formylglycine generating enzyme (FGE). Due to mutations in the encoding SUMF1 gene, FGE's catalytic capacity is impaired resulting in reduced cellular sulfatase activities. Both, FGE protein stability and residual activity determine disease severity and have previously been correlated with the clinical MSD phenotype. Here, we report a patient with a late infantile severe course of disease. The patient is compound heterozygous for two so far undescribed SUMF1 mutations, c.156delC (p.C52fsX57) and c.390A>T (p.E130D). In patient fibroblasts, mRNA of the frameshift allele is undetectable. In contrast, the allele encoding FGE-E130D is expressed. FGE-E130D correctly localizes to the endoplasmic reticulum and has a very high residual molecular activity in vitro (55% of wildtype FGE); however, it is rapidly degraded. Thus, despite substantial residual enzyme activity, protein instability determines disease severity, which highlights that potential MSD treatment approaches should target protein folding and stabilization mechanisms.