SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency
SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency
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DOI：
10.1038/ejhg.2010.219
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发表时间：
2011-03-01
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;Ennemann, Eva Charlotte;Gaertner, Jutta
多种硫酸酯酶缺乏症 (MSD) 是由编码甲酰甘氨酸生成酶 (FGE) 的硫酸酯酶修饰因子 1 基因突变引起的。 FGE 翻译后通过生成催化残基甲酰甘氨酸来激活所有新合成的硫酸酯酶。 FGE 功能受损会导致硫酸酯酶活性降低。患者表现出单一硫酸酯酶缺乏症的综合临床症状。对于 10 名 MSD 患者，我们确定了临床表型、FGE 表达、定位和稳定性，以及残余 FGE 和硫酸酯酶活性。两种无义突变的组合导致新生儿非常严重的临床表型，导致 FGE 活性几乎完全消除、FGE 蛋白高度不稳定和硫酸酯酶活性几乎检测不到。 FGE G263V 导致婴儿晚期轻度表型，导致蛋白质不稳定，但残余 FGE 活性较高。其他错义突变导致婴儿晚期严重表型，因为不稳定的蛋白质具有较低的残留 FGE 活性。具有相同突变的患者表现出相似的临床表型。这些数据证实了 MSD 的表型结果取决于残留 FGE 活性以及蛋白质稳定性的假设。预测分子特征突变的临床过程似乎是可行的，这将有助于遗传咨询和制定旨在增强 FGE 的治疗策略。欧洲人类遗传学杂志 (2011) 19, 253-261; doi：10.1038/ejhg.2010.219； 2011 年 1 月 12 日在线发布
Multiple Sulfatase Deficiency (MSD) is caused by mutations in the sulfatase-modifying factor 1 gene encoding the formylglycine-generating enzyme (FGE). FGE post translationally activates all newly synthesized sulfatases by generating the catalytic residue formylglycine. Impaired FGE function leads to reduced sulfatase activities. Patients display combined clinical symptoms of single sulfatase deficiencies. For ten MSD patients, we determined the clinical phenotype, FGE expression, localization and stability, as well as residual FGE and sulfatase activities. A neonatal, very severe clinical phenotype resulted from a combination of two nonsense mutations leading to almost fully abrogated FGE activity, highly unstable FGE protein and nearly undetectable sulfatase activities. A late infantile mild phenotype resulted from FGE G263V leading to unstable protein but high residual FGE activity. Other missense mutations resulted in a late infantile severe phenotype because of unstable protein with low residual FGE activity. Patients with identical mutations displayed comparable clinical phenotypes. These data confirm the hypothesis that the phenotypic outcome in MSD depends on both residual FGE activity as well as protein stability. Predicting the clinical course in case of molecularly characterized mutations seems feasible, which will be helpful for genetic counseling and developing therapeutic strategies aiming at enhancement of FGE. European Journal of Human Genetics (2011) 19, 253-261; doi:10.1038/ejhg.2010.219; published online 12 January 2011