Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease
Expanding the genetic cause of multiple sulfatase deficiency: A novel SUMF1 variant in a patient displaying a severe late infantile form of the disease
复制标题
DOI：
10.1016/j.ymgme.2017.05.013
复制
发表时间：
2017-07-01
影响因子：
3.8
通讯作者：
Lugowska, Agnieszka
中科院分区：
文献类型：
--
作者：
Jaszczuk, Ilona;Schlotawa, Lars;Lugowska, Agnieszka
多发性硫酸酯酶缺乏症（MSD）是一种罕见的由细胞硫酸酯酶缺陷引起的遗传性代谢性疾病。磺化酶的活性依赖于由SUMF1基因编码的甲酰甘氨酸生成酶（FGE）催化的翻译后修饰。SUMF1病理变异引起MSD，这是一种具有复杂表型的综合征。我们描述了由尚未描述的病理变异引起的第一例波兰MSD患者。与已知缺失等位基因c.519 +5_519 + 8del杂合组合[p.Ala149_Ala173del]。患者最初临床表现为婴幼儿晚期偏色差性脑白质营养不良，以发育迟缓为最明显的临床症状，其次为视觉、听觉和运动能力的下降。鱼鳞病的短暂症状和轻微的畸形特征指导了实验室对MSD的检查。由于MSD是一种罕见的疾病，有一个可变的临床谱，我们彻底描述了我们的病人的临床结果。在细胞培养中表达的FGE- e113k变体正确定位于内质网，但与野生型FGE相比，它保留在细胞内。fge介导的永生化MSD细胞中类固醇硫酸酯酶的激活分析显示，FGE-E113K仅表现出大约。野生型FGE活性的15%。根据晶体结构，我们预测谷氨酸-113与赖氨酸的交换会引起二级结构的强烈不稳定，可能会影响C235-C346之间正确二硫桥接的折叠以及活性位点槽的扭曲，从而影响细胞内稳定性和FGE的活性。因此，SUMF1基因的新变异明显导致FGE蛋白功能受损，导致严重的晚期婴儿型MSD。(C) 2017爱思唯尔公司版权所有。
Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular sulfatases. Activity of sulfatases depends on post-translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G>A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c.519 +5_519 + 8del [p.Ala149_Ala173del]. The clinical picture of the patient initially suggested late infantile metachromatic leukodystrophy, with developmental delay followed by regression of visual, hearing and motor abilities as the most apparent clinical symptoms. Transient signs of ichthyosis and minor dysmorphic features guided the laboratory workup towards MSD. Since MSD is a rare disease and there is a variable clinical spectrum, we thoroughly describe the clinical outcome of our patient. The FGE-E113K variant, expressed in cell culture, correctly localized to the endoplasmic reticulum but was retained intracellularly in contrast to the wild type FGE. Analysis of FGE-mediated activation of steroid sulfatase in immortalized MSD cells revealed that FGE-E113K exhibited only approx. 15% of the activity of wild type FGE. Based on the crystal structure we predict that the exchange of glutamate-113 against lysine should induce a strong destabilization of the secondary structure, possibly affecting the folding for correct disulfide bridging between C235-C346 as well as distortion of the active site groove that could affect both the intracellular stability as well as the activity of FGE. Thus, the novel variant of the SUMF1 gene obviously results in functionally impaired FGE protein leading to a severe late infantile type of MSD. (C) 2017 Elsevier Inc. All rights reserved.