First pilot newborn screening for four lysosomal storage diseases in an Italian region: Identification and analysis of a putative causative mutation in the GBA gene
First pilot newborn screening for four lysosomal storage diseases in an Italian region: Identification and analysis of a putative causative mutation in the GBA gene
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DOI：
10.1016/j.cca.2012.07.011
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发表时间：
2012-11-20
影响因子：
5
通讯作者：
Beccari, Tommaso
中科院分区：
文献类型：
--
作者：
Paciotti, Silvia;Persichetti, Emanuele;Beccari, Tommaso
我们报告了意大利地区首次新生儿筛查四种溶酶体疾病的试点研究，包括庞贝病、戈谢病、法布里病和粘多糖病1型。在滤纸上用酶促法对干血斑进行筛选。对3403名新生儿进行了筛查。一名新生儿白细胞中β -葡萄糖苷酶活性降低。分子分析显示，突变N370S和序列变异E388K为复合杂合状态，与戈歇病发病尚无相关性。通过体外表达评估E388K替代对β -葡萄糖苷酶活性的功能影响，结果表明突变蛋白保留了野生型活性的48%。结构模型预测，定位于酶表面的E388K替代物将改变局部电荷分布，在天然蛋白质中，显示出压倒性的负电荷存在。然而，新生儿和一个4岁的妹妹显示出相同的基因组改变，目前没有症状。这种新生儿溶酶体疾病的试点筛查似乎是可行和负担得起的，可以推广到大量人口。此外，其他已有或即将有治疗方法的溶酶体疾病也可纳入筛查范围。(C) 2012 Elsevier B.V.版权所有
We report the first newborn screening pilot study in an Italian region for four lysosomal disorders including Pompe disease, Gaucher disease, Fabry disease and mucopolysaccharidosis type 1.The screening has been performed using enzymatic assay on Dry Blood Spot on filter paper. A total of 3403 newborns were screened. One newborn showed a reduction of beta-glucosidase activity in leucocytes. Molecular analysis revealed a status of compound heterozygous for the panethnic mutation N370S and for the sequence variation E388K, not yet correlated to Gaucher disease onset. The functional consequences of the E388K replacement on beta-glucosidase activity were evaluated by in vitro expression, showing that the mutant protein retained 48% of wild type activity. Structural modeling predicted that the E388K replacement, localized to a surface of the enzyme, would change the local charges distribution which, in the native protein, displays an overwhelming presence of negative charges. However, the newborn, and a 4 year old sister showing the same genomic alterations, are currently asymptomatic.This pilot newborn screening for lysosomal diseases appears to be feasible and affordable to be extended to large populations. Moreover other lysosomal diseases for which a therapy is available or will be available, could be included in the screening. (C) 2012 Elsevier B.V. All rights reserved.