Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants
Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants
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DOI：
10.3390/jcm9030679
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发表时间：
2020-03-01
影响因子：
3.9
通讯作者：
Bembi, Bruno
中科院分区：
文献类型：
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作者：
Dardis, Andrea;Zampieri, Stefania;Bembi, Bruno
C型尼曼-皮克病（NPC）是一种由NPC 1或NPC 2基因突变引起的常染色体隐性溶酶体贮积病。2009年，44名意大利NPC患者的分子特征已经发表。在这里，我们提出了一个更新的105名意大利NPC患者的遗传学研究结果属于83个无关的家庭（77 NPC 1和6 NPC 2）。NPC 1和NPC 2基因的研究遵循最近发表的算法。84个不同的NPC 1和5个NPC 2等位基因被确定。只有两个NPC 1等位基因未检测到。62%的NPC 1等位基因是由于错义变异。最常见的NPC 1突变是p.F284Lfs*26（占等位基因的5.8%）。所有NPC 2突变均为纯合子状态，除一个突变外，其余均为重度突变。在新诊断的患者中，发现了18种新的NPC 1突变。通过菲律宾染色和NPC 1蛋白分析或患者成纤维细胞中的mRNA表达证实了7/9错义等位基因和3/4内含子变体的致病性。综上所述，我们以前发表的数据和新的结果提供了一个整体的图片，鼻咽癌患者的分子特征诊断到目前为止，在意大利。
Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). NPC1 and NPC2 genes were studied following an algorithm recently published. Eighty-four different NPC1 and five NPC2 alleles were identified. Only two NPC1 alleles remained non detected. Sixty-two percent of NPC1 alleles were due to missense variants. The most frequent NPC1 mutation was the p.F284Lfs*26 (5.8% of the alleles). All NPC2 mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel NPC1 mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient's fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy.