Duarte-Pereira Sara, Silva Sarah S, Azevedo Luísa, Castro Luísa, Amorim António, Silva Raquel M
IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal.
1] IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal [2] Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal.
Sci Rep. 2014 Sep 9;4:6311. doi: 10.1038/srep06311.
Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase domain containing 1 (NAPRT1) are the main human NAD salvage enzymes. NAD regulates energy metabolism and cell signaling, and the enzymes that control NAD availability are linked to pathologies such as cancer and neurodegeneration. Here, we have screened normal and tumor samples from different tissues and populations of origin for mutations in human NAMPT and NAPRT1, and evaluated their potential pathogenicity. We have identified several novel polymorphisms and showed that NAPRT1 has a greater genetic diversity than NAMPT, where any alteration can have a greater functional impact. Some variants presented different frequencies between normal and tumor samples that were most likely related to their population of origin. The novel mutations described that affect protein structure or expression levels can be functionally relevant and should be considered in a disease context. Particularly, mutations that decrease NAPRT1 expression can predict the usefulness of Nicotinic Acid in tumor treatments with NAMPT inhibitors.
烟酰胺磷酸核糖转移酶（NAMPT）和含烟酸盐磷酸核糖转移酶结构域1（NAPRT1）是人类主要的NAD补救酶。NAD调节能量代谢和细胞信号传导，而控制NAD可用性的酶与癌症和神经退行性变等疾病相关。在此，我们对来自不同组织和起源人群的正常和肿瘤样本进行了筛查，以寻找人类NAMPT和NAPRT1中的突变，并评估其潜在致病性。我们鉴定出了几种新的多态性，并表明NAPRT1比NAMPT具有更大的遗传多样性，其中任何改变都可能产生更大的功能影响。一些变体在正常和肿瘤样本之间呈现出不同的频率，这很可能与其起源人群有关。所描述的影响蛋白质结构或表达水平的新突变可能具有功能相关性，在疾病背景下应予以考虑。特别是，降低NAPRT1表达的突变可以预测烟酸在使用NAMPT抑制剂进行肿瘤治疗中的有效性。
