The human LARGE gene from 22q12,3-q13.1 is a new, distinct member of the glycosyltransferase gene family
The human LARGE gene from 22q12,3-q13.1 is a new, distinct member of the glycosyltransferase gene family
复制标题
DOI：
10.1073/pnas.96.2.598
复制
发表时间：
1999-01-19
影响因子：
11.1
通讯作者：
Dumanski, JP
中科院分区：
文献类型：
--
作者：
Peyrard, M;Seroussi, E;Dumanski, JP
脑膜瘤是一种覆盖中枢神经系统的脑膜肿瘤，常发生人类22号染色体的缺失。脑膜瘤中的纯合和杂合缺失确定了22q12.3-q13.1中>1 Mbp的候选区域，并指导我们在该区段进行基因克隆。我们的特点是N-乙酰氨基葡萄糖转移酶基因家族的一个新成员，大基因。它占据了超过664个酶，是人类最大的基因之一。由LARGE编码的预测的756-aa N-乙酰葡糖胺基转移酶显示在其他糖基转移酶中不存在的特征。人样乙酰葡糖胺转移酶多肽长得多，并含有推定的卷曲螺旋结构域。我们表征了小鼠LARGE直系同源物，其编码的蛋白质与人类对应物具有97.75%的同一性。如通过北方印迹分析和原位组织化学评估的，两种基因均显示普遍表达。小鼠基因的染色体定位显示小鼠染色体8 C1对应于人22 q12.3-q13.1。蛋白质和鞘糖脂的异常糖基化已被证明是肿瘤形成和/或进展潜力增加的机制。神经节苷脂GD 3（NellAc α 2，8 NeuAc α 2，3Gal β 1，4Glc-Cer）在脑膜瘤中过表达，其与22号染色体上的缺失相关。这是首次发现糖基转移酶基因参与肿瘤特异性基因组重排。人样乙酰葡糖胺转移酶蛋白的异常功能可能通过改变神经节苷脂的组成和/或通过对肿瘤细胞中其他糖基化分子的影响而与脑膜瘤的发生/进展相关。
Meningioma, a tumor of the meninges covering the central nervous system, shows frequent loss of material from human chromosome 22, Homozygous and heterozygous deletions in meningiomas defined a candidate region of >1 Mbp in 22q12.3-q13.1 and directed us to gene cloning in this segment. We characterized a new member of the N-acetylglucosaminyltransferase gene family, the LARGE gene. It occupies >664 kilobases and is one of the largest human genes. The predicted 756-aa N-acetylglucosaminyltransferase encoded by LARGE displays features that are absent in other glycosyltransferases. The human like-acetylglucosaminyltransferase polypeptide is much longer and contains putative coiled-coil domains. We characterized the mouse LARGE ortholog, which encodes a protein 97.75% identical with the human counterpart. Both genes reveal ubiquitous expression as assessed by Northern blot analysis and in situ histochemistry, Chromosomal mapping of the mouse gene reveals that mouse chromosome 8C1 corresponds to human 22q12.3-q13.1. Abnormal glycosylation of proteins and glycosphingolipids has been shown as a mechanism behind an increased potential of tumor formation and/or progression. Human tumors overexpress ganglioside GD3 (NellAc alpha 2,8NeuAc alpha 2,3Gal beta 1,4Glc-Cer), which in meningiomas correlates with deletions on chromosome 22, It is the first time that a glycosyltransferase gene is involved in tumor-specific genomic rearrangements. An abnormal function of the human like-acetylglucosaminyltransferase protein may be linked to the development/progression of meningioma by altering the composition of gangliosides and/or by effect(s) on other glycosylated molecules in tumor cells.