ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy
ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy
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DOI：
10.1093/hmg/ddi169
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发表时间：
2005-06-15
影响因子：
3.5
通讯作者：
Noebels, JL
中科院分区：
文献类型：
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作者：
Senechal, KR;Thaller, C;Noebels, JL
LGI 1的突变与常染色体显性部分性癫痫伴听觉特征（ADPEAF）有关，ADPEAF是一种不寻常的遗传性人类部分性癫痫表型。此外，在胶质母细胞瘤患者样品和胶质母细胞瘤细胞系中观察到LGI 1表达的降低。LGI 1是LGI基因家族的成员之一，编码类似于63 kDa的蛋白，在颞叶内的神经元中具有强的区域表达。虽然LGI蛋白的功能仍然未知，但结构分析表明LGI 1可以定位于膜或分泌。在这里，我们表明，LGI 1 -4表现出重叠模式的扩散mRNA表达在成年小鼠大脑中，与每个家庭成员的特定定位特征的一些领域。我们发现小鼠LGI 1蛋白在转染到293 T细胞后分泌旺盛。LGI家族成员，LGI 3，LGI 4和新鉴定的LGI 2剪接形式，LGI 2B，也在培养物中分泌，表明分泌是该蛋白质家族的保守特征。在LGI 1中引入突变，包括在ADPEAF家系中鉴定的突变，揭示了突变蛋白要么不分泌要么不稳定。这些结果表明，功能丧失是LGI 1介导的ADPEAF的致病基础。
Mutations in LGI1 have been linked to autosomal dominant partial epilepsy with auditory features (ADPEAF), an unusual inherited human partial epilepsy phenotype. In addition, decreases in LGI1 expression are observed in glioblastoma patient samples and glioblastoma cell lines. LGI1, one member of the LGI gene family, encodes a similar to 63 kDa protein, with strong regional expression in neurons within the temporal lobe. Although the function of LGI proteins remains unknown, structural analyses suggest that LGI1 could be either localized to the membrane or secreted. Here, we show that LGI1-4 exhibit overlapping patterns of diffuse mRNA expression in the adult mouse brain, with some areas of specific localization characteristic of each family member. We find robust secretion of mouse LGI1 protein following transfection into 293T cells. LGI family members, LGI3, LGI4 and a newly identified splice form of LGI2, LGI2B, are also secreted in culture, indicating that secretion is a conserved feature of this protein family. Introduction of mutations in LGI1, including those identified in ADPEAF pedigrees, reveals that the mutant proteins either are not secreted or are unstable. These results demonstrate loss-of-function as a pathogenic basis for LGI1-mediated ADPEAF.