Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family
Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family
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DOI：
10.1111/j.1468-1331.2010.03311.x
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发表时间：
2011-09-01
影响因子：
5.1
通讯作者：
Satoh, J. -I.
中科院分区：
文献类型：
--
作者：
Numasawa, Y.;Yamaura, C.;Satoh, J. -I.
背景：Nasu-Hakola病(NHD)是一种罕见的常染色体隐性遗传病，其特征是进行性老年期痴呆和多灶性骨囊肿的形成，由DAP12和TREM2基因突变引起，DAP12和TREM2是表达在破骨细胞、树突状细胞、巨噬细胞和小胶质细胞上的受体/适配器信号复合体。以前没有报道过日本的TREM2突变患者。其中，两人在生命的第四个十年期间死于NHD。对患者活体标本进行基因组DNA分析、DNA克隆和淋巴细胞蛋白免疫印迹分析。结果：我们在TREM2基因剪接供体共有位点(c.482+2T>；C)内含子3的第二个位置发现了单核苷酸T到C的纯合子转换，导致外显子3的跳跃和截断蛋白的异常表达。我们在患者脑中发现了136个与炎症反应和免疫细胞转运有关的上调基因和188个下调基因，其中包括一组GABA受体亚单位和突触蛋白。结论：这是首次报道由TREM2剪接突变引起的日本NHD家族，该突变同时导致神经炎症和神经变性。
Background: Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by a combination of progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of DAP12 and TREM2, which constitute a receptor/adapter signaling complex expressed on osteoclasts, dendritic cells, macrophages, and microglia. No Japanese patients with TREM2 mutations have been reported previously.Methods: We reported three siblings affected with NHD in a Japanese family. Amongst them, two died of NHD during the fourth decade of life. The analysis of genomic DNA, cDNA cloning, and western blot of lymphocyte proteins was performed on samples of the living patient. The transcriptome was studied in the autopsied brain of one patient.Results: We identified a homozygous conversion of a single nucleotide T to C at the second position of intron 3 in the splice-donor consensus site (c.482+2T>C) of the TREM2 gene, resulting in exon 3 skipping and aberrant expression of truncated proteins. We identified 136 upregulated genes involved in inflammatory response and immune cell trafficking and 188 downregulated genes including a battery of GABA receptor subunits and synaptic proteins in the patient's brain.Conclusions: This is the first report of a Japanese NHD family caused by a splicing mutation of TREM2 that induces both neuroinflammation and neurode-generation.