Department of Neurology, Toride Kyodo General Hospital, Toride City, Japan.
Eur J Neurol. 2011 Sep;18(9):1179-83. doi: 10.1111/j.1468-1331.2010.03311.x. Epub 2010 Dec 22.
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.
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.
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.
This is the first report of a Japanese NHD family caused by a splicing mutation of TREM2 that induces both neuroinflammation and neurodegeneration.
Nasu-Hakola 病（NHD）是一种罕见的常染色体隐性遗传病，其特征是进行性早发性痴呆和多灶性骨囊肿的形成，由 DAP12 和 TREM2 的基因突变引起，这些基因构成了表达在破骨细胞、树突状细胞、巨噬细胞和小胶质细胞上的受体/适配器信号复合物。以前没有报道过日本 TREM2 突变患者。
我们报道了一个日本家庭中三个受 NHD 影响的兄弟姐妹。其中，两名患者在四十多岁时死于 NHD。对存活患者的样本进行了基因组 DNA、cDNA 克隆和淋巴细胞蛋白的 western blot 分析。对一名患者的尸检大脑进行了转录组研究。
我们发现 TREM2 基因的剪接供体位点（c.482+2T>C）的第二个核苷酸 T 到 C 的纯合转换，导致外显子 3 跳过和截短蛋白的异常表达。我们在患者大脑中发现了 136 个上调的基因，涉及炎症反应和免疫细胞迁移，以及 188 个下调的基因，包括一系列 GABA 受体亚基和突触蛋白。
这是首例由 TREM2 剪接突变引起的日本 NHD 家族的报道，该突变可诱导神经炎症和神经退行性变。
