Mutations in TREM2 Lead to Pure Early-Onset Dementia Without Bone Cysts
Mutations in TREM2 Lead to Pure Early-Onset Dementia Without Bone Cysts
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DOI：
10.1002/humu.20836
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发表时间：
2008-09-01
期刊：
影响因子：
3.9
通讯作者：
Megarbane, Andre
中科院分区：
文献类型：
--
作者：
Chouery, Eliane;Delague, Valerie;Megarbane, Andre
使用382个STR标记进行全基因组筛选，以定位和识别与黎巴嫩一个有三名受影响受试者的无骨囊肿早发性痴呆（EOD）有关的基因。在染色体6p21.2位点上发现了一个独特的遗传纯合位点。通过荧光测序探索候选基因，并通过定性和定量RT-PCR证实所鉴定的突变的影响。基因分析揭示了TREM 2基因内含子1的5'共有供体剪接位点中的一种新的缺失，c.40+3delAGG，已知该缺失导致PLOSL（多囊脂膜性骨发育不良伴硬化性白质脑病），也称为Nasu-Hakola病。计算机模拟分析预测新供体剪接位点的强度较低。定性RT-PCR显示正常的转录本，而定量RT-PCR显示TREM 2转录本的两倍以上下调。研究了已知在TREM 2缺陷样品中被破坏的六种基因SPP 1、NEDD 9、FSCN、BCL 3、NFKBIA和CCL 2的表达谱，并且显示出与TREM 2突变样品相同的表达谱，除了正常调节的CCL 2。我们的患者中TREM 2的表达显著降低，并且所研究的六种基因的表达谱证实了TREM 2在这种不具有骨囊肿的EOD的独特表型中的作用。据我们所知，这是第一次报告TREM 2突变导致纯粹的痴呆症。(C)2008 Wiley-Liss，Inc.
A genome-wide screen using 382 STR markers to localize and identify the gene implicated in early-onset dementia (EOD) without bone cysts in a Lebanese family with three affected subjects was conducted. A unique locus homozygous by descent at chromosome 6p21.2 locus was identified. Candidate genes were explored by fluorescent sequencing and the effect of the identified mutation was confirmed by qualitative and quantitative RT-PCR. The genetic analysis revealed a novel deletion, c.40+3delAGG, in the 5' consensus donor splice site in intron 1 of TREM2 gene which is known to be responsible for PLOSL (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy) also designated as Nasu-Hakola disease. In silico analysis predicted a lower strength for the novel donor splice site. Qualitative RT-PCR revealed normal transcript while quantitative RT-PCR showed over twofold down-regulation of TREM2 transcripts. The expression profile of six genes SPP1, NEDD9, FSCN, BCL3, NFKBIA and CCL2 known as disrupted in TREM2-deficient samples was studied and showed same expression profile as TREM2-mutated samples except for CCL2 which was normally regulated. The significantly-reduced expression of TREM2 in our patients and the expression profiles of the six studied genes confirm a role for TREM2 in this distinct phenotype of EOD without bone cysts. To our knowledge, this is the first report of mutations in TREM2 causing a pure dementia. (C) 2008 Wiley-Liss, Inc.