Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
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DOI：
10.1038/nature05017
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发表时间：
2006-08-24
期刊：
影响因子：
64.8
通讯作者：
Van Broeckhoven, Christine
中科院分区：
文献类型：
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作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
具有未知性质泛素免疫反应性神经元包涵体（细胞质和细胞核）的额颞叶痴呆（FTD）与含有MAPT（微管相关蛋白tau）的染色体17q21区域（FTDU-17）有关（1-3）。FTDP-17患者一直被证明缺乏tau免疫反应性病理（1-3），这是与MAPT突变（FTDP-17）相关的FTD伴帕金森病的特征(4)。此外，在FTDU-17患者中，通过基因组测序(5)和机械拉伸染色体的荧光原位杂交(6)，排除了MAPT突变和MAPT区域的基因组重排。在这里，我们证明FTDU-17是由前颗粒蛋白（PGRN）基因编码突变引起的，PGRN是一种参与多种生理和病理过程的生长因子，包括肿瘤发生(7)。除了由于过早终止密码子产生截断的PGRN蛋白外(8)，我们还在内含子0的剪接供体位点（IVS0+5G> C）发现了一个突变，表明突变转录物因核降解而丢失。这一发现是在广泛记录的比利时FTDU-17创始人家族中得出的(3)。转录和蛋白质分析证实了突变等位基因的缺失和PGRN表达的减少。我们还在Met1翻译起始密码子中发现了一个突变（c. 3G> a），表明由于缺乏突变等位基因的翻译而导致PGRN的丢失。我们的数据提供了证据，证明PGRN单倍体功能不全导致神经退行性变，因为PGRN介导的神经元存活减少。此外，在比利时的一系列家族性FTD患者中，PGRN突变的频率是MAPT突变的3.5倍，强调了PGRN在FTD发病机制中的主要参与。
Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions ( both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau)(1-3). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology(1-3), a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17)(4). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing(5) and fluorescence in situ hybridization on mechanically stretched chromosomes(6). Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis(7). Besides the production of truncated PGRN proteins due to premature stop codons(8), we identified a mutation within the splice donor site of intron 0 (IVS0+5G> C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family(3). Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation ( c. 3G>A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.