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首页> 外文期刊>Nature >Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
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Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

机译：前颗粒蛋白中的无效突变会导致泛素阳性额颞叶痴呆，与染色体17q21相关

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摘要

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.
机译：具有未知性质的遍在蛋白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）已与含有MAPT（微管相关蛋白tau）（1-3）的染色体17q21区（FTDU-17）相关联。 FTDU-17患者一直被证明缺乏tau免疫反应性病理（1-3），这是FTD的特征，其帕金森病与MAPT突变有关（FTDP-17）（4）。此外，在FTDU-17患者中，基因组测序（5）和机械拉伸染色体上的荧光原位杂交都排除了MAPT中的突变和MAPT区中的基因组重排（6）。在这里，我们证明FTDU-17是由编码前颗粒蛋白（PGRN）的基因突变引起的，PGRN是一种涉及多种生理和病理过程（包括肿瘤发生）的生长因子（7）。除了由于终止密码子过早而产生截短的PGRN蛋白外，我们还发现内含子0的剪接供体位点内有一个突变（IVS0 + 5G> C），表明该突变体转录本因核降解而丢失。这项发现是在广泛记录的比利时FTDU-17创始人家族中做出的（3）。转录本和蛋白质分析证实了突变等位基因的缺失和PGRN表达的降低。我们还确定了Met1翻译起始密码子中的突变（c。3G> A），表明由于缺少突变等位基因的翻译而导致PGRN丢失。我们的数据提供了证据，表明PGRN单倍剂量不足会导致PGRN介导的神经元存活减少，从而导致神经变性。此外，在比利时的一系列家族性FTD患者中，PGRN突变的频率比MAPT中突变的频率高3.5倍，这说明PGRN在FTD发病机理中的主要参与。

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  • 来源
    《Nature》 |2006年第7105期|p. 920-924|共5页
  • 作者

    Cruts M; Gijselinck I; van der Zee J; Engelborghs S; Wils H; Pirici D; Rademakers R; Vandenberghe R; Dermaut B; Martin JJ;

  • 作者单位

    Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, BE-2610 Antwerp, Belgium;

    Inst Born Bunge, Neurogenet Lab, BE-2610 Antwerp, Belgium;

    Inst Born Bunge, Lab Neurochem & Behav, BE-2610 Antwerp, Belgium;

    Inst Born Bunge, Neuropathol Lab, BE-2610 Antwerp, Belgium;

    Univ Antwerp, BE-2610 Antwerp, Belgium;

    Middleheim Gen Hosp, Dept Neurol, Memory Clin, BE-2610 Antwerp, Belgium;

    Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Pathol, BE-3000 Louvain, Belgium;

    Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Neurol, BE-3000 Louvain, Belgium;

    Univ Ghent, State Univ Ghent Hosp, Dept Neurol, BE-9000 Ghent, Belgium;

    Erasmus Med Ctr Rotterdam, Dept Epidemiol & Biostat, Genet Epidemiol Grp, NL-3000 DR Rotterdam, Netherlands;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自然科学总论;
  • 关键词

    VALOSIN-CONTAINING PROTEIN; GROWTH-FACTOR; LOBAR DEGENERATION; PICKS-DISEASE; TAU; INCLUSIONS; EXPRESSION; GRANULIN; FAMILY; GENE;

    机译：含缬氨酸的蛋白;生长因子;肺退化;斑点病;TAU;包涵体;表达;粒蛋白;家族;基因;

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