Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
复制标题
DOI：
10.1038/nature05016
复制
发表时间：
2006-08-24
期刊：
影响因子：
64.8
通讯作者：
Hutton, Mike
中科院分区：
文献类型：
--
作者：
Baker, Matt;Mackenzie, Ian R.;Hutton, Mike
额颞叶痴呆（FTD）是65岁以下人群中第二常见的痴呆病因（1）。很大比例的FTD患者（35 - 50%）有痴呆家族史，这与该疾病具有很强的遗传因素相符（2）。1998年，编码微管相关蛋白tau（MAPT）的基因发生突变被证明可导致与17q21号染色体相关的伴有帕金森综合征的家族性额颞叶痴呆（FTDP - 17）（3）。具有明确MAPT突变的患者的神经病理学特征是由过度磷酸化的tau组成的细胞质神经原纤维缠结（3,4）。然而，在多个有明显证据表明与17q21号染色体同一区域（D17S1787 - D17S806）存在连锁的FTD家族中，未发现MAPT突变，且患者始终缺乏tau免疫反应性包涵体病理改变（5 - 12）。相反，这些患者具有泛素（ub）免疫反应性神经元细胞质包涵体和特征性的透镜状泛素免疫反应性神经元核内包涵体（11 - 13）。在此我们证明，在这些家族中，FTD是由颗粒蛋白前体（PGRN）的突变引起的，这些突变可能产生无效等位基因。PGRN位于17q21.31号染色体上MAPT着丝粒方向1.7 Mb处，编码一种68.5 kDa的分泌型生长因子，参与包括发育、伤口修复和炎症等多种过程的调节（14）。PGRN还与肿瘤发生密切相关（14）。此外，在许多神经退行性疾病包括克雅氏病、运动神经元疾病和阿尔茨海默病中，活化的小胶质细胞中PGRN表达增加（15,16）。我们的研究结果确定PGRN突变是神经退行性疾病的一个病因，并表明PGRN功能对神经元存活的重要性。
Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years(1). A large proportion of FTD patients ( 35 - 50%) have a family history of dementia, consistent with a strong genetic component to the disease(2). In 1998, mutations in the gene encoding the microtubule-associated protein tau ( MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP- 17)(3). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau(3,4). However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787 - D17S806), mutations in MAPT have not been found and the patients consistently lack tauimmunoreactive inclusion pathology(5-12). In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions(11-13). Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation(14). PGRN has also been strongly linked to tumorigenesis(14). Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt - Jakob disease, motor neuron disease and Alzheimer's disease(15,16). Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.