The genetics of chromosome 17q21-linked tau-negative FTD

描述(由申请人提供)：额颞叶痴呆(FTD)是一种异质性疾病，以早期行为改变、认知能力下降和额叶和颞叶萎缩为特征。显微镜下的病理在不同类型的疾病中有明显的不同，有些病例中有tau阳性的神经元包涵体。然而，大多数FTD病例(约60%)缺乏tau阳性病变，主要表现为皮质浅层神经纤维的微空泡化。然而，这些病例中的一部分(10%-15%)在运动神经元中确实存在泛素阳性包涵体，并显示有运动神经元变性(MND)的证据，因此将其命名为FTD-MND病例。在FTD家系中的遗传连锁研究发现，在17号、3号和9号染色体上有三个基因座。在大多数常染色体显性遗传的17号染色体连锁病例(FTDP-17)中，tau基因的30多个突变是主要原因。发现tau突变的FTDP-17患者会出现tau神经纤维病变，许多家族还会在神经胶质细胞中出现tau包涵体。越来越清楚的是，一部分与染色体17q21连锁的家系缺乏tau基因的任何明显突变，而且确实具有在带有明确tau突变的家系中看到的神经原纤维病变。重要的是，这些染色体17q21连锁的家族表现出泛素阳性的神经元包涵体，在某些家系中也可以看到核内泛素阳性包涵体。这些家系的遗传原因可能是tau基因的一种未知突变，例如内含子深处，或tau基因的严重改变，如重复。或者，这种疾病可能是由该区域的另一种基因引起的。本研究的总体目标是鉴定与tau阴性的FTD相关的基因突变，并研究该基因突变的基因型/表型关系和致病机制。该基因的鉴定将是了解FTD的病因以及确定这种疾病与MND的关系的关键一步。

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a heterogeneous condition characterized by early behavioral change, cognitive decline and atrophy of the frontal and temporal lobes. The microscopic pathology varies markedly in different forms of the disease with some cases having tau-positive neuronal inclusions. However, the majority of FTD cases (approximately 60%) lack tau-positive lesions displaying mainly a microvacuolization of the superficial neuropil in the cortex. A proportion of these cases (10-15%) however do have ubiquitin-positive inclusions in motor neurons and show evidence of motor neuron degeneration (MND) leading to their designation as FTD-MND cases. Genetic linkage studies in FTD families have revealed three loci on chromosomes 17, 3 and 9. Over 30 mutations in the tau gene account for the majority of autosomal-dominant chromosome 17-linked cases (FTDP-17). FTDP-17 patients with identified tau mutations develop tau neurofibrillary pathology and many families also develop tau inclusions in glial cells. It is becoming increasingly clear that a proportion of chromosome 17q21-linked families lack any apparent mutations in the tau gene and, moreover, do possess the neurofibrillary pathology seen in families with defined tau mutations. Importantly, these chromosome 17q21-linked families exhibit ubiquitin positive neuronal inclusions, and a intranuclear ubiquitin positive inclusions are also seen in certain pedigrees. It is possible that the genetic cause of these families results from an unidentified mutation in the tau gene e.g. deep within an intron or from gross alterations of the tau locus, such as duplication. Alternatively, this disease could be caused by an alternative gene in this region. The overall aim of this proposal is to identify gene mutations associated with tau-negative FTD with neuronal and intranuclear ubiqutin positive inclusion linked to chr17q21 and to study the genotype/phenotype relationship and pathogenic mechanism of mutations in this gene. The identification of this gene will be a crucial step towards understanding the etiology of FTD as well as determining how this disease relates to MND.