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

描述（由申请方提供）：额颞叶痴呆（FTD）是一种异质性疾病，其特征为早期行为改变、认知下降和额叶和颞叶萎缩。显微镜病理学在不同形式的疾病中显著不同，一些病例具有tau阳性神经元包涵体。然而，大多数FTD病例（约60%）缺乏tau蛋白阳性病变，主要表现为皮质浅表神经元的微空泡化。然而，这些病例中的一部分（10-15%）在运动神经元中确实具有泛素阳性包涵体，并显示运动神经元变性（MND）的证据，导致其被指定为FTD-MND病例。在FTD家族中的遗传连锁研究揭示了17、3和9号染色体上的三个基因座。tau基因中超过30个突变占常染色体显性17连锁病例（FTDP-17）的大多数。具有鉴定的tau突变的FTDP-17患者发展tau神经病理学，并且许多家族还在神经胶质细胞中发展tau包涵体。越来越清楚的是，一部分染色体17 q21连锁家族在tau基因中缺乏任何明显的突变，而且确实具有在具有确定的tau突变的家族中观察到的神经病理学。重要的是，这些染色体17 q21连锁的家族表现出泛素阳性神经元包涵体，核内泛素阳性包涵体也见于某些家系。这些家族的遗传原因可能是由于tau基因中未识别的突变，例如内含子深处或tau基因座的总体改变，如重复。或者，这种疾病可能是由该区域的替代基因引起的。本提案的总体目的是鉴定与tau阴性FTD相关的基因突变，其中神经元和核内泛素阳性包涵体与chr 17 q21相关，并研究该基因突变的基因型/表型关系和致病机制。该基因的鉴定将是理解FTD病因以及确定该疾病与MND如何相关的关键一步。

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.