GENETICS OF FTD AND MOTOR NEURON DISEASE

额颞叶痴呆（FTD）是一种异质性疾病，其特征是早期行为改变、认知能力下降以及额叶和颞叶萎缩。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，导致其神经元变性。 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基因的30多个突变导致了大多数常染色体显性17- 1连锁病例（FTDP-17）。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。最近，Hosler及其同事在FTD和MND患者家族中报告了染色体9 q21 -22（chr.9q21-22）上的一个位点。在这些家庭中发生的疾病是符合常染色体显性遗传模式。我们已经检查了我们自己的家庭FTD-MND，也发现了连锁的证据，在这些家庭中的同一位点上的第9染色体。此外，我们已经使用了单倍型分析，在一系列的家庭从英格兰西北部建议减少约7厘米的关键区域chr 9 q21 -22。本提案的总体目标是鉴定与FTD-MND相关的基因突变，并研究该基因中突变的基因型/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。

Fronto-temporal 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 17-1inked cases (FTDP-17). FTDP-17 patients with identified tau mutations develop tau neurofibrillary pathology and many families also develop tau inclusions in glial cells. Recently a locus on chromosome 9q21-22 (chr.9q21-22) was reported by Hosler and colleagues in families with affected members with both FTD and MND. The occurrence of the disease in these families is consistent with an autosomal dominant pattern of inheritance. We have examined our own families with FTD-MND and have also found evidence of linkage to the same locus on chr. 9 in these families. In addition, we have used haplotype analysis in a series of families from Northwest England to suggest a reduced approximate 7 cM critical region on chr9q21-22. The overall aim of this proposal is to identify gene mutations associated with FTD-MND linked to chr.9q21-22 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.