GENETICS OF FTD AND MOTOR NEURON DISEASE

额颞叶痴呆(FTD)是一种以早期行为改变、认知功能减退和额叶、颞叶萎缩为特征的异质性疾病。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%)确实在运动神经元中有泛素阳性包涵体，并显示有证据表明运动神经元变性(MND)导致其 指定为FTD-MND病例。在FTD家系中的遗传连锁研究发现，在17、3和9号染色体上有3个基因座。在大多数常染色体显性遗传的17-1号染色体连锁病例(FTDP-17)中，tau基因有30多个突变。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。最近，Hosler和他的同事报道了染色体9q21-22(chr.9q21-22)上的一个基因座，该基因座位于同时患有FTD和MND的家系中。这些家系的发病符合常染色体显性遗传模式。我们检查了我们自己的FTD-MND家系，也发现了与CHR上相同基因座连锁的证据。这些家庭中有9人。此外，我们对英格兰西北部的一系列家系进行了单倍型分析，建议在chr9q21-22上减少大约7 cM的临界区。本研究的总体目标是鉴定与CHr.9q21-22连锁的FTD-MND相关基因突变，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。

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.