Genetics of Frontotemporal Dementia (FTD) and Motor Neuron Disease

额颞叶痴呆 (FTD) 和运动神经元疾病的遗传学

• 批准号: 7425014
• 负责人: MICHAEL L. HUTTON
• 金额: $ 18.16万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7425014
• 关键词: 9q21; Accounting; Affect; Animal Model; Atrophic; Behavioral; Candidate Disease Gene; Cells; Chromosomes; Chromosomes, Human, Pair 17; Clinic; Clinical; Collaborations; Condition; Dementia; Disease; Disease Progression; Doctor of Philosophy; England; Etiology; FTD with parkinsonism; Family; Frequencies; Frontotemporal Dementia; Gene Mutation; Generations; Genes; Genetic; Genetic Crossing Over; Genotype; Haplotypes; Histopathology; Impaired cognition; Individual; Inheritance Patterns; Lesion; Link; Linkage Disequilibrium Mapping; Microscopic; Modeling; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Nature; Neurofibrillary Tangles; Neuroglia; Neurons; Neuropil; Nucleic Acid Regulatory Sequences; Pathology; Patients; Phenotype; Prevalence; Range; Reporting; Research Personnel; Role; Series; Temporal Lobe; Transgenic Animals; Transgenic Organisms; Ubiquitin; experience; genetic linkage; member; motor neuron degeneration; mouse model; programs; segregation; tau Proteins; tau mutation

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.

额叶痴呆（FTD）是一种异质状况，其特征是早期行为变化，额叶和颞叶的萎缩。显微镜病理学在不同形式的疾病中明显变化，某些情况有tau阳性神经元包含物。然而，大多数FTD病例（约60％）缺乏tau阳性病变，主要显示皮质中浅表神经胶质的微伏型。但是，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夹杂物，并显示了运动神经元变性（MND）的证据 称为FTD-MND情况。 FTD家族中的遗传连锁研究揭示了染色体17、3和9的三个基因座。tau基因中的30多个突变占大多数常染色体染色体17-111键病例（FTDP-17）。 FTDP-17鉴定出Tau突变的患者会发展出TAU神经原纤维病理，许多家庭也会在神经胶质细胞中发展tau夹杂物。最近，Hosler及其同事在患有FTD和MND的受影响成员的家庭中报道了染色体9q21-22（Chr.9Q21-22）上的一个基因座（CHR.9Q21-22）。这些家族中该疾病的发生与常染色体显性遗传模式一致。我们已经检查了自己的FTD-MND家庭，还发现了与Chr上同一基因座有联系的证据。 9在这些家庭中。此外，我们在来自英格兰西北部的一系列家庭中使用了单倍型分析，以表明CHR9Q21-22上的大约7 cm关键区域减少了。该提案的总体目的是确定与Chr.9Q21-22相关的FTD-MND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。该基因的鉴定将是理解FTD病因的关键步骤，并确定该疾病与MND的关系。