Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p
Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p
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DOI：
10.1007/s00415-010-5815-x
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发表时间：
2011-04-01
影响因子：
6
通讯作者：
Morris, Huw R.
中科院分区：
文献类型：
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作者：
Pearson, Justin P.;Williams, Nigel M.;Morris, Huw R.
常染色体显性遗传额颞叶痴呆和肌萎缩侧索硬化症(FTD/ALS)家族以前曾被连接到染色体9p21上的一个基因座。我们描述了一个常染色体显性遗传性FTD/ALS大家庭的临床表型和病理，该家系有9名成员，来自英国南威尔士的格温特。我们还利用单倍型共享方法进一步提炼了染色体9p21上的基因座，并评估了9p21连锁家系的异质性。在这个家庭中，受影响的个人同时患有FTD或ALS或同时患有这两种疾病。此外，还有明显的表型变异，包括共济失调、帕金森症、精神病和视觉空间认知缺陷。所描述的三个病例的病理特征与之前在类似家系中报道的2型FTD病理一致。然而，我们也报告了独特的小脑和神经胶质病理和相当大比例的TDP-43阴性包涵体。未发现FTD或ALS的已知基因突变。我们在9p21号染色体上发现了一个4.8兆碱基的大单倍型，所有受影响的家庭成员都有这个单倍型。该单倍型与先前报道的染色体9p21上的FTD/ALS连锁区重叠并受到限制。对该区域的测序没有发现任何致病外显子突变的证据。这表明致病改变影响非编码DNA，疾病是由基因或蛋白质表达的变化引起的。
Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression.