Mackenzie Ian R, Butland Stefanie L, Devon Rebecca S, Dwosh Emily, Feldman Howard, Lindholm Caroline, Neal Scott J, Ouellette B F Francis, Leavitt Blair R
Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
BMC Neurol. 2006 Aug 31;6:32. doi: 10.1186/1471-2377-6-32.
Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease.
We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII.
No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity.
We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.
许多额颞叶痴呆（FTD）病例为家族性，通常呈常染色体显性遗传模式。一些病例是由于17号染色体上编码tau的基因突变，脑组织中出现异常tau蛋白聚集（FTDP - 17T）。其余大多数家族性病例未表现出tau蛋白病理改变，但显示出与痴呆和运动神经元病患者相似的神经病理学特征，其特点是新皮层和海马中存在泛素免疫反应性（ub - ir）、营养不良性神经突和神经元胞质内含物（FTLD - U）。最近，我们描述了一组家族性FTD患者，尸检证实有FTLD - U病理改变，并且还发现了ub - ir神经元核内包涵体（NII）。NII是其他几种神经退行性疾病的特征性表现，这些疾病的遗传基础是编码多聚谷氨酰胺的三核苷酸重复区域异常扩增。目前尚不清楚家族性FTLD - U的遗传基础，然而NII的存在提示部分病例可能代表一种多聚谷氨酰胺扩增疾病。
我们研究了来自4个不同家族的5名患有NII的受累成员以及1名患有家族性FTLD - U但无NII的受累个体的DNA和死后脑组织。使用全基因组计算方法确定一组候选基因，对患者DNA进行CAA/CAG三核苷酸扩增筛查。检测含有编码至少五个谷氨酰胺的CAA/CAG三核苷酸重复序列的基因（n = 63），包括目前已知与人类疾病相关的9个基因。将CAA/CAG片段大小与已发表的正常值（如有）以及健康对照者（n = 94）的片段大小进行比较。采用高分辨率琼脂糖凝胶电泳测量等位基因大小（CAA/CAG重复序列的数量）。对于估计等于或大于对照人群中测得的最大值的任何等位基因，通过毛细管电泳确认CAA/CAG片段长度。此外，对患有NII的受试者的死后脑组织切片进行免疫组织化学检测，使用识别含有扩增多聚谷氨酰胺的蛋白质的单克隆抗体（1C2）。
在我们所有的FTLD - U患者的DNA中均未发现明显的编码多聚谷氨酰胺的重复序列扩增。FTLD - U病例中的NII未显示1C2免疫反应性。
我们没有发现证据表明伴有NII的常染色体显性FTLD - U是一种多聚谷氨酰胺扩增疾病。
