Mukherjee Odity, Pastor Pau, Cairns Nigel J, Chakraverty Sumi, Kauwe John S K, Shears Shantia, Behrens Maria I, Budde John, Hinrichs Anthony L, Norton Joanne, Levitch Denise, Taylor-Reinwald Lisa, Gitcho Michael, Tu P-H, Tenenholz Grinberg Lea, Liscic Rajka M, Armendariz Javier, Morris John C, Goate Alison M
Washington University Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Ann Neurol. 2006 Sep;60(3):314-22. doi: 10.1002/ana.20963.
Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques.
In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred.
Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide.
HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.
最近有报道称，与17q21 - 22相关的家族性常染色体显性额颞叶痴呆，其大脑中存在泛素阳性、tau阴性包涵体，携带颗粒蛋白前体基因（PGRN）的无效突变。遗传性言语障碍性脱抑制性痴呆（HDDD）是一种额颞叶痴呆，具有明显的行为改变和语言缺陷。先前的一项研究发现，在一个HDDD家族（HDDD2）中与17号染色体存在显著连锁，但在微管相关蛋白tau（MAPT）基因中未发现突变。纵向随访使我们能够识别新病例，并进一步描述该家族中的痴呆特征。本研究的目的是制定研究标准，以对在这个大家系中观察到的痴呆的不同临床表型进行分类，识别受影响个体中的致病突变，并将其与该家系中的表型特征相关联，以及使用免疫组织化学技术评估神经病理学特征。
在本研究中，我们描述了对HDDD2家系进行的详细临床、病理和突变分析。
神经病理学上，HDDD2代表一种伴有泛素阳性、tau阴性包涵体的家族性额颞叶脑叶变性（FTLD - U）。我们制定了研究分类标准，并确定了三个不同的诊断阈值，这有助于定位疾病位点。具有最强连锁证据的染色体区域位于FTLD - U的最小关键区域内。对PGRN基因的每个外显子进行测序，导致在信号肽内鉴定出一个新的错义突变，Ala - 9 Asp。
HDDD2是由PGRN基因中的错义突变引起的FTLD - U，该突变与疾病以及高危个体中的疾病单倍型共分离。这种突变是首次报道的导致FTLD - U的PGRN基因信号肽中的致病性错义突变。鉴于先前关于无效突变的报道及其在基因中的位置，提出了两种可能的病理机制：（1）由于分泌效率低下，蛋白质可能在内质网中积累；（2）突变RNA可能由于通过无义介导的衰变降解而具有较低的表达。
