Boeve Bradley F, Baker Matt, Dickson Dennis W, Parisi Joseph E, Giannini Caterina, Josephs Keith A, Hutton Michael, Pickering-Brown Stuart M, Rademakers Rosa, Tang-Wai David, Jack Clifford R, Kantarci Kejal, Shiung Maria M, Golde Todd, Smith Glenn E, Geda Yonas E, Knopman David S, Petersen Ronald C
Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.
Brain. 2006 Nov;129(Pt 11):3103-14. doi: 10.1093/brain/awl268. Epub 2006 Oct 9.
We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G-->A) which is predicted to destroy the 5'-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1G-->A mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease--the 'hypoprogranulinopathies'.
我们之前报道过一个家族中有三例痴呆症患者，其中先证者表现出额颞叶痴呆和帕金森综合征（FTDP）的典型特征。在先证者中发现早老素1（PSEN1）基因第352密码子处有一个精氨酸插入（insR352），但血浆和脑脊液分析表明神经退行性变机制与淀粉样蛋白病理生理过程无直接关联。对先证者进行了每年一次的功能、临床、神经心理、神经精神和放射学状态评估，结果显示在最初4年的评估中变化相对呈线性。先证者63岁死亡后，神经病理学检查发现额颞叶变性（FTLD）伴泛素阳性包涵体（FTLD-U）。我们最近发现了几个与原颗粒蛋白（PGRN）基因突变相关的家族性FTDP家族，特别是在那些有神经元核内包涵体的病例中。我们的先证者确实发现有此类包涵体，对该先证者的PGRN分析显示外显子1剪接供体位点（IVS1+1G→A）发生了G到A的突变，预计这会破坏外显子1的5'剪接位点并去除起始甲硫氨酸密码子，从而完全阻止任何PGRN蛋白的产生。这些发现表明，PSEN1基因的insR352不是致病的，而PGRN基因的IVS1+1G→A突变导致与FTLD-U病理相关的FTDP，并代表了一种新的神经退行性疾病——“低原颗粒蛋白病”。
