van Herpen Esther, Rosso Sonia M, Serverijnen Lies-Anne, Yoshida Hirotaka, Breedveld Guido, van de Graaf Raoul, Kamphorst Wouter, Ravid Rivka, Willemsen Rob, Dooijes Dennis, Majoor-Krakauer Daniëlle, Kros Johan M, Crowther R Anthony, Goedert Michel, Heutink Peter, van Swieten John C
Department of Clinical Genetics, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Ann Neurol. 2003 Nov;54(5):573-81. doi: 10.1002/ana.10721.
Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe two Dutch families with familial frontotemporal dementia associated with the novel missense mutation L315R in exon 11 of tau. The age at onset of disease showed a large variation within each family, ranging from 25 to 64 years. Incomplete penetrance was established in an 82-year-old mutation carrier with no signs of dementia and appeared probable in two additional subjects. The brains of two affected subjects were studied and showed extensive tau pathology in neurons (Pick-like inclusions) and astroglial cells, particularly in the frontotemporal cortex and the hippocampal formation. Sarkosyl-insoluble tau extracted from the cerebral cortex showed the presence of straight and twisted tau filaments and a pattern of pathological tau bands similar to that of Pick's disease. Upon dephosphorylation, only five of the six brain tau isoforms were observed, with the shortest isoform being undetectable. All six tau isoforms were present in soluble brain tau. Recombinant tau proteins with the L315R mutation showed a reduced ability to promote microtubule assembly.
tau基因的突变会导致与17号染色体相关的家族性额颞叶痴呆和帕金森症。在此，我们描述了两个患有家族性额颞叶痴呆的荷兰家族，其与tau基因第11外显子中的新型错义突变L315R相关。每个家族中疾病的发病年龄差异很大，范围从25岁到64岁。在一名82岁无痴呆迹象的突变携带者中确定了不完全外显率，另外两名受试者也可能存在不完全外显率。对两名受影响受试者的大脑进行了研究，结果显示神经元（Pick样包涵体）和星形胶质细胞中存在广泛的tau病理变化，尤其是在额颞叶皮质和海马结构中。从大脑皮质提取的 Sarkosyl不溶性tau显示存在直的和扭曲的tau细丝，以及与Pick病相似的病理性tau条带模式。去磷酸化后，仅观察到六种脑tau异构体中的五种，最短的异构体未检测到。所有六种tau异构体均存在于可溶性脑tau中。具有L315R突变的重组tau蛋白促进微管组装的能力降低。
