Tacik Pawel, DeTure Michael, Lin Wen-Lang, Sanchez Contreras Monica, Wojtas Aleksandra, Hinkle Kelly M, Fujioka Shinsuke, Baker Matthew C, Walton Ronald L, Carlomagno Yari, Brown Patricia H, Strongosky Audrey J, Kouri Naomi, Murray Melissa E, Petrucelli Leonard, Josephs Keith A, Rademakers Rosa, Ross Owen A, Wszolek Zbigniew K, Dickson Dennis W
Department of Neurology, Mayo Clinic, Jacksonville, USA.
Acta Neuropathol. 2015 Aug;130(2):199-214. doi: 10.1007/s00401-015-1425-0. Epub 2015 Apr 22.
Globular glial tauopathies (GGTs) are 4-repeat tauopathies neuropathologically characterized by tau-positive, globular glial inclusions, including both globular oligodendroglial inclusions and globular astrocytic inclusions. No mutations have been found in 25 of the 30 GGT cases reported in the literature who have been screened for mutations in microtubule associated protein tau (MAPT). In this report, six patients with GGT (four with subtype III and two with subtype I) were screened for MAPT mutations. They included 4 men and 2 women with a mean age at death of 73 years (55-83 years) and mean age at symptomatic onset of 66 years (50-77 years). Disease duration ranged from 5 to 14 years. All were homozygous for the MAPT H1 haplotype. Three patients had a positive family history of dementia, and a novel MAPT mutation (c.951G>C, p.K317N) was identified in one of them, a patient with subtype III. Recombinant tau protein bearing the lysine-to-asparagine substitution at amino acid residue 317 was used to assess functional significance of the variant on microtubule assembly and tau filament formation. Recombinant p.K317N tau had reduced ability to promote tubulin polymerization. Recombinant 3R and 4R tau bearing the p.K317N mutation showed decreased 3R tau and increased 4R tau filament assembly. These results strongly suggest that the p.K317N variant is pathogenic. Sequencing of MAPT should be considered in patients with GGT and a family history of dementia or movement disorder. Since several individuals in our series had a positive family history but no MAPT mutation, genetic factors other than MAPT may play a role in disease pathogenesis.
球状胶质tau蛋白病（GGTs）是4重复tau蛋白病，其神经病理学特征为tau阳性的球状胶质包涵体，包括球状少突胶质细胞包涵体和球状星形胶质细胞包涵体。在文献报道的30例GGT病例中，有25例经筛查微管相关蛋白tau（MAPT）未发现突变。在本报告中，对6例GGT患者（4例为III型，2例为I型）进行了MAPT突变筛查。他们包括4名男性和2名女性，平均死亡年龄为73岁（55 - 83岁），平均症状出现年龄为66岁（50 - 77岁）。病程为5至14年。所有患者均为MAPT H1单倍型纯合子。3例患者有痴呆家族史，其中1例III型患者发现了一种新的MAPT突变（c.951G>C，p.K317N）。使用在氨基酸残基317处赖氨酸到天冬酰胺取代的重组tau蛋白来评估该变体对微管组装和tau丝形成的功能意义。重组p.K317N tau促进微管蛋白聚合的能力降低。携带p.K317N突变的重组3R和4R tau显示3R tau减少，4R tau丝组装增加。这些结果强烈表明p.K317N变体具有致病性。对于有痴呆家族史或运动障碍的GGT患者，应考虑对MAPT进行测序。由于我们系列中的几个个体有阳性家族史但没有MAPT突变，MAPT以外的遗传因素可能在疾病发病机制中起作用。
