From the Dino Ferrari Center (A.D.F., D.R., I.T., M.R., A.B., F.F., S.S., S.C., N.B., G.P.C.), Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan; Department of Medical Biotechnology and Translational Medicine (F.G., E.N.-O.), 2nd Neurology, Humanitas Clinical and Research Center, Rozzano, Milan; Division of Pathology (F.M.C., S.B.), Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, University of Milan; Departments of Molecular Medicine (A.V., E.D.M., O.Z.), Industrial and Information Engineering (R.B.), and Public Health, Neuroscience, Experimental and Forensic Medicine (M.C.), University of Pavia; Departments of Neurological Emergency (I.L., G. Micieli, O.Z.) and General Neurology (I.R., M.C.), IRCCS C. Mondino National Neurological Institute, Pavia, Italy; Mitochondrial Research Group (E.F.), Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK; and Department of Neurorehabilitation (G. Mora), IRCCS Salvatore Maugeri Foundation, Milan, Italy.
Neurology. 2014 Jun 3;82(22):1990-8. doi: 10.1212/WNL.0000000000000476. Epub 2014 May 7.
To investigate the molecular defect underlying a large Italian kindred with progressive adult-onset respiratory failure, proximal weakness of the upper limbs, and evidence of lower motor neuron degeneration.
We describe the clinical features of 5 patients presenting with prominent respiratory insufficiency, proximal weakness of the upper limbs, and no signs of frontotemporal lobar degeneration or semantic dementia. Molecular analysis was performed combining linkage and exome sequencing analyses. Further investigations included transcript analysis and immunocytochemical and protein studies on established cell models.
Genome-wide linkage analysis showed an association with chromosome 17q21. Exome analysis disclosed a missense change in MAPT segregating dominantly with the disease and resulting in D348G-mutated tau protein. Motor neuron cell lines overexpressing mutated D348G tau isoforms displayed a consistent reduction in neurite length and arborization. The mutation does not seem to modify tau interactions with microtubules. Neuropathologic studies were performed in one affected subject, which exhibited α-motoneuron loss and atrophy of the spinal anterior horns with accumulation of phosphorylated tau within the surviving motor neurons. Staining for 3R- and 4R-tau revealed pathology similar to that observed in familial cases harboring MAPT mutations.
Our study broadens the phenotype of tauopathies to include lower motor neuron disease and implicate tau degradation pathway defects in motor neuron degeneration.
研究一个意大利大家族中进行性成人发病呼吸衰竭、上肢近端无力和下运动神经元变性的潜在分子缺陷。
我们描述了 5 名患者的临床特征，这些患者表现为明显的呼吸功能不全、上肢近端无力，没有额颞叶变性或语义性痴呆的迹象。采用连锁和外显子组测序分析相结合的方法进行分子分析。进一步的研究包括在已建立的细胞模型上进行转录分析以及免疫细胞化学和蛋白研究。
全基因组连锁分析显示与 17q21 染色体相关。外显子组分析显示 MAPT 中的错义变化呈显性遗传与疾病共分离，导致 D348G-突变的 tau 蛋白。过表达突变 D348G tau 异构体的运动神经元细胞系显示出一致的神经突长度和分支减少。该突变似乎不会改变 tau 与微管的相互作用。对一名受影响的患者进行了神经病理学研究，该患者表现出α运动神经元丧失和脊髓前角萎缩，存活的运动神经元内积累了磷酸化 tau。对 3R-和 4R-tau 的染色显示出与携带 MAPT 突变的家族病例中观察到的病理相似。
我们的研究拓宽了 tau 病的表型，包括下运动神经元疾病，并提示 tau 降解途径缺陷与运动神经元变性有关。
