Alessio Di Fonzo1, Dario Ronchi1, Francesca Gallia1, Fulvia Milena Cribiù1, Ilaria Trezzi1, Annalisa Vetro1, Erika Della Mina1, Ivan Limongelli1, Riccardo Bellazzi1, Ivana Ricca1, Giuseppe Micieli1, Elisa Fassone1, Mafalda Rizzuti1, Andreina Bordoni1, Francesco Fortunato1, Sabrina Salani1, Gabriele Mora1, Stefania Corti1, Mauro Ceroni1, Silvano Bosari1, Orsetta Zuffardi1, Nereo Bresolin1, Eduardo Nobile-Orazio1, Giacomo Pietro Comi2. 1. 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. 2. 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. giacomo.comi@unimi.it.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Our study broadens the phenotype of tauopathies to include lower motor neuron disease and implicate tau degradation pathway defects in motor neuron degeneration.
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Our study broadens the phenotype of tauopathies to include lower motor neuron disease and implicate tau degradation pathway defects in motor neuron degeneration.