The present proposal seeks support for the continuation of an investigative program of human and experimentally induced muscle diseases. The diseases are approached through analysis of the light microscopic and ultrastructural reactions in the muscle fiber, neuromuscular junction, intramuscular nerves and blood vessels. Individual diseases are studied systematically by combined light microscopic histochemistry, immunocytochemistry, phase and electron microscopy, immunoelectron microscopy and freeze-fracture electron microscopy. Whenever possible, the observations are quantitated by morphometric methods and correlated with available physiologic and biochemical data. The two main themes for the renewal period pertain to defects of neuromuscular transmission and mechanisms of muscle fiber injury. In acquired myasthenia gravis/the relative contributions of the immunopathologic mechanisms which result in end-plate acetylcholine receptor (AChR) deficiency will be evaluated. In a congenital myasthenic syndrome attributed to impaired acetylcholine resynthesis or mobilization, an ultrastructural correlate will be sought for the stimulation induced failure of neuromuscular transmission. In three clinically and morphologically distinct myasthenic syndromes associated with congenital end-plate AChR deficiency, detailed analyses of end-plate ultrastructure, AChR distribution and cholinergic binding sites will be carried out. In the Lambert-Eaton myasthenic syndrome the hypothesis will be tested that presynaptic membrane active zones represent the target of pathogenic autoantibodies. In Duchenne dystrophy and other myopathies necrotic and prenecrotic muscle fibers will be studied to define the ultrastructural binding site of the complement membrane attack complex. The pathogenesis of inflammatory myopathies will be investigated by monoclonal antibody analysis of the mononuclear cells in muscle; subsets of these cells involved in muscle fiber destruction will be defined, and the ultrastructural aspects of this mechanism will be elucidated. In dermatomyositis the hypothesis will be tested that the pathologic features of the disease are mediated by a circulating autoantibody.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS006277-20
Application #
3393459
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1977-05-01
Project End
1991-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
20
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Durmus, Hacer; Shen, Xin-Ming; Serdaroglu-Oflazer, Piraye et al. (2018) Congenital myasthenic syndromes in Turkey: Clinical clues and prognosis with long term follow-up. Neuromuscul Disord 28:315-322
Shen, Xin-Ming; Brengman, Joan M; Shen, Shelley et al. (2018) Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ?-subunit. JCI Insight 3:
Engel, Andrew G; Shen, Xin-Ming; Selcen, Duygu (2018) The unfolding landscape of the congenital myasthenic syndromes. Ann N Y Acad Sci 1413:25-34
Yi?, Uluç; Becker, Kerstin; Kurul, Semra H?z et al. (2017) Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights. J Child Neurol 32:759-765
Aharoni, Sharon; Sadeh, Menachem; Shapira, Yehuda et al. (2017) Congenital myasthenic syndrome in Israel: Genetic and clinical characterization. Neuromuscul Disord 27:136-140
Shen, Xin-Ming; Scola, Rosana H; Lorenzoni, Paulo J et al. (2017) Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome. Ann Clin Transl Neurol 4:130-138
Shen, Xin-Ming; Okuno, Tatsuya; Milone, Margherita et al. (2016) Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating. Hum Mutat 37:1051-9
Shen, Xin-Ming; Brengman, Joan; Neubauer, David et al. (2016) Investigation of Congenital Myasthenia Reveals Functional Asymmetry of Invariant Acetylcholine Receptor (AChR) Cys-loop Aspartates. J Biol Chem 291:3291-301
Engel, Andrew G; Shen, Xin-Ming; Selcen, Duygu et al. (2015) Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 14:420-34
Engel, A G; Shen, X-M; Selcen, D et al. (2015) Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 14:461

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