Support is requested for a multifaceted investigation of congenital myasthenic syndromes (CMS). The CMS are heterogeneous and disabling diseases in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanism(s). We will use the candidate gene approach to find the cause of different CMS, determine the mechanism by which the mutant gene causes the CMS, and then use this information to generate structure-function correlations and devise strategies for therapy. The candidate gene approach rests on determining (1) the clinical phenotype, (2) the morphologic phenotype based on cytochemical and ultrastructural features of the endplate (EP), (3) the number of acetylcholine (ACh) receptors (AChRs) per EP, (4) the electrophysiologic phenotype reflected by parameters of neuromuscular transmission in vitro. The mechanism by which the mutant gene causes a CMS is investigated by engineering the mutant and corresponding wild-type gene into a suitable expression system which is then interrogated by appropriate electrophysiologic and biochemical tests. Structure-function correlations rest on further mutagenesis studies and on analysis of the mechanism by which a change in the structure of the mutated protein alters the function of that protein, and how this alteration affecs the safety margin of neuromuscular transmission. Strategies for therapy are based on determining the molecular defect caused by the mutation and whether the identified defect increases or decreases the synaptic response to ACh.

Public Health Relevance

Congenital myasthenic syndromes (CMS) arise from defects in proteins at the nerve-muscle junction. They frequently go undiagnosed or misdiagnosed yet their consequences are often highly disabling. The CMS will be studied by a multifaceted approach that will improve their diagnosis, treatment, and prevention.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Stewart, Randall R
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Mayo Clinic, Rochester
United States
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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; 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
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
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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