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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Ohkawara, Bisei; Cabrera-Serrano, Macarena; Nakata, Tomohiko et al. (2014) LRP4 third *-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. Hum Mol Genet 23:1856-68
Selcen, Duygu; Shen, Xin-Ming; Milone, Margherita et al. (2013) GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity. Neurology 81:370-8
Witoonpanich, R; Pulkes, T; Dejthevaporn, C et al. (2012) Phenotypic heterogeneity in a large Thai slow-channel congenital myasthenic syndrome kinship: Correction. Neuromuscul Disord 22:478
Sadeh, Menachem; Shen, Xin-Ming; Engel, Andrew G (2011) Beneficial effect of albuterol in congenital myasthenic syndrome with epsilon-subunit mutations. Muscle Nerve 44:289-91
Selcen, D; Juel, V C; Hobson-Webb, L D et al. (2011) Myasthenic syndrome caused by plectinopathy. Neurology 76:327-36
Liewluck, Teerin; Shen, Xin-Ming; Milone, Margherita et al. (2011) Endplate structure and parameters of neuromuscular transmission in sporadic centronuclear myopathy associated with myasthenia. Neuromuscul Disord 21:387-95
Shen, Xin-Ming; Crawford, Thomas O; Brengman, Joan et al. (2011) Functional consequences and structural interpretation of mutations of human choline acetyltransferase. Hum Mutat 32:1259-67
Liewluck, Teerin; Lovell, Tracy L; Bite, Anna V et al. (2010) Sporadic centronuclear myopathy with muscle pseudohypertrophy, neutropenia, and necklace fibers due to a DNM2 mutation. Neuromuscul Disord 20:801-4
Selcen, Duygu; Muntoni, Francesco; Burton, Barbara K et al. (2009) Mutation in BAG3 causes severe dominant childhood muscular dystrophy. Ann Neurol 65:83-9
Selcen, Duygu; Milone, Margherita; Shen, Xin-Ming et al. (2008) Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann Neurol 64:71-87

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