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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS006277-48
Application #
8438377
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Stewart, Randall R
Project Start
1977-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
48
Fiscal Year
2013
Total Cost
$490,358
Indirect Cost
$181,957
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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, A G; Shen, X-M; Selcen, D et al. (2015) Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 14:461
Selcen, Duygu; Ohkawara, Bisei; Shen, Xin-Ming et al. (2015) Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia. JAMA Neurol 72:889-96
Engel, Andrew G; Shen, Xin-Ming; Selcen, Duygu et al. (2015) Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 14:420-34
Selcen, Duygu; Shen, Xin-Ming; Brengman, Joan et al. (2014) DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies. Neurology 82:1822-30
Malfatti, Edoardo; Nilsson, Johanna; Hedberg-Oldfors, Carola et al. (2014) A new muscle glycogen storage disease associated with glycogenin-1 deficiency. Ann Neurol 76:891-8
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
Shen, Xin-Ming; Selcen, Duygu; Brengman, Joan et al. (2014) Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology 83:2247-55
Régal, Luc; Shen, Xin-Ming; Selcen, Duygu et al. (2014) PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology 82:1254-60

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