The long range of this research is to understand the pathophysiology and molecular mechanisms involved in the impairment of neuromuscular transmission in the slow-channel congenital myasthenic syndrome (SCCMS). The rapid advances in the molecular genetics of the SCCMS have established that it is associated with a variety of missense mutations in the genes coding for the subunits of the muscle acetylcholine receptor (nAChR). Although the common effect of each mutation identified in the SCCMS to date is to prolong the duration of the acetylcholine- induced channel bursts and consequently the endplate currents the severity and pattern of the clinical and pathological findings vary greatly. This suggests that each SCCMS-associated mutation has a differential effect on other aspects of nAChR function, and that the combined effect the properties of each nAChR mutation determines the clinicopathological phenotype. In this project we propose to explore specific, novel aspects of the molecular phenotype of each SCCMS mutation and to assess the relative contribution of each to neuromuscular weakness. Specially, we propose to: 1) Identify the all the mutations in the genes encoding the a,b,d and e subunits of the nAChR for patients with slow-channel syndrome and other candidate nAChR disorders. This will be accomplished by nucleotide sequence analysis. 2)Confirm the effect of each new mutation on nAChR function and compare the effects of all pathogenic nAChR mutations on nAChR channel gating and desensitization.
Aims 2 -4 will be accomplished using in vitro expression systems. 3)Compare the effects of all pathogenic nAChR mutations on Ca2+ permeability. 4)Compare the effects of all pathogenic nAChR mutation on receptor assembly and stability. 5)Compare the pathogenicity in vivo of SCCMS-associated mutations differing in nAChR desensitization and calcium permeability. This will be accomplished by generation and systematic comparison of additional transgenic mouse models for the SCCMS. These studies extend the focus of this project from the first phase, the identification of mutations responsible for the SCCMS, to the second phase in which the molecular pathogenesis and genotype-phenotype correlation in the SCCMS are investigated by expression of the mutations in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033202-06
Application #
6126262
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Nichols, Paul L
Project Start
1995-04-01
Project End
2003-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
6
Fiscal Year
2000
Total Cost
$275,319
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Otero-Cruz, José David; Báez-Pagán, Carlos Alberto; Dorna-Pérez, Luisamari et al. (2010) Decoding pathogenesis of slow-channel congenital myasthenic syndromes using recombinant expression and mice models. P R Health Sci J 29:4-17
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