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Congenital Myasthenic Syndromes: Multiple Molecular Targets at the Neuromuscular Junction
Author(s) -
ENGEL ANDREW G.,
OHNO KINJI,
SHEN XINMING,
SINE STEVEN M.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1254.016
Subject(s) - postsynaptic potential , neuromuscular junction , acetylcholine receptor , congenital myasthenic syndrome , protein subunit , acetylcholinesterase , choline acetyltransferase , acetylcholine , synaptic cleft , chemistry , microbiology and biotechnology , neuroscience , neurotransmission , biology , endocrinology , biochemistry , receptor , enzyme , gene
A bstract : Congenital myasthenic syndromes (CMS) stem from defects in presynaptic, synaptic, and postsynaptic proteins. The presynaptic CMS are associated with defects that curtail the evoked release of acetylcholine (ACh) quanta or ACh resynthesis. Defects in ACh resynthesis have now been traced to mutations in choline acetyltransferase. A synaptic CMS is caused by mutations in the collagenic tail subunit (ColQ) of the endplate species of acetylcholinesterase that prevent the tail subunit from associating with catalytic subunits or from becoming inserted into the synaptic basal lamina. Most postsynaptic CMS are caused by mutations in subunits of the acetylcholine receptor (AChR) that alter the kinetic properties or decrease the expression of AChR. The kinetic mutations increase or decrease the synaptic response to ACh and result in slow‐ and fast‐channel syndromes, respectively. Most low‐expressor mutations reside in the AChR ε subunit and are partially compensated by residual expression of the fetal‐type γ subunit. In a subset of CMS patients, endplate AChR deficiency is caused by mutations in rapsyn, a molecule that plays a critical role in concentrating AChR in the postsynaptic membrane.