Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junction.
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 epsilon subunit and are partially compensated by residual expression of the fetal-type gamma 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.
Neuromuscular Disease Research Laboratory, Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA. age@mayo.edu
Andrew G
AG
Engel
Kinji
K
Ohno
Xin-Ming
XM
Shen
Steven M
SM
Sine
D000818:Animals; D001049:Apnea / Q000150:complications; D002795:Choline O-Acetyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009124:Muscle Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000145:classification / Q000235:genetics* / Q000503:physiopathology; D062553:NAV1.4 Voltage-Gated Sodium Channel; D009469:Neuromuscular Junction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics*; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics
D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D021122:Protein Subunits; D011978:Receptors, Nicotinic; C106251:SCN4A protein, human; D015222:Sodium Channels; C051609:peripheral membrane protein 43K; D002795:Choline O-Acetyltransferase