TY - JOUR
T1 - What have we learned from the congenital myasthenic syndromes
AU - Engel, Andrew G.
AU - Shen, Xin Ming
AU - Selcen, Duygu
AU - Sine, Steven M.
N1 - Funding Information:
Acknowledgements Work in our laboratories was supported by NIH grants to A.G. Engel (NS-6277) and to S.M. Sine (NS-31744) and by a Muscular Dystrophy Association grant to A.G. Engel.
PY - 2010/1
Y1 - 2010/1
N2 - The congenital myasthenic syndromes have now been traced to an array of molecular targets at the neuromuscular junction encoded by no fewer than 11 disease genes. The disease genes were identified by the candidate gene approach, using clues derived from clinical, electrophysiological, cytochemical, and ultrastructural features. For example, electrophysiologic studies in patients suffering from sudden episodes of apnea pointed to a defect in acetylcholine resynthesis and CHAT as the candidate gene (Ohno et al., Proc Natl Acad Sci USA 98:2017-2022, 2001); refractoriness to anticholinesterase medications and partial or complete absence of acetylcholinesterase (AChE) from the endplates (EPs) has pointed to one of the two genes (COLQ and ACHE T ) encoding AChE, though mutations were observed only in COLQ. After a series of patients carrying mutations in a disease gene have been identified, the emerging genotype-phenotype correlations provided clues for targeted mutation analysis in other patients. Mutations in EP-specific proteins also prompted expression studies that proved pathogenicity, highlighted important functional domains of the abnormal proteins, and pointed to rational therapy.
AB - The congenital myasthenic syndromes have now been traced to an array of molecular targets at the neuromuscular junction encoded by no fewer than 11 disease genes. The disease genes were identified by the candidate gene approach, using clues derived from clinical, electrophysiological, cytochemical, and ultrastructural features. For example, electrophysiologic studies in patients suffering from sudden episodes of apnea pointed to a defect in acetylcholine resynthesis and CHAT as the candidate gene (Ohno et al., Proc Natl Acad Sci USA 98:2017-2022, 2001); refractoriness to anticholinesterase medications and partial or complete absence of acetylcholinesterase (AChE) from the endplates (EPs) has pointed to one of the two genes (COLQ and ACHE T ) encoding AChE, though mutations were observed only in COLQ. After a series of patients carrying mutations in a disease gene have been identified, the emerging genotype-phenotype correlations provided clues for targeted mutation analysis in other patients. Mutations in EP-specific proteins also prompted expression studies that proved pathogenicity, highlighted important functional domains of the abnormal proteins, and pointed to rational therapy.
KW - Acetylcholine esterase
KW - Acetylcholine receptor
KW - Choline acetyltransferase
KW - Congenital myasthenic syndromes
KW - Dok-7
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U2 - 10.1007/s12031-009-9229-0
DO - 10.1007/s12031-009-9229-0
M3 - Article
C2 - 19688192
AN - SCOPUS:75049083573
SN - 0895-8696
VL - 40
SP - 143
EP - 153
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 1-2
ER -