What have we learned from the congenital myasthenic syndromes.
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.
Engel
Andrew G
AG
Department of Neurology and Muscle Research Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. age@mayo.edu
Shen
Xin-Ming
XM
Selcen
Duygu
D
Sine
Steven M
SM
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008967:Molecular Biology / Q000379:methods / Q000639:trends*; D009154:Mutation / Q000235:genetics; D020294:Myasthenic Syndromes, Congenital / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology
D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D000109:Acetylcholine
J Gen Physiol. 1997 Jun;109(6):757-66
9222901
Biochemistry. 2006 Dec 12;45(49):14621-31
17144655
J Biol Chem. 1997 Jan 31;272(5):3016-21
9006950
J Clin Invest. 2008 May;118(5):1867-76
18398509
Neuromuscul Disord. 2003 Mar;13(3):245-51
12609506
Ann Neurol. 1996 Nov;40(5):810-7
8957026
Ann Neurol. 1977 Apr;1(4):315-30
214017
Muscle Nerve. 2003 Feb;27(2):180-7
12548525
J Mol Biol. 1990 Aug 5;214(3):613-7
2388258
Eur J Paediatr Neurol. 2005;9(1):7-12
15701560
EMBO J. 2004 May 19;23(10):2047-58
15131697
Nat Rev Neurosci. 2003 May;4(5):339-52
12728262
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):758-62
7531341
J Gen Physiol. 2000 Sep;116(3):449-62
10962020
Hum Mol Genet. 1997 May;6(5):767-74
9158151
Ann Neurol. 1996 Jun;39(6):712-23
8651643
Ann Neurol. 1982 Jun;11(6):553-69
6287911
Am J Hum Genet. 1998 Oct;63(4):967-75
9758617
Brain. 2006 Aug;129(Pt 8):2061-76
16870884
Neurotherapeutics. 2007 Apr;4(2):252-7
17395135
J Physiol. 2003 Mar 15;547(Pt 3):729-60
12562900
Ann Neurol. 2006 Jul;60(1):128-36
16685696
J Neurosci. 1997 Aug 1;17(15):5651-65
9221765
J Physiol. 2007 Mar 15;579(Pt 3):671-7
17272341
Ann Neurol. 2002 Jan;51(1):102-12
11782989
J Physiol. 2006 May 15;573(Pt 1):35-43
16527851
Ann Neurol. 2008 Jul;64(1):71-87
18626973
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2017-22
11172068
Neurology. 1987 Feb;37(2):206-14
3027611
Hum Mol Genet. 1996 Sep;5(9):1217-27
8872460
Neuromuscul Disord. 2002 Aug;12(6):548-53
12117478
Neuron. 1996 Jul;17(1):157-70
8755487
Brain. 2005 Feb;128(Pt 2):345-55
15615813
J Neurocytol. 2003 Jun-Sep;32(5-8):1017-37
15034283
J Neurosci. 2007 Apr 11;27(15):4110-9
17428989
Neuromuscul Disord. 2005 Jul;15(7):498-512
15951177
Science. 2006 Jun 23;312(5781):1802-5
16794080
Nature. 2006 Mar 23;440(7083):448-55
16554804
Ann Neurol. 1998 Apr;43(4):480-4
9546329
J Biol Chem. 2004 Mar 19;279(12):10997-1005
14702351
Hum Mol Genet. 2004 Dec 15;13(24):3229-40
15496425
Neuroreport. 1998 Jun 1;9(8):1907-11
9665624
Neuron. 1995 Jul;15(1):229-39
7619526
Neurology. 2003 May 27;60(10):1710-3
12771277
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9654-9
9689136
Arch Neurol. 2003 May;60(5):761-3
12756141
Science. 2006 Sep 29;313(5795):1975-8
16917026
Electroencephalogr Clin Neurophysiol Suppl. 1987;39:91-102
2443341