A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis.
Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C>G SNP (odds ratio=8.6; P=0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5'-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C>G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.
Heckmann
J M
JM
Neurology Research Group, Department of Medicine, University of Cape Town, Cape Town, South Africa. jeanine.heckmann@uct.ac.za
Uwimpuhwe
H
H
Ballo
R
R
Kaur
M
M
Bajic
V B
VB
Prince
S
S
D000818:Animals; D044383:Black People / Q000235:genetics; D018958:CD55 Antigens / Q000096:biosynthesis / Q000235:genetics*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003171:Complement Pathway, Classical / Q000235:genetics*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009157:Myasthenia Gravis / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D010291:Paresis; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D018958:CD55 Antigens; D008070:Lipopolysaccharides
Ann Neurol. 2009 Jan;65(1):67-75
19194881
J Exp Med. 1978 Apr 1;147(4):973-83
206648
J Neuropathol Exp Neurol. 1980 Mar;39(2):160-72
7373347
Proc Natl Acad Sci U S A. 1983 Sep;80(17):5430-4
6225118
J Neuroimmunol. 2008 Sep 15;201-202:13-20
18632162
Nat Protoc. 2006;1(3):1559-82
17406449
Cell Immunol. 2003 May;223(1):46-51
12914757
J Exp Med. 2005 May 16;201(10):1523-30
15883171
J Immunol. 2007 Dec 15;179(12):8562-7
18056404
Physiol Genomics. 2004 Jan 15;16(2):184-93
14583597
Proc Natl Acad Sci U S A. 1983 Aug;80(16):5066-70
6576376
Genomics. 2006 Sep;88(3):316-22
16503113
J Immunol. 1990 Jan 15;144(2):740-4
1688584
J Neuropathol Exp Neurol. 1978 Mar-Apr;37(2):212-23
147324
Nat Med. 2003 Apr;9(4):431-8
12612546
J Immunol. 1993 Jan 1;150(1):151-60
7678027
J Neuroimmunol. 1996 Dec;71(1-2):173-7
8982117
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10
16381825
J Exp Med. 1984 Nov 1;160(5):1558-78
6238120
J Biol Chem. 2005 Jan 7;280(1):476-83
15520008
Mayo Clin Proc. 1977 May;52(5):267-80
870771
J Biol Chem. 1993 Nov 25;268(33):24892-901
7693708
Ann N Y Acad Sci. 2008;1132:220-4
18567871
Blood. 1994 Aug 15;84(4):1276-82
7519480
Clin Exp Immunol. 2006 Nov;146(2):278-86
17034580
Nature. 1987 Feb 5-11;325(6104):545-9
2433596
Nucleic Acids Res. 1994 Feb 25;22(4):669-77
8127716
J Immunol. 2006 Sep 15;177(6):3837-47
16951346
J Exp Med. 1987 Nov 1;166(5):1221-8
2445886
BMC Genet. 2006 Apr 20;7:22
16626483
Exp Neurol. 2006 Dec;202(2):287-93
16859686
Science. 2002 Feb 1;295(5556):813-8
11823631
Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4675-9
1711208
N Engl J Med. 2006 Sep 21;355(12):1233-43
16990386
Cell. 1989 Dec 1;59(5):827-36
2512012
Invest Ophthalmol Vis Sci. 1990 Jun;31(6):1136-48
1693916
Am J Pathol. 2007 Apr;170(4):1258-66
17392165
N Engl J Med. 1978 May 18;298(20):1116-22
643030
Biotechniques. 2005 Jul;39(1):75-85
16060372
J Biol Chem. 1991 Jan 15;266(2):1250-7
1824699
Exp Neurol. 2004 Oct;189(2):333-42
15380483
J Immunol. 1989 Apr 15;142(8):2654-9
2703710
J Clin Invest. 2002 Nov;110(9):1269-74
12417565
Immunology. 2000 Sep;101(1):104-11
11012760
J Immunol. 2003 Oct 1;171(7):3847-54
14500686
J Mol Med (Berl). 2005 Feb;83(2):97-109
15592805
Neuromuscul Disord. 2007 Dec;17(11-12):929-34
17720497
J Immunol. 1992 Nov 1;149(9):2906-13
1383332
Clin Exp Immunol. 2006 Nov;146(2):294-302
17034582
Methods. 2001 Dec;25(4):402-8
11846609
Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12062-7
11572940
J Exp Med. 2005 Feb 21;201(4):567-77
15710649
Mol Cell Biol. 2000 Dec;20(24):9113-9
11094063
Immunology. 2006 Dec;119(4):522-8
16999828