Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome.
Factor H autoantibodies have been reported in approximately 10% of patients with atypical hemolytic uremic syndrome (aHUS) and are associated with deficiency of factor H-related proteins 1 and 3. In this study we examined the prevalence of factor H autoantibodies in the Newcastle cohort of aHUS patients, determined whether the presence of such autoantibodies is always associated with deficiency of factor H-related proteins 1 and 3, and examined whether such patients have additional susceptibility factors and/or mutations in the genes encoding complement regulator/activators. We screened 142 patients with aHUS and found factor H autoantibodies in 13 individuals (age 1-11 years). The presence of the autoantibodies was confirmed by Western blotting. By using multiplex ligation-dependent probe amplification we measured complement factor H-related (CFHR)1 and CFHR3 copy number. In 10 of the 13 patients there were 0 copies of CFHR1, and in 3 patients there were 2. In 3 of the patients with 0 copies of CFHR1 there was 1 copy of CFHR3, and these individuals exhibited a novel deletion incorporating CFHR1 and CFHR4. In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation.
Moore
Iain
I
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom.
Strain
Lisa
L
Pappworth
Isabel
I
Kavanagh
David
D
Barlow
Paul N
PN
Herbert
Andrew P
AP
Schmidt
Christoph Q
CQ
Staniforth
Scott J
SJ
Holmes
Lucy V
LV
Ward
Roy
R
Morgan
Lynn
L
Goodship
Timothy H J
TH
Marchbank
Kevin J
KJ
D001053:Apolipoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001798:Blood Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003176:Complement C3 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D003180:Complement C3b Inactivator Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017244:Complement Factor I / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D006463:Hemolytic-Uremic Syndrome / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007223:Infant; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017384:Sequence Deletion
D001053:Apolipoproteins; D001323:Autoantibodies; D001798:Blood Proteins; C497857:CD46 protein, human; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; C105092:CFHR4 protein, human; D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D051916:Membrane Cofactor Protein; D017242:Complement Factor H; C493611:CFI protein, human; D017244:Complement Factor I