title: Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome.
abstract: We investigated the phenotypic expression of factor H mutations in two patients with atypical hemolytic uremic syndrome (HUS). Factor H in serum was assayed by rocket immunoelectrophoresis, immunoblotting, and double immunodiffusion and in tissue by immunohistochemistry. Functional activity was analyzed by hemolysis of sheep erythrocytes and binding to endothelial cells. A homozygous mutation in complement control protein (CCP) domain 10 of factor H was identified in an adult man who first developed membranoproliferative glomerulonephritis and later HUS. C3 levels were very low. The patient had undetectable factor H levels in serum and a weak factor H 150 kDa band. Double immunodiffusion showed partial antigenic identity with factor H in normal serum owing to the presence of factor H-like protein 1. Strong specific labeling for factor H was detected in glomerular endothelium, mesangium and in glomerular and tubular epithelium as well as in bone marrow cells. A heterozygous mutation in CCP 20 of factor H was found in a girl with HUS. C3 levels were moderately decreased at onset. Factor H levels were normal and a normal 150 kDa band was present. Double immunodiffusion showed antigenic identity with normal factor H. Factor H labeling was minimal in the renal cortex. Factor H dysfunction was demonstrated by increased sheep erythrocyte hemolysis and decreased binding to endothelial cells. In summary, two different factor H mutations associated with HUS were examined: in one, factor H accumulated in cells, and in the other, membrane binding was reduced.
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Vaziri-Sani
authors.forename: L
authors.initials: L
authors.lastname: Holmberg
authors.forename: A G
authors.initials: AG
authors.lastname: Sjöholm
authors.forename: A-C
authors.initials: AC
authors.lastname: Kristoffersson
authors.forename: M
authors.initials: M
authors.lastname: Manea
authors.forename: V
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: I
authors.initials: I
authors.lastname: Fehrman-Ekholm
authors.forename: R
authors.initials: R
authors.lastname: Raafat
authors.forename: D
authors.initials: D
authors.lastname: Karpman
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000737:chemistry; D002648:Child; D003176:Complement C3 / Q000032:analysis; D017242:Complement Factor H / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D004727:Endothelium / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D004912:Erythrocytes / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D015432:Glomerulonephritis, Membranoproliferative / Q000150:complications / Q000235:genetics; D006461:Hemolysis / Q000235:genetics / Q000502:physiology; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000209:etiology / Q000235:genetics*; D006801:Humans; D005779:Immunodiffusion; D007122:Immunoelectrophoresis; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000737:chemistry; D008297:Male; D050527:Mesangial Cells / Q000737:chemistry; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D012756:Sheep
chemical_list: D003176:Complement C3; D017242:Complement Factor H