title: A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome.
abstract: A novel heterozygous mutation in the clusterin gene, nucleotide position A1298C (glutamine>proline Q433P), was detected in exon 7 of a child with recurrent hemolytic uremic syndrome (HUS). The same mutation was found in the child's two siblings and mother but not in 120 controls. In addition, a previously described heterozygous mutation was detected in the gene encoding membrane cofactor protein (MCP) causing a 6 base-pair deletion 811-816delGACAGT in exon 6. It was found in the patient, both siblings and the father. One sibling had recovered from post-streptococcal glomerulonephritis. Clusterin levels in the patient, siblings and parents were normal as was the migration pattern in a gel. Patient serum induced C3 and C9 deposition on normal washed platelets, and platelet activation, as detected by flow cytometry. The same phenomenon was found in serum taken from the siblings and the mother but not in the sample from the father and controls. Addition of clusterin to patient serum did not inhibit complement activation on platelets. The Q433P mutant, in isolated form, was further studied by binding to the components of the terminal complement complex. The mutant did not bind to C5b-7 that was immobilized onto a BIAcore chip, whereas wild-type clusterin did, indicating that the mutation could lead to defective inhibition of formation of the membrane attack complex under these conditions. Hemolysis of rabbit erythrocytes was inhibited by wild-type clusterin but not by the mutant. Mutated clusterin could thus not prevent assembly of the membrane attack complex on platelets and erythrocytes.
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Anne-lie
authors.initials: AL
authors.lastname: Ståhl
authors.forename: AnnCharlotte
authors.initials: A
authors.lastname: Kristoffersson
authors.forename: Anders I
authors.initials: AI
authors.lastname: Olin
authors.forename: Martin L
authors.initials: ML
authors.lastname: Olsson
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Roodhooft
authors.forename: Willem
authors.initials: W
authors.lastname: Proesmans
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
mesh_terms: D000293:Adolescent; D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D051152:Clusterin / Q000097:blood / Q000235:genetics*; D003176:Complement C3 / Q000276:immunology; D003182:Complement C5 / Q000378:metabolism; D003186:Complement C9 / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism; D005091:Exons; D005260:Female; D006461:Hemolysis; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D009154:Mutation; D011485:Protein Binding; D011817:Rabbits
chemical_list: D051152:Clusterin; D003176:Complement C3; D003182:Complement C5; D003186:Complement C9; D007074:Immunoglobulin G; C042295:complement C5b-8 complex; D023201:CD40 Ligand; C037453:complement C5b-7 complex; D003165:Complement System Proteins