Clustering of Missense Mutations in the C-Terminal Region of Factor H in Atypical Hemolytic Uremic Syndrome

Abstract

Hemolytic-uremic syndrome (HUS) is a microvasculature disorder leading to microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Most cases of HUS are associated with epidemics of diarrhea caused by verocytotoxin-producing bacteria, but atypical cases of HUS not associated with diarrhea (aHUS) also occur. Early studies describing the association of aHUS with deficiencies of factor H suggested a role for this complement regulator in aHUS. Molecular evidence of factor H involvement in aHUS was first provided by Warwicker et al., who demonstrated that aHUS segregated with the chromosome 1q region containing the factor H gene (HF1) and who identified a mutation in HF1 in a case of familial aHUS with normal levels of factor H. We have performed the mutational screening of the HF1 gene in a novel series of 13 Spanish patients with aHUS who present normal complement profiles and whose plasma levels of factor H are, with one exception, within the normal range. These studies have resulted in the identification of five novel HF1 mutations in four of the patients. Allele HF1 Delta exon2, a genomic deletion of exon 2, produces a null HF1 allele and results in plasma levels of factor H that are 50% of normal. T956M, W1183L, L1189R, and V1197A are missense mutations that alter amino acid residues in the C-terminal portion of factor H, within a region--SCR16-SCR20--that is involved in the binding to solid-phase C3b and to negatively charged cellular structures. This remarkable clustering of mutations in HF1 suggests that a specific dysfunction in the protection of cellular surfaces by factor H is a major pathogenic condition underlying aHUS.

Hemolytic Uremic Syndrome

“…In sporadic forms, the mutation was either inherited from a healthy parent or, more rarely-only four cases reported-ensued de novo in the proband (100,102). The mutation frequency is up to 40% in familial forms, whereas only 13 to 17% of sporadic forms had HF1 mutations (100,119).…”

Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

“…Among the reported cases, approximately 50% had mutations of the complement regulatory proteins factor H (CFH) (7)(8)(9)(10)(11)(12), membrane cofactor protein (13)(14)(15), or factor I (16)(17)(18); mutations occurred less frequently in factor B (19), C3 (20), and thrombomodulin (21).…”

The C-terminus of complement factor H is essential for host cell protection

“…Recent data have shown that FH binds to cell surfaces via its C-terminal recognition domain which is contained in CCPs 19-20 (Pangburn, 2002;Manuelian et al, 2003;Jokiranta el al., 2005;Józsi et al, 2006;Ferreira et al, 2006). This has medical relevance since FH mutations associated with atypical hemolytic uremic syndrome (aHUS) cluster in the C-terminus of the protein (Caprioli et al, 2001;Pérez-Caballero et al, 2001;Richards et al, 2001). Recombinant FH proteins which have aHUSassociated amino acid exchanges in the C-terminal CCPs 19 and 20 and patient-derived mutant FH proteins show defective binding to heparin, glycosaminoglycans, C3b/C3d and to endothelial cells (Hellwage et al, 2002;Sánchez-Corral et al, 2002Manuelian et al, 2003;Jokiranta et al, 2005;Józsi et al, 2006).…”