Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome

Hemolytic-uremic syndrome (HUS) is a microvasculature disorder leading to m icroangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure . Most cases of HUS are associated with epidemics of diarrhea caused by ver ocytotoxin-producing bacteria, but atypical cases of HUS not associated wit h diarrhea (aHUS) also occur. Early studies describing the association of a HUS with deficiencies of factor H suggested a role for this complement regu lator in aHUS. Molecular evidence of factor H involvement in aHUS was first provided by Warwicker et al., who demonstrated that aHUS segregated with t he chromosome 1q region containing the factor H gene (HF1) and who identifi ed a mutation in HF1 in a case of familial aHUS with normal levels of facto r 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 profi les and whose plasma levels of factor H are, with one exception, within the normal range. These studies have resulted in the identification of five no vel HF1 mutations in four of the patients. Allele HF1 Delta exon2, a genomi c deletion of exon 2, produces a null HF1 allele and results in plasma leve ls of factor H that are 50% of normal. T956M, W1183L, L1189R, and V1197A ar e missense mutations that alter amino acid residues in the C-terminal porti on 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 rem arkable clustering of mutations in HF1 suggests that a specific dysfunction in the protection of cellular surfaces by factor H is a major pathogenic c ondition underlying aHUS.