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

被引:249
作者
Pérez-Caballero, D
González-Rubio, C
Gallardo, ME
Vera, M
López-Trascasa, M
de Córdoba, SR
Sánchez-Corral, P
机构
[1] CSIC, Ctr Invest Biol, Dept Inmunol, E-28006 Madrid, Spain
[2] Hosp Univ La Paz, Unidad Inmunol, Madrid, Spain
关键词
D O I
10.1086/318201
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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页码:478 / 484
页数:7
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