TY - JOUR
T1 - Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome
AU - Pérez-Caballero, David
AU - González-Rubio, Carolina
AU - Esther Gallardo, M.
AU - Vera, Mariá
AU - López-Trascasa, Margarita
AU - Rodríguez de Córdoba, Santiago
AU - Sánchez-Corral, Pilar
N1 - Funding Information:
We thank the families with aHUS and all the clinicians, particularly Drs. Ángel Alonso and Mª Auxiliadora Bajo, for their collaboration and donation of blood samples. We would also like to thank S. Vara de Rey, D. Beltrán Valero de Bernabé, L. Gulliksen, and the DNA Sequencing Laboratory at the Centro de Investigaciones Biológicas, for their contribution to this work. We also thank the reviewers of the manuscript, for their helpful comments. This research was supported by Spanish Fondo de Investigaciones Sanitarias grant FIS 98/0687, Comisión Interministerial de Ciencia y Tecnología grant SAF-99/0013-C02-01, and Comunidad de Madrid grants 08.1/0008/1998 and 08.6/0028/2000. D.P.-C. and P.S.-C. have been awarded grants from Glaxo Wellcome/CSIC and the Comunidad de Madrid, respectively.
PY - 2001
Y1 - 2001
N2 - 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 HF1Δexon2, 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.
AB - 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 HF1Δexon2, 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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U2 - 10.1086/318201
DO - 10.1086/318201
M3 - Article
C2 - 11170895
AN - SCOPUS:0035121908
SN - 0002-9297
VL - 68
SP - 478
EP - 484
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -