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

D. Pérez-Caballero, C. González-Rubio, M. Esther Gallardo, Maria Vera Ugalde, M. López-Trascasa, S. Rodríguez de Córdoba, P. Sánchez-Corral

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)478-484
Number of pages7
JournalAmerican Journal of Human Genetics
Volume68
Issue number2
DOIs
StatePublished - 2001
Externally publishedYes

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Complement Factor H
Missense Mutation
Cluster Analysis
Hemolytic-Uremic Syndrome
Mutation
Diarrhea
Alleles
Hemolytic Anemia
Cellular Structures
Microvessels
Atypical Hemolytic Uremic Syndrome
Acute Kidney Injury
Thrombocytopenia
Genes
Exons
Reference Values
Chromosomes
Bacteria
Amino Acids

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Pérez-Caballero, D., González-Rubio, C., Esther Gallardo, M., Vera Ugalde, M., López-Trascasa, M., Rodríguez de Córdoba, S., & Sánchez-Corral, P. (2001). Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. American Journal of Human Genetics, 68(2), 478-484. https://doi.org/10.1086/318201

Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. / Pérez-Caballero, D.; González-Rubio, C.; Esther Gallardo, M.; Vera Ugalde, Maria; López-Trascasa, M.; Rodríguez de Córdoba, S.; Sánchez-Corral, P.

In: American Journal of Human Genetics, Vol. 68, No. 2, 2001, p. 478-484.

Research output: Contribution to journalArticle

Pérez-Caballero, D, González-Rubio, C, Esther Gallardo, M, Vera Ugalde, M, López-Trascasa, M, Rodríguez de Córdoba, S & Sánchez-Corral, P 2001, 'Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome', American Journal of Human Genetics, vol. 68, no. 2, pp. 478-484. https://doi.org/10.1086/318201
Pérez-Caballero D, González-Rubio C, Esther Gallardo M, Vera Ugalde M, López-Trascasa M, Rodríguez de Córdoba S et al. Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. American Journal of Human Genetics. 2001;68(2):478-484. https://doi.org/10.1086/318201
Pérez-Caballero, D. ; González-Rubio, C. ; Esther Gallardo, M. ; Vera Ugalde, Maria ; López-Trascasa, M. ; Rodríguez de Córdoba, S. ; Sánchez-Corral, P. / Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. In: American Journal of Human Genetics. 2001 ; Vol. 68, No. 2. pp. 478-484.
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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 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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