Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome.
The factor H-related protein family (CFHR) is a group of minor plasma proteins genetically and structurally related to complement factor H (fH). Notably, deficiency of CFHR1/CFHR3 associates with protection against age-related macular degeneration and with the presence of anti-fH autoantibodies in atypical hemolytic uremic syndrome (aHUS). We have developed a proteomics strategy to analyze the CFHR proteins in plasma samples from controls, patients with aHUS, and patients with type II membranoproliferative glomerulonephritis. Here, we report on the identification of persons carrying novel deficiencies of CFHR1, CFHR3, and CFHR1/CFHR4A, resulting from point mutations in CFHR1 and CFHR3 or from a rearrangement involving CFHR1 and CFHR4. Remarkably, patients with aHUS lacking CFHR1, but not those lacking CFHR3, present anti-fH autoantibodies, suggesting that generation of these antibodies is specifically related to CFHR1 deficiency. We also report the characterization of a novel CFHR1 polymorphism, resulting from a gene conversion event between CFH and CFHR1, which strongly associates with aHUS. The risk allotype CFHR1*B, with greater sequence similarity to fH, may compete with fH, decreasing protection of cellular surfaces against complement damage. In summary, our comprehensive analyses of the CFHR proteins have improved our understanding of these proteins and provided further insights into aHUS pathogenesis.
Abarrategui-Garrido
Cynthia
C
Research Unit, Hospital Universitario La Paz and Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046Madrid, Spain.
Martínez-Barricarte
Rubén
R
López-Trascasa
Margarita
M
de Córdoba
Santiago Rodríguez
SR
Sánchez-Corral
Pilar
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001323:Autoantibodies / Q000097:blood; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003180:Complement C3b Inactivator Proteins / Q000172:deficiency / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D005260:Female; D005785:Gene Conversion; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood / Q000235:genetics; D006463:Hemolytic-Uremic Syndrome / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008268:Macular Degeneration / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015345:Oligonucleotide Probes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D040901:Proteomics; D055815:Young Adult
D001323:Autoantibodies; D001798:Blood Proteins; C493495:CFH protein, human; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D015345:Oligonucleotide Probes; D020033:Protein Isoforms; D017242:Complement Factor H