Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome

Abstract

Factor H autoantibodies have been reported in approximately 10% of patients with atypical hemolytic uremic syndrome (aHUS) and are associated with deficiency of factor H-related proteins 1 and 3. In this study we examined the prevalence of factor H autoantibodies in the Newcastle cohort of aHUS patients, determined whether the presence of such autoantibodies is always associated with deficiency of factor H-related proteins 1 and 3, and examined whether such patients have additional susceptibility factors and/or mutations in the genes encoding complement regulator/activators. We screened 142 patients with aHUS and found factor H autoantibodies in 13 individuals (age 1-11 years). The presence of the autoantibodies was confirmed by Western blotting. By using multiplex ligation-dependent probe amplification we measured complement factor H-related (CFHR)1 and CFHR3 copy number. In 10 of the 13 patients there were 0 copies of CFHR1, and in 3 patients there were 2. In 3 of the patients with 0 copies of CFHR1 there was 1 copy of CFHR3, and these individuals exhibited a novel deletion incorporating CFHR1 and CFHR4. In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation. (Blood. 2010;115:379-387)

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

“…36 The latter has been shown to result in the deletion of genes encoding the fH-related proteins (CFHR1, CFHR3, and CFHR4) 8,10 and the formation of hybrid genes (CFH/CFHR1). 6 These genomic disorders could be considered as being forms of "macrohomology."…”

“…7 We have also shown that NAHR in this region leads to deletions incorporating CFHR3/CFHR1 and CFHR1/CFHR4, which are associated with the presence of fH autoantibodies in aHUS. [8][9][10] We routinely use multiplex ligation-dependent probe amplification (MLPA) 11 to screen for genomic disorders in aHUS. In this study, we report the finding of a deletion in the C terminal region of CFH in a large aHUS family.…”

Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

“…Few descriptive reports on clinical and biologic data and treatments for CFH antibody-positive aHUS have been published (25,26,(29)(30)(31)(32)(33)(35)(36)(37). This study sought to evaluate the frequency of deletions in the CFHR1-5 genes and the presence of CFH antibodies in pediatric patients with aHUS and in healthy blood donors.…”

A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

“…The most frequently observed NAHR is the deletion of CFHR3-CFHR1 that is strongly associated with anti-FH autoantibodies and aHUS. 7,[10][11][12] Several hybrid genes deriving from NAHR in the CFH-CFHR region have been also identified in aHUS, [13][14][15] including hybrid CFH/CFHR1 and CFH/CFHR3 genes. Recently, a hybrid CFHR1/CFH gene that encodes a fusion protein with the first three short consensus repeats (SCRs) of FHR1 and the last two SCRs of FH has been reported in a sporadic case of aHUS.…”