Alternative titles; symbols
ORPHA: 2134, 544472;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33 | {Hemolytic uremic syndrome, atypical, susceptibility to, 4} | 612924 | Autosomal dominant | 3 | CFB | 138470 |
A number sign (#) is used with this entry because susceptibility to the development of atypical hemolytic uremic syndrome-4 (AHUS4) can be conferred by mutation in the gene encoding complement factor B (CFB; 138470).
Atypical hemolytic uremic syndrome-4 (AHUS4) is characterized by thrombocytopenia, Coomb test-negative microangiopathic hemolytic anemia, and acute renal failure, in the absence of E. coli infection (summary by Goicoechea de Jorge et al., 2007).
For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400).
Carreras et al. (1981) reported a Spanish family in which 3 individuals, aged between 15 months and 34 years, developed aHUS. Histologic examination showed microangiopathy. The disorder showed recurrence and was associated with persistent hypocomplementemia, decreased serum C3 (120700), and a particular HLA haplotype on chromosome 6p21 (see, e.g., HLA-A; 142800).
In affected members of a large Spanish kindred with atypical hemolytic uremic syndrome-4 (Carreras et al., 1981), Goicoechea de Jorge et al. (2007) identified a heterozygous mutation in the CFB gene (F286L; 138470.0005) that segregated with low levels of C3. Functional expression studies showed that the mutant CFB resulted in increased formation of the C3bB complex, indicating a gain-of-function effect that enhanced the generation of C3b. This explains the increased levels of CFB cleavage and C3 consumption found in mutation carriers. However, the mutant protein also showed increased decay, suggesting that the gain-of-function effect occurs only when the supply of CFB is unlimited. Goicoechea de Jorge et al. (2007) noted that the family showed incomplete penetrance for the F286L mutation. Further genetic analysis showed that all members with the F286L mutation who developed aHUS also carried the at-risk MCP (120920) haplotype described by Esparza-Gordillo et al. (2005). Goicoechea de Jorge et al. (2007) identified a second heterozygous mutation in the CFB gene (K323E; 138470.0006) in another unrelated patient with aHUS; this patient also carried the MCP haplotype. These findings indicated that the aHUS phenotype results from multiple different genetic hits in the complement pathway, and that persistent activation of the alternative pathway can also result in aHUS.
Carreras, L., Romero, R., Requesens, C., Oliver, A. J., Carrera, M., Clavo, M., Alsina, J. Familial hypocomplementemic hemolytic uremic syndrome with HLA-A3, B7 haplotype. JAMA 245: 602-604, 1981. [PubMed: 7452889]
Esparza-Gordillo, J., Goicoechea de Jorge, E., Buil, A., Berges, L. C., Lopez-Trascasa, M., Sanchez-Corral, P., Rodriguez de Cordoba, S. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum. Molec. Genet. 14: 703-712, 2005. Note: Erratum: Hum. Molec. Genet. 14: 1107 only, 2005. [PubMed: 15661753] [Full Text: https://doi.org/10.1093/hmg/ddi066]
Goicoechea de Jorge, E. G., Harris, C. L., Esparza-Gordillo, J., Carreras, L., Arranz, E. A., Garrido, C. A., Lopez-Trascasa, M., Sanchez-Corral, P., Morgan, B. P., Rodriguez de Cordoba, S. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc. Nat. Acad. Sci. 104: 240-245, 2007. Note: Erratum: Proc. Nat. Acad. Sci. 104: 10749 only, 2007. [PubMed: 17182750] [Full Text: https://doi.org/10.1073/pnas.0603420103]