Alternative titles; symbols
ORPHA: 2134, 544472;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q25 | {Hemolytic uremic syndrome, atypical, susceptibility to, 3} | 612923 | Autosomal dominant | 3 | CFI | 217030 |
A number sign (#) is used with this entry because susceptibility to the development of atypical hemolytic uremic syndrome-3 (AHUS3) can be conferred by heterozygous mutation in the gene encoding complement factor I (CFI; 217030) on chromosome 4q25.
Atypical hemolytic uremic syndrome-2 (AHUS2) is clinically manifest as a combination of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment, in the absence of a triggering Shiga toxin-producing E. coli infection (Caprioli et al., 2006).
For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400).
Fremeaux-Bacchi et al. (2004) reported 3 unrelated patients with aHUS. The first patient was a 32-year-old woman who developed aHUS after pregnancy. Renal biopsy showed thrombotic microangiopathy. She had decreased serum factor I, factor B (CFB; 138470), and C3, indicating consumptive depletion of these complement proteins. Her unaffected father also carried the mutation; he had decreased serum factor I. The second patient developed aHUS with severe microangiopathic hemolytic anemia, hypertension, and proteinuria at age 17 months. He had a relapse 6 months later. Two years later, his renal function was normal, but he required antihypertensive treatment. His clinically unaffected mother also carried the mutation. Although serum factor I levels were normal in both the patient and his mother, both showed decreased serum C3 and factor B. The third patient was a 26-year-old woman who had recurrence of HUS following a second renal transplantation and thrombotic microangiopathy. Serum factor I levels were 36% of normal.
In 3 unrelated patients with aHUS, Fremeaux-Bacchi et al. (2004) identified heterozygous mutations in the complement factor I gene (217030.0004-217030.0006). In 2 families, a clinically unaffected parent also carried the mutation, suggesting incomplete penetrance and that heterozygous mutations in the CFI gene confer susceptibility to aHUS.
Caprioli et al. (2006) identified 5 different CFI mutations (see, e.g., 217030.0008-217030.0009) in 7 (4.5%) of 156 patients with AHUS. Three of 5 patients had decreased serum C3 levels. Normal renal function was preserved in 33.3% of patients with CFI mutations. Kidney transplant was not effective in preventing recurrence in these patients.
Esparza-Gordillo et al. (2006) reported a large Spanish pedigree with aHUS in which 2 affected members had 3 molecular risk factors: a mutation in the MCP gene that decreased MCP expression on the cell surface, a mutation in the CFI gene that resulted in premature termination, and a SNP haplotype of MCP that had been shown to decrease transcriptional activity. Family members with only 1 or 2 of these molecular defects did not develop the disease. The findings indicated an additive effect for mutations in the MCP and CFI genes and supported the notion that aHUS results from defective protection of cellular surfaces from complement activation. Esparza-Gordillo et al. (2006) also commented that the concurrence of multiple hits in complement regulatory proteins may be necessary to confer susceptibility to the disease. This would also explain the observed decreased penetrance of most mutations.
Caprioli, J., Noris, M., Brioschi, S., Pianetti, G., Castelletti, F., Bettinaglio, P., Mele, C., Bresin, E., Cassis, L., Gamba, S., Porrati, F., Bucchioni, S., Monteferrante, F., Fang, C. J., Liszewski, M. K., Kavanagh, D., Atkinson, J. P., Remuzzi, G. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108: 1267-1279, 2006. [PubMed: 16621965] [Full Text: https://doi.org/10.1182/blood-2005-10-007252]
Esparza-Gordillo, J., de Jorge, E. G., Garrido, C. A., Carreras, L., Lopez-Trascasa, M., Sanchez-Corral, P., de Cordoba, S. R. Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Molec. Immun. 43: 1769-1775, 2006. [PubMed: 16386793] [Full Text: https://doi.org/10.1016/j.molimm.2005.11.008]
Fremeaux-Bacchi, V., Dragon-Durey, M.-A., Blouin, J., Vigneau, C., Kuypers, D., Boudailliez, B., Loirat, C., Rondeau, E., Fridman, W. H. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J. Med. Genet. 41: e84, 2004. Note: Electronic Article. [PubMed: 15173250] [Full Text: https://doi.org/10.1136/jmg.2004.019083]