A Complement Factor B Mutation in a Large Kindred with Atypical Hemolytic Uremic Syndrome |
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Authors: | Michinori Funato Osamu Uemura Katsumi Ushijima Hidenori Ohnishi Kenji Orii Zenichiro Kato Satoshi Yamakawa Takuhito Nagai Osamu Ohara Hideo Kaneko Naomi Kondo |
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Institution: | 1. Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan 2. Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan 3. Department of Pediatric Nephrology, Aichi Children’s Health and Medical Center, Obu, Japan 4. Department of Pediatrics, Yokkaichi Municipal Hospital, Yokkaichi, Japan 5. Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan 6. Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Japan
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Abstract: | Purpose Gain-of-function mutations in complement factor B (CFB) were recently identified in patients with atypical hemolytic uremic syndrome (aHUS), but are extremely rare. Our purpose is to describe a large kindred with aHUS associated with a CFB mutation and to further understand CFB-mutated aHUS patients. Methods and Results We report a large kindred in which 3 members had aHUS. This kindred revealed that 9 of 12 members, including 2 affected patients, had persistent activation of the alternative pathway with low complement component 3 and that those 9 members showed a CFB mutation (c.1050G?>?C, p.Lys350Asn) in exon 8. This missense mutation was heterozygous in 8 of them and homozygous in only one. From structural studies, this mutation is shown to be located in close proximity to the Mg2-binding site within a von Willebrand factor type A domain of CFB, resulting in a gain-of-function effect of CFB and predisposition to aHUS. At present, 2 of the 3 members with aHUS have maintained normal renal function for a long-term period. Conclusions This kindred illustrates that a CFB mutation (c.1050G?>?C, p.Lys350Asn) can result in aHUS. In the future, phenotype-genotype correlations and outcome in CFB-mutated aHUS patients need to be further investigated by accumulation of a number of cases. |
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