Journal article
Mutation of complement factor B causing massive fluid-phase dysregulation of the alternative complement pathway can result in atypical hemolytic uremic syndrome
Kidney international, Vol.98(5), pp.1265-1274
11/2020
DOI: 10.1016/j.kint.2020.05.028
PMCID: PMC7606633
PMID: 32540405
Abstract
Atypical hemolytic uremic syndrome is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. Its pathogenesis is driven most frequently by dysregulated cell-surface control of the alternative pathway of complement secondary to inherited and/or acquired factors. Here we evaluated two unrelated patients with atypical hemolytic uremic syndrome. The first, a five-year-old Caucasian female, presented at 10 months with schistocytes, thrombocytopenia and kidney injury. The second, a 55-year-old Caucasian female, presented at age 31 following caesarean section for preeclampsia. Complement biomarker testing was remarkable for undetectable levels of C3 in both. Circulating levels of C5 and properdin were also low consistent with over-activity of the alternative and terminal pathways of complement. Genetic testing identified a heterozygous novel variant in CFB (c.1101 C>A, p.Ser367Arg) in both patients. Functional studies found strong fluid-phase C3 cleavage when normal and proband sera were mixed. Cell-surface C3b deposition was strongly positive when patient serum was supplemented with C3. In vitro control of C3 convertase activity could be restored with increased concentrations of factor H. Thus, CFB p.Ser367Arg is a gain-of-function pathogenic variant that leads to dysregulation of the alternative pathway in the fluid-phase and increased C3b deposition on cell surfaces. Our study highlights the complexities of complement-mediated diseases like atypical hemolytic uremic syndrome and illustrates the importance of functional studies at the variant level to gain insight into the disease phenotype.
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Details
- Title: Subtitle
- Mutation of complement factor B causing massive fluid-phase dysregulation of the alternative complement pathway can result in atypical hemolytic uremic syndrome
- Creators
- Yuzhou Zhang - University of IowaRobin A Kremsdorf - Brown UniversityC. John Sperati - Johns Hopkins MedicineKammi J Henriksen - University of ChicagoMari Mori - The Ohio State UniversityRenee X Goodfellow - University of IowaGabriella R Pitcher - University of IowaCindy L Benson - Rhode Island HospitalNicolo Ghiringhelli Borsa - University of IowaRonald P Taylor - University of VirginiaCarla M Nester - University of IowaRichard J.H Smith - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Kidney international, Vol.98(5), pp.1265-1274
- DOI
- 10.1016/j.kint.2020.05.028
- PMID
- 32540405
- PMCID
- PMC7606633
- NLM abbreviation
- Kidney Int
- ISSN
- 0085-2538
- eISSN
- 1523-1755
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: R01 110023
- Language
- English
- Date published
- 11/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256928202771
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