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Abstract: PO2238

A Mutation in Complement Factor B Causing Massive Fluid-Phase Dysregulation of the Alternative Complement Pathway Can Result in Atypical Hemolytic Uremic Syndrome

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Zhang, Yuzhou, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Kremsdorf, Robin Amy, Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States
  • Sperati, John, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Henriksen, Kammi J., Department of Pathology, University of Chicago, Chicago, Illinois, United States
  • Mori, Mari, Division of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States
  • Goodfellow, Renee X., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Pitcher, Gabriella R., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Ghiringhelli Borsa, Nicolo, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Taylor, Ronald P., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Nester, Carla Marie, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
  • Smith, Richard J., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States
Introduction

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. Pathogenesis is driven most frequently by dysregulated cell-surface control of the alternative pathway (AP) of complement secondary to inherited and/or acquired factors.

Case Description

We present two unrelated aHUS patients (a 5-year-old female and a 55-year-old female) who presented with the classic signs of thrombotic microangiopathy associated with renal failure with the additional finding of an undetectable C3 level. Circulating levels of C5 and properdin were also low, consistent with over-activity of both the alternative and the terminal pathways of complement. Genetic testing identified a heterozygous novel variant in the complement factor B gene (CFB c.1101 C>A, p.Ser367Arg). Functional studies demonstrated 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.

Discussion

CFB p.Ser367Arg is a gain-of-function pathogenic variant that leads to dysregulation of the AP in the fluid-phase and increased C3b deposition on cell surfaces. This report highlights the complexities of complement-mediated diseases like aHUS and illustrates the importance of functional studies to characterize variants of unknown significance and to gain insight into the disease phenotype.