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Published on: February 2, 2018
Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome
Elena Goicoechea de Jorge1, Claire L Harris, Jorge Esparza-Gordillo
1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Summary
Mutations in the factor B gene (BF) cause atypical hemolytic uremic syndrome (aHUS) by overactivating the complement alternative pathway. This discovery highlights the pathway's role in aHUS and supports complement-inhibition therapies.
Area of Science:
- Immunology
- Genetics
- Nephrology
Background:
- Atypical hemolytic uremic syndrome (aHUS) is a severe condition causing acute kidney failure in children.
- Genetic defects in complement-regulatory proteins are found in about a third of aHUS patients, suggesting impaired cell surface protection against complement activation.
- Persistent complement alternative pathway activation is observed in a subgroup of aHUS patients.
Purpose of the Study:
- To investigate the genetic basis of aHUS in patients with persistent complement alternative pathway activation.
- To identify specific mutations contributing to the pathogenesis of aHUS.
Main Methods:
- Genetic analysis of families with aHUS.
- Functional studies of identified mutations in the factor B (BF) gene.
- Assessing complement alternative pathway convertase (C3bBb) formation and regulation.
Main Results:
- Two families with aHUS exhibited mutations in the factor B (BF) gene.
- Identified BF mutations (F286L and K323E) are gain-of-function mutations.
- These mutations enhance C3bBb convertase formation and/or resistance to inactivation by complement regulators.
Conclusions:
- Genetic variations in factor B (BF) predispose individuals to aHUS.
- The complement alternative pathway plays a crucial role in aHUS pathogenesis.
- Findings support the therapeutic potential of complement-inhibition strategies for aHUS.
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