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Genetics and complement in atypical HUS

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Abstract

Central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS) is over-activation of the alternative pathway of complement. Following the initial discovery of mutations in the complement regulatory protein, factor H, mutations have been described in factor I, membrane cofactor protein and thrombomodulin, which also result in decreased complement regulation. Autoantibodies to factor H have also been reported to impair complement regulation in aHUS. More recently, gain of function mutations in the complement components C3 and Factor B have been seen. This review focuses on the genetic causes of aHUS, their functional consequences, and clinical effect.

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Abbreviations

HUS:

Hemolytic uremic syndrome

D+ve HUS:

Diarrhoeal-associated hemolytic uremic syndrome

aHUS:

Atypical hemolytic uremic syndrome

AP:

Alternative pathway

CP:

Classical pathway

CCPs:

Complement control protein modules

RCA:

Regulators of complement activation

ESRF:

End-stage renal failure

SNPs:

Single nucleotide polymorphisms

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Acknowledgements

DK is funded by Kidney Research UK, The Academy of Medical Science, and the Mason Medical Research Trust.

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Authors and Affiliations

  1. The Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK

    David Kavanagh & Tim Goodship

  2. Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK

    David Kavanagh

Authors
  1. David Kavanagh
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  2. Tim Goodship
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Corresponding author

Correspondence to David Kavanagh.

Questions

Questions

(Answers appear following the reference list)

  1. 1.

    Familial atypical HUS

    1. a)

      Is completely penetrant.

    2. b)

      Has been causally associated with Eculizumab treatment.

    3. c)

      Is predisposed to by mutations in complement factor H.

    4. d)

      Always presents in childhood.

    5. e)

      Never recurs following renal transplantation.

  2. 2.

    In atypical HUS

    1. a)

      Complement factor B mutations are the commonest genetic cause.

    2. b)

      Individuals with membrane cofactor mutations never have disease recurrence.

    3. c)

      Individuals who present during pregnancy never have complement mutations.

    4. d)

      Complement factor H mutations are the rarest genetic cause.

    5. e)

      Autoantibodies to factor H have been associated with disease.

  3. 3.

    Atypical hemolytic uremic syndrome is associated with mutations in complement regulatory genes. A low recurrence rate of aHUS post renal transplantation is associated with mutations in which of the following genes?

    1. a)

      Complement factor I

    2. b)

      Complement factor H

    3. c)

      Membrane cofactor protein

    4. d)

      Complement factor B

    5. e)

      C3

  4. 4.

    In aHUS, autoantibodies to complement factor H

    1. a)

      Do not result in impaired complement regulation at host cell surfaces.

    2. b)

      Are associated with a deletion of the CFHR1 and CFHR3 genes.

    3. c)

      Always bind to the C-terminal region of complement factor H.

    4. d)

      Never cross react with the complement factor H-related 1 protein.

    5. e)

      Cannot be removed by plasma exchange.

Answers:

  1. 1.

    c

  2. 2.

    e

  3. 3.

    c

  4. 4.

    b

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Kavanagh, D., Goodship, T. Genetics and complement in atypical HUS. Pediatr Nephrol 25, 2431–2442 (2010). https://doi.org/10.1007/s00467-010-1555-5

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  • DOI: https://doi.org/10.1007/s00467-010-1555-5

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