A Novel Homozygous In-Frame Deletion in Complement Factor 3 Underlies Early-Onset Autosomal Recessive Atypical Hemolytic Uremic Syndrome - Case Report.
alternative complement pathway
atypical hemolytic uremic syndrome (aHUS)
complement factor C3
eculizumab
homozygous deletion
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
21
09
2020
accepted:
24
05
2021
entrez:
12
7
2021
pubmed:
13
7
2021
medline:
16
9
2021
Statut:
epublish
Résumé
Atypical hemolytic uremic syndrome (aHUS) is mostly attributed to dysregulation of the alternative complement pathway (ACP) secondary to disease-causing variants in complement components or regulatory proteins. Hereditary aHUS due to C3 disruption is rare, usually caused by heterozygous activating mutations in the A male neonate with eculizumab-responsive fulminant aHUS and C3 hypocomplementemia, and six of his healthy close relatives were investigated. Genetic analysis on genomic DNA was performed by exome sequencing of the patient, followed by targeted Sanger sequencing for variant detection in his close relatives. Complement components analysis using specific immunoassays was performed on frozen plasma samples from the patient and mother. Exome sequencing revealed a novel homozygous variant in exon 26 of Our findings represent the first description of aHUS secondary to a novel homozygous deletion in C3 with ensuing unbalanced C3 over-activation, highlighting a critical role for the disrupted C3-TED domain in the disease mechanism.
Sections du résumé
Background and Objectives
Atypical hemolytic uremic syndrome (aHUS) is mostly attributed to dysregulation of the alternative complement pathway (ACP) secondary to disease-causing variants in complement components or regulatory proteins. Hereditary aHUS due to C3 disruption is rare, usually caused by heterozygous activating mutations in the
Design Setting Participants & Measurements
A male neonate with eculizumab-responsive fulminant aHUS and C3 hypocomplementemia, and six of his healthy close relatives were investigated. Genetic analysis on genomic DNA was performed by exome sequencing of the patient, followed by targeted Sanger sequencing for variant detection in his close relatives. Complement components analysis using specific immunoassays was performed on frozen plasma samples from the patient and mother.
Results
Exome sequencing revealed a novel homozygous variant in exon 26 of
Conclusions
Our findings represent the first description of aHUS secondary to a novel homozygous deletion in C3 with ensuing unbalanced C3 over-activation, highlighting a critical role for the disrupted C3-TED domain in the disease mechanism.
Identifiants
pubmed: 34248927
doi: 10.3389/fimmu.2021.608604
pmc: PMC8264753
doi:
Substances chimiques
Complement C3
0
Complement Membrane Attack Complex
0
Types de publication
Case Reports
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
608604Informations de copyright
Copyright © 2021 Pollack, Eisenstein, Mory, Paperna, Ofir, Baris-Feldman, Weiss, Veszeli, Csuka, Shemer, Glaser, Prohászka and Magen.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Nature. 2005 Sep 22;437(7058):505-11
pubmed: 16177781
J Immunol. 2012 Feb 15;188(4):2030-7
pubmed: 22250080
Protein Sci. 2021 Jan;30(1):70-82
pubmed: 32881101
Clin J Am Soc Nephrol. 2009 Aug;4(8):1356-62
pubmed: 19590060
Biosci Rep. 2014 Oct 22;34(5):
pubmed: 25188723
Front Immunol. 2020 Jul 16;11:1348
pubmed: 32765494
Clin J Am Soc Nephrol. 2013 Apr;8(4):554-62
pubmed: 23307876
Nature. 2006 Nov 9;444(7116):213-6
pubmed: 17051160
Nat Genet. 2013 May;45(5):531-6
pubmed: 23542698
Nat Struct Mol Biol. 2011 Apr;18(4):463-70
pubmed: 21317894
Med Genet. 2018;30(4):400-409
pubmed: 30930551
Kidney Int. 2018 Aug;94(2):408-418
pubmed: 29907460
PLoS Pathog. 2010 Sep 30;6(9):e1001122
pubmed: 20941397
Transfus Med Rev. 2019 Oct;33(4):199-206
pubmed: 31672340
J Am Soc Nephrol. 2014 Jan;25(1):55-64
pubmed: 24029428
Front Immunol. 2019 May 01;10:853
pubmed: 31118930
Mol Immunol. 2007 Jan;44(1-3):3-10
pubmed: 16875735
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
J Atheroscler Thromb. 2019 Feb 1;26(2):99-110
pubmed: 30393246
Blood. 2012 May 3;119(18):4182-91
pubmed: 22246034
Blood. 2015 Apr 9;125(15):2359-69
pubmed: 25608561
Proc Natl Acad Sci U S A. 1985 Feb;82(3):708-12
pubmed: 2579379
Nat Immunol. 2009 Jul;10(7):728-33
pubmed: 19503104
J Allergy Clin Immunol. 2016 Feb;137(2):640-644.e1
pubmed: 26435005
J Am Soc Nephrol. 2013 Feb;24(3):475-86
pubmed: 23431077
Blood. 2008 Dec 15;112(13):4948-52
pubmed: 18796626
Scand J Immunol. 2006 Mar;63(3):155-68
pubmed: 16499568
Methods Mol Biol. 2020;2165:175-198
pubmed: 32621225
Mol Immunol. 2015 Aug;66(2):263-73
pubmed: 25879158
N Engl J Med. 2009 Oct 22;361(17):1676-87
pubmed: 19846853
J Med Genet. 2014 Nov;51(11):756-64
pubmed: 25261570
Semin Hematol. 2018 Jul;55(3):150-158
pubmed: 30032752
Pediatr Nephrol. 2016 Jan;31(1):15-39
pubmed: 25859752
Blood. 2010 Jan 14;115(2):379-87
pubmed: 19861685
J Immunol. 2018 Apr 1;200(7):2464-2478
pubmed: 29500241