Toggle Main Menu Toggle Search

Open Access padlockePrints

Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype

Lookup NU author(s): Dr Veronique Fremaux-Bacchi, Professor Tim Goodship

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%-10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation. J Am Soc Nephrol 24: 475-486, 2013. doi: 10.1681/ASN.2012090884


Publication metadata

Author(s): Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, de Cordoba SR, Pinto S, Goodship THJ, Alberti M, Ribes D, Valoti E, Remuzzi G, Noris M, European Working Party Complement

Publication type: Article

Publication status: Published

Journal: Journal of the American Society of Nephrology

Year: 2013

Volume: 24

Issue: 3

Pages: 475-486

Print publication date: 01/03/2013

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology

URL: http://dx.doi.org/10.1681/ASN.2012090884

DOI: 10.1681/ASN.2012090884


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
ANR
Fondazione ART per la Ricerca sui Trapianti ART ONLUS (Milano, Italy)
Compagnia di San Paolo (Torino, Italy)
Fondazione Aiuti per la Ricerca sulle Malattie Rare ARMR ONLUS (Bergamo, Italy)
Fundacion Renal Inigo Alvarez de Toledo
Progetto Alice ONLUS (Milano, Italy)
305608European Union
GGP07193Telethon Project
G0701325United Kingdom Medical Research Council
PS09/00268Spanish Ministerio de Economia y Competitividad
S2010/BMD-2316Comunidad de Madrid
PHRC AOM 08198Delegation Regionale a la Recherche Clinique, Assistance Publique-Hopitaux de Paris
SAF2010-26583Spanish Ministerio de Economia y Competitividad

Share