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Thrombotic Microangiopathy in Inverted Formin 2-Mediated Renal Disease

Lookup NU author(s): Rachel Challis, Dr Edwin Wong, Dr Vicky Brocklebank, Dr Valerie Wilson, Professor Kevin MarchbankORCiD, Dr Mauro Santibanez Koref, Professor Tim Goodship, Professor David KavanaghORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


The demonstration of impaired complement regulation in the thrombotic microangiopathy, atypical haemolytic uraemic syndrome (aHUS) has resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. Complement abnormalities account for approximately 50% of aHUS cases however recently mutations in the non-complement gene DGKE have been described in individuals not responsive to eculizumab.We report here a family where the proposita presented with aHUS but did not respond to Eculizumab. Her mother had previously presented with a post renal transplant thrombotic microangiopathy (TMA). Both also had Charcot Marie Tooth (CMT). Using whole exome sequencing we identified a mutation in INF2 in the mutational hotspot for focal segmental glomerulosclerosis (FSGS). Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally significant mutation in INF2. In this family renal transplantation was associated with post transplant TMA. In all individuals with INF2 mutations presenting with a TMA, aHUS risk haplotypes were also present, potentially accounting for the genetic pleiotropy.Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway complement blockade.

Publication metadata

Author(s): Challis RC, Ring T, Xu Y, Wong EKS, Flossmann O, Roberts ISD, Ahmed S, Wetherall M, Salkus G, Brocklebank B, Fester J, Strain L, Wilson V, Wood KM, Marchbank KJ, Santibanez-Koref M, Goodship THJ, Kavanagh D

Publication type: Article

Publication status: Published

Journal: Journal of the American Society of Nephrology

Year: 2017

Volume: 28

Issue: 4

Pages: 1084-1091

Print publication date: 01/04/2017

Online publication date: 14/12/2016

Acceptance date: 19/10/2016

Date deposited: 11/10/2016

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology


DOI: 10.1681/ASN.2015101189


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