Thrombotic Microangiopathy in Inverted Formin 2-Mediated Renal Disease

Rachel C Challis, Troels Ring, Yaobo Xu, Edwin K S Wong, Oliver Flossmann, Ian S D Roberts, Saeed Ahmed, Michael Wetherall, Giedrius Salkus, Vicky Brocklebank, Julian Fester, Lisa Strain, Valerie Wilson, Katrina M Wood, Kevin J Marchbank, Mauro Santibanez-Koref, Timothy H J Goodship, David Kavanagh

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35 Citations (Scopus)


The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-ε have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for 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. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, 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 C blockade.

Original languageEnglish
JournalAmerican Society of Nephrology. Journal
Issue number4
Pages (from-to)1084-1091
Number of pages8
Publication statusPublished - 2017


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