title: Thrombotic Microangiopathy in Inverted Formin 2-Mediated Renal Disease.
abstract: 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-εhave 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 inINF2In this family, renal transplantation was associated with post-transplant TMA. All individuals withINF2mutations 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.
authors.affiliation: National Renal Complement Therapeutics Centre, Institutes of *Genetic Medicine and.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Challis
authors.affiliation: Department of Nephrology, Aalborg University Hospital and.
authors.forename: Troels
authors.initials: T
authors.lastname: Ring
authors.affiliation: National Renal Complement Therapeutics Centre, Institutes of *Genetic Medicine and.
authors.forename: Yaobo
authors.initials: Y
authors.lastname: Xu
authors.affiliation: National Renal Complement Therapeutics Centre, Institutes of *Genetic Medicine and.
authors.forename: Edwin K S
authors.initials: EK
authors.lastname: Wong
authors.affiliation: Renal Unit, Royal Berkshire Hospital, Reading, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Flossmann
authors.affiliation: Department of Cellular Pathology, Oxford University Hospitals National Health Service Trust, Oxford, United Kingdom.
authors.forename: Ian S D
authors.initials: IS
authors.lastname: Roberts
authors.affiliation: Department of Nephrology, City Hospitals Sunderland National Health Service Foundation Trust, Sunderland, United Kingdom.
authors.forename: Saeed
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Pathology, Gateshead Health National Health Service Foundation Trust, Gateshead, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Wetherall
authors.affiliation: Department of Pathology, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Giedrius
authors.initials: G
authors.lastname: Salkus
authors.affiliation: National Renal Complement Therapeutics Centre, Institutes of *Genetic Medicine and.
authors.forename: Vicky
authors.initials: V
authors.lastname: Brocklebank
authors.affiliation: Egton Surgery, Whitby, United Kingdom; and.
authors.forename: Julian
authors.initials: J
authors.lastname: Fester
authors.affiliation: National Renal Complement Therapeutics Centre, Northern Molecular Genetics Service and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Strain
authors.affiliation: National Renal Complement Therapeutics Centre, Northern Molecular Genetics Service and.
authors.forename: Valerie
authors.initials: V
authors.lastname: Wilson
authors.affiliation: Department of Cellular Pathology, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, United Kingdom.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Wood
authors.affiliation: Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Marchbank
authors.affiliation: National Renal Complement Therapeutics Centre, Institutes of *Genetic Medicine and.
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: National Renal Complement Therapeutics Centre, Institutes of *Genetic Medicine and.
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.affiliation: National Renal Complement Therapeutics Centre, Institutes of *Genetic Medicine and david.kavanagh@ncl.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
mesh_terms: D000293:Adolescent; D065766:Atypical Hemolytic Uremic Syndrome / Q000150:complications* / Q000235:genetics*; D002648:Child; D005260:Female; D000080865:Formins; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D057049:Thrombotic Microangiopathies / Q000209:etiology*
chemical_list: D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins
keywords: complement; focal segmental glomerulosclerosis; hemolytic uremic syndrome