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. 2017 Apr;28(4):1084-1091.
doi: 10.1681/ASN.2015101189. Epub 2016 Dec 14.

Thrombotic Microangiopathy in Inverted Formin 2 - Mediated Renal Disease

Rachel C Challis  1 , Troels Ring  2 , Yaobo Xu  1 , Edwin K S Wong  1 , Oliver Flossmann  3 , Ian S D Roberts  4 , Saeed Ahmed  5 , Michael Wetherall  6 , Giedrius Salkus  7 , Vicky Brocklebank  1 , Julian Fester  8 , Lisa Strain  9 , Valerie Wilson  9 , Katrina M Wood  10 , Kevin J Marchbank  11 , Mauro Santibanez-Koref  1 , Timothy H J Goodship  1 , David Kavanagh  12
Affiliations

Thrombotic Microangiopathy in Inverted Formin 2 - Mediated Renal Disease

Rachel C Challis et al. J Am Soc Nephrol. 2017 Apr.

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-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.

Keywords: complement; focal segmental glomerulosclerosis; hemolytic uremic syndrome.

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Figures

Figure 1.
Figure 1.
Pedigrees of families with INF2 genetic variants. The pedigrees demonstrate the segregation of the renal/neurologic phenotype with the rare genetic variant, c.305T>A (p.V102D) in family 1 (A), and c.530G>A (p.R177H) in family 2 (D). Individuals tested but not carrying the mutation are shown (nmd, no mutation detected). The number of alleles carrying the aHUS risk haplotype CFH-H3 (CFHrisk) and CD46GGAAC (CD46risk) are shown on the pedigree. Sanger sequencing trace of wild type (WT) and mutant (Mut) for c.305T>A (p.V102D) (B) and c.530G>A (p.R177H) (E). Alignment of human, chimpanzee, orangutan, mouse, rat, dog, opossum, platypus, and zebrafish INF2 demonstrating amino acid conservation (C and F) (performed using http://genome.ucsc.edu/cgibin/hgTrackUi?hgsid=309786867&c=chr21&g=cons46way#a_cfg_phyloP).
Figure 2.
Figure 2.
Thrombotic microangiopathy in renal biopsy from patients with INF2 mutations. Renal biopsies. Native renal biopsy from family 1, patient III:2. (A) Two arterioles (right) showing features of active thrombosis and a small artery (left) with relatively slight intimal edema with fibrosis (hematoxylin and eosin stain [H&E]). (B) Glomerulus (left) showing global sclerosis and occluded arteriole (right) (periodic acid–Schiff [PAS]). Native renal biopsy from family 1, patient II:2 demonstrating end-stage changes with diffuse global sclerosis (C). Renal transplant biopsy from family 1, patient II:2 demonstrating (D) an occluded arteriole (PAS) and (E) a capillary loop with abundant subendothelial fluffy material (electron microscopy). Native renal biopsy from family 2, patient III:2 demonstrating (F) a sclerosed glomeruli and (G) a segmental sclerosing lesion. Renal transplant biopsy from family 2, patient III:1. Mucoid intimal thickening is seen in an interlobular artery with red cell fragmentation in the wall and luminal thrombus (H). Mesangiolysis is also seen 3–6 o’clock (I) (silver stain). Native renal biopsy from family 2, patient III:2 showing a subacute/chronic arterial TMA with fibroproliferative obliteration of small arteries and arterioles (J) (H&E) and (K) (trichrome). Renal transplant biopsy from family 2, patient III:2 demonstrating end stage change with fibrous obliteration of arteries. (L) (H&E).
Figure 3.
Figure 3.
Hotspots for inverted formin 2 (INF2) variants in FSGS, CMT, and aHUS. A representation of the domain structure of INF2 showing the DID domain, formin homology domains (FH1, FH2), and the DAD domain. Genetic variants associated with isolated FSGS are shown below the domain structure. Genetic variants with a combined FSGS/CMT phenotype are shown above the domain structure. Variants from Mademan et al. The locations of the aHUS-associated mutations demonstrated in the study are shown in red.
Figure 4.
Figure 4.
Predicted structure of DID domain of inverted formin 2 (INF2). A structural model of the DID domain (amino acids 1–234) was generated using Phyre2 (A). Blue spheres represent the amino acids involved in binding to DAD domain: (R106, N110, A149, I152). The position of the p.V102D and R177H mutations are highlighted in red. The p.V102D lies in the eighth α-helix of the DID (amino acids) domain. (B) Surface representation of the modeled structure highlighting the surface-exposed amino acids responsible for DAD binding (R106, N110, A149, I152). The mutant p.V102D is not buried but may be expected to disrupt the architecture of the eighth α-helix. The p.R177H variant resides before the 13th α-helix of the DID domain and is surface-exposed. (C) Semi transparent representation of the surface of the INF2 model highlighting the variants.
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