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A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome

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Abstract

Background

Mutations in complement factor H (CFH) are associated with complement dysregulation and the development of an aggressive form of atypical hemolytic uremic syndrome (aHUS) that progresses to end-stage renal disease (ESRD) and in most patients has a high rate of recurrence following transplantation. Sequence analysis of CFH and its downstream complement factor H-related genes (CFHR1-5) reveals several macrohomologous blocks caused by large genomic duplications. This high degree of sequence identity renders this area susceptible to nonallelic homologous recombination (NAHR) events, resulting in large-scale deletions, duplications, and the generation of hybrid CFH genes.

Case-Diagnosis

Here, we report the finding of a novel CFHR1/CFH hybrid gene created by a de novo NAHR event in a 14-year-old girl with aHUS. The resulting fusion protein contains the first three short consensus repeats (SCRs) of CFHR1 and the terminal two SCRs of CFH.

Conclusions

This finding demonstrates a novel pathogenic mechanism for the development of aHUS. Additionally, since standard Sanger sequencing is unable to detect such rearrangements, all aHUS patients should receive comprehensive genetic screening that includes analysis of copy number variation in order to identify patients with poor clinical prognoses.

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Support

This study was supported by grants from the Doris Duke Clinical Research Foundation (SJE), the University of Iowa Institute for Clinical and Translational Science (SJE), the Foundation for Children with Atypical HUS (RJHS), and NIH grant DK074409 (RJHS).

Financial disclosure

The authors declare that they have no relevant financial interests.

Author information

Authors and Affiliations

  1. Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, 5270 CBRB Building, Iowa City, IA, 52242, USA

    Stephen J. Eyler, Nicole C. Meyer, Yuzhou Zhang, Xue Xiao, Carla M. Nester & Richard J. H. Smith

  2. Interdepartmental PhD Program in Genetics, Carver College of Medicine, University of Iowa, 5270 CBRB Building, Iowa City, IA, 52242, USA

    Xue Xiao & Richard J. H. Smith

  3. Departments of Pediatrics and Internal Medicine, Divisions of Nephrology, Carver College of Medicine, University of Iowa, 5270 CBRB Building, Iowa City, IA, 52242, USA

    Carla M. Nester & Richard J. H. Smith

Authors
  1. Stephen J. Eyler
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  2. Nicole C. Meyer
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  3. Yuzhou Zhang
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  4. Xue Xiao
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  5. Carla M. Nester
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  6. Richard J. H. Smith
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Corresponding author

Correspondence to Richard J. H. Smith.

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Supplemental Figure 1

Competitive surface binding may contribute to local complement dysregulation—a proposed mechanism. The C-terminal CFH SCRs of the CFHR1/CFH fusion protein allow it to compete with CFH for surface binding to glycosaminoglycans (GAGs) and C3b on host cell surfaces. Less surface bound CFH contributes to alternative pathway dysregulation. CFH SCRs 1-4 contain the cofactor and decay acceleration activity domains and are absent in the fusion protein. Homology in the C-terminal SCRs of CFHR1 allow it compete for surface binding as well, though it does so with lesser affinity (GIF 14 kb).

Figure S1

High resolution image (EPS 20204 kb)

Supplementary Table S1

MLPA probe sequences (DOC 39 kb)

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Eyler, S.J., Meyer, N.C., Zhang, Y. et al. A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome. Pediatr Nephrol 28, 2221–2225 (2013). https://doi.org/10.1007/s00467-013-2560-2

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  • DOI: https://doi.org/10.1007/s00467-013-2560-2

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