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Novel factor H mutation associated with familial membranoproliferative glomerulonephritis type I

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Abstract

Background

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare disease, accounting for 3–5 % of all cases of primary nephritic syndrome. We report an uncommon case of familial MPGN type I associated with a new mutation in the complement factor H gene (CFH).

Methods

Clinical data were collected on three siblings with known factor H deficiency who presented with MPGN. All underwent immunological and genetic assays. Their parents and ten healthy adults served as controls for the DNA analysis.

Results

All three children presented with recurrent episodes of hematuria and proteinuria, the youngest starting at age 5 months. One child currently has nephrotic syndrome and end-stage renal disease. All of the children were found to be homozygous for a C.262C > A (p.Pro88Thr) mutation in exon 3 of CFH that is associated with a quantitative/functional deficiency of factor H. The parents of the three siblings were found to be heterozygous for the mutation. None of the controls carried this mutation.

Conclusions

Different mutations in CFH may be responsible for different glomerular diseases, including MPGN type I. A modifier gene or an environmental trigger may contribute to this phenotype–genotype discrepancy. Understanding the role of the alternative complement pathway in this disease would allow us to offer these patients more targeted therapy, including a clinical trial of eculizumab.

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References

  1. Bonilla-Felix M, Parra C, Dajani T, Ferris M, Swinford RD, Portman RJ, Verani R (1999) Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int 55:1885–1890

    Article  CAS  PubMed  Google Scholar 

  2. Orth SR, Ritz E (1998) The nephrotic syndrome. N Engl J Med 338:1202–1211

    Article  CAS  PubMed  Google Scholar 

  3. Habib R, Kleinknechet C, Gubler MC, Levy M (1973) Idiopathic membranoproliferative glomerulonephritis in children. Report of 105 cases. Clin Nephrol 1:194–214

    CAS  PubMed  Google Scholar 

  4. Sethi S, Fervenza FC (2012) Membranoproliferative glomerulonephritis—a new look at an old entity. N Engl J Med 366:1119–1131

    Article  CAS  PubMed  Google Scholar 

  5. Pickering MC, D’Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, Alpers CE, Bajema IM, Bedrosian C, Braun M, Doyle M, Fakhouri F, Fervenza FC, Fogo AB, Frémeaux-Bacchi V, Gale DP, Goicoechea de Jorge E, Griffin G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul Morgan B, Nast CC, Noel LH, Peters DK, Rodríguez de Córdoba S, Servais A, Sethi S, Song WC, Tamburini P, Thurman JM, Zavros M, Cook HT (2013) C3 glomerulopathy: consensus report. Kidney Int 84:1079–1089

    Article  PubMed Central  PubMed  Google Scholar 

  6. Servias A, Fremeaux Bacchi V, Lequinterc M, Salomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F (2007) Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with hemolytic uraemic syndrome. J Med Genet 44:193–199

    Article  Google Scholar 

  7. Schwartz R, Rother U, Ander D, Gretz N, Scharer K, Kirshfink M (2001) Complement analysis in children with idiopathic membranoproliferative GN: a long-term follow up. Pediatr Allergy Immunol 12:166–172

    Article  Google Scholar 

  8. Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, Markowitz GS, D'Agati VD (2009) Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol 4:22–32

    Article  PubMed Central  PubMed  Google Scholar 

  9. Servais A, Noel AH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grünfeld JP, Niaudet P, Lesavre P, Frémeaux-Bacchi V (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454–464

    Article  CAS  PubMed  Google Scholar 

  10. Leroy V, Fremeaux-Bacchi V, Peuchmaur M, Baudouin V, Deschênes G, Macher MA, Loirat C (2011) Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation. Pediatr Nephrol 26:419–424

    Article  PubMed  Google Scholar 

  11. Vaziri Sani F, Holmberg L, Sjoholm AG, Kristofferrson AC, Manea M, Fremeaux Bacchi V, Ferhrman Ekholm I, Raafat R, Karpman D (2006) Phenorypic expression of factor H mutations in patients with atypical HUS. Kidney Int 69:981–988

    Article  CAS  PubMed  Google Scholar 

  12. Dragon-Durey MA, Frémeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L (2004) Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 15:787–795

    Article  CAS  PubMed  Google Scholar 

  13. Radhakrishnan S, Lunn A, Kirshfink M, Thorner P, Hebert D, Langlois V, Pluthero F, Licht C (2012) Eculizumab and refractory membranoproliferative glomerulonephritis. N Engl J Med 366:1165–1166

    Article  CAS  PubMed  Google Scholar 

  14. Frémeaux-Bacchi V, Weiss L, Brun P, Kazatchkine MD (1994) Selective disappearance of C3NeF IgG autoantibody in the plasma of a patient with membranoproliferative glomerulonephritis following renal transplantation. Nephrol Dial Transplant 9:811–814

    PubMed  Google Scholar 

  15. Zipfel RF, Skerka C (2009) Complement regulators and inhibitory protein. Nat Rev Immunol 9:729–740

    CAS  PubMed  Google Scholar 

  16. Noris M, Remuzzi G (2009) Atypical hemolytic uremic syndrome. N Engl J Med 361:1676–1687

    Article  CAS  PubMed  Google Scholar 

  17. Goodship TH, Pappworth IY, Toth T, Denton M, Houlberg K, McCormick F, Warland D, Moore I, Hunze EM, Staniforth SJ, Hayes C, Cavalcante DP, Kavanagh D, Strain L, Herbert AP, Schmidt CQ, Barlow PN, Harris CL, Marchbank KJ (2012) Factor H autoantibodies in membranoproliferative glomerulonephritis. Mol Immunol 52:200–206

    Article  CAS  PubMed  Google Scholar 

  18. Williams DG (1997) C3 nephritic factor and mesangiocapillary glomerulonephritis. Pediatr Nephrol 11:96–98

    Article  CAS  PubMed  Google Scholar 

  19. Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M (2005) Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 16:1392–1403

    Article  PubMed  Google Scholar 

  20. Pickering MC, Cook HT (2011) Complement and glomerular disease: new insights. Curr Opin Nephrol Hypertens 20:271–277

    Article  CAS  PubMed  Google Scholar 

  21. Alexander JJ, Aneziokoro OGB, Chang A, Hack BK, Markaryan A, Jacob A, Luo R, Thirman M, Haas M, Quigg RJ (2006) Distinct and separable roles of the complement system in factor H deficient bone marrow chimeric mice with immune complex disease. J Am Soc Nephrol 17:1354–1361

    Article  CAS  PubMed  Google Scholar 

  22. Alexander JJ, Pickering MC, Hass M, Osawe I, Quigg RJ (2005) Complement factor H limits immune complex deposition and prevents inflammation and scarring in glomeruli of mice with chronic serum sickness. J Am Soc Nephrol 16:52–57

    Article  CAS  PubMed  Google Scholar 

  23. Alexander JJ, Wang Y, Chang A, Jacob A, Minto AW, Karmegam M, Haas M, Quigg RJ (2007) Mouse podocyte complement facto H: the functional analogue to human complement receptor 1. J Am Soc Nephrol 18:1157–1166

    Article  CAS  PubMed  Google Scholar 

  24. Lihua B, Haas M, Quigg RJ (2011) Complement factor H deficiency accelerates development of lupus nephritis. J Am Soc Nephrol 22:285–295

    Article  Google Scholar 

  25. Lapeyraque AL, Fremeaux-Bacci V, Robitallie P (2011) Efficacy of eculizumab in patient with factor H associated atypical hemolytic uremic syndrome. Pediatr Nephrol 26:621–624

    Article  PubMed  Google Scholar 

  26. Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic uremic syndrome. N Engl J Med 360:544–546

    Article  CAS  PubMed  Google Scholar 

  27. Daina E, Noris M, Remuzzi G (2012) Eculizumab in patient with dense deposit disease. N Engl J Med 366:1161–1163

    Article  CAS  PubMed  Google Scholar 

  28. Vivarelli M, Pasini A, Emma F (2012) Eculizumab for the treatment of dense-deposit disease. N Engl J Med 366:1163–1165

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from Comitato Telethon Fondazione ONLUS (Rome, Italy), project GGP09075, by Fondazione ART per la Ricerca sui Trapianti ART ONLUS (Milan, Italy), Fondazione Aiuti per La Ricerca sulle Malattie Rare ARMR ONLUS (Bergamo, Italy), and European Union Seventh Framework Programme FP7-EURenoOmics, project number 305608.

The authors thank Dr. R. Piras and D. Serena Bettoni for the sC5b9 evaluation, Drs. Annalisa Sorosina, Marta Alberti, and Ramona Maranta for the complement gene sequencing, and Drs. Marina Noris, Roberta Donadelli, and Elena Bresin for interpreting the mutational analysis and performing genetic counseling.

R. Piras is a recipient of a research contract from Progetto DDD ONLUS, Associazione per la Lotta Alla DDD.

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Authors and Affiliations

  1. Institute of Nephrology, Schneider Children’s Medical Center of Israel, Petach, Tikva, Israel, 49202

    Hadas Alfandary & Miriam Davidovits

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Miriam Davidovits

Authors
  1. Hadas Alfandary
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  2. Miriam Davidovits
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Correspondence to Hadas Alfandary.

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Alfandary, H., Davidovits, M. Novel factor H mutation associated with familial membranoproliferative glomerulonephritis type I. Pediatr Nephrol 30, 2129–2134 (2015). https://doi.org/10.1007/s00467-015-3166-7

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  • DOI: https://doi.org/10.1007/s00467-015-3166-7

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