Variations in the Complement Regulatory Genes Factor H (CFH) and Factor H Related 5 (CFHR5) are Associated with Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease)

Maria Asuncion Abrera-Abeleda ¹, Carla Nishimura ¹, Jenna L.H. Smith ¹, Sanjjev Sethi ², Jennifer L. McRae ³, Brendan F. Murphy ³, Giuliana Silvestri ⁴, Christine Skerka ⁵, Mihaly Jozsi ⁵, Peter F. Zipfel ⁵, Gregory S. Hageman ¹ and Richard J.H. Smith ^1*

¹ Carver College of Medicine, The University of Iowa, United States
² The Mayo Clinic, United States
³ St Vincent's Hospital, Australia
⁴ Queen's University, Northern Ireland
⁵ Leibniz-Institute for Natural Products Research and Infection Biology - Hans Knoell Institute, Germany

^* To whom correspondence should be addressed. E-mail: richard-smith{at}uiowa.edu.

Accepted 31 October 2005

Abstract

Introduction: Membranoproliferative glomerulonephritis type II or Dense Deposit Disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end-stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in complement Factor H (CFH) are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology.

Subjects: Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 persons in whom age-related macular degeneration had been excluded.

Results: Indirect immunofluorescence using an anti-CFHR5 monoclonal antibody demonstrated positive granular staining in renal biopsy specimens from patients with MPGN II/DDD. Allele frequencies of four single nucleotide polymorphisms (SNPs) in CFH and three SNPs in CFHR5 were significantly different between MPGN II/DDD patients and controls.

Conclusion: Specific allele variants of CFH and CFHR5 are preferentially associated with the MPGN II/DDD disease phenotype. Determining how these allele variants affect regulation of the alternative pathway of the complement cascade may lead to specific therapies to prevent end-stage renal failure in patients with this disease.

Keywords: complement factor H, complement factor H-related 5, dense deposit disease, end-stage renal failure, membranoproliferative glomerulonephritis type II

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