Membranoproliferative glomerulonephritis type II or Dense Deposit Disease (MPGNII/DDD) is characterized by the deposition of electron-dense material within the glomerular basement membrane (GBM) of the kidney and within Bruch's membrane in the eye. The diagnosis is usually made in children between the ages of 5-15 years. Within 10 years about half of these children progress to end-stage renal disease, occasionally with the late comorbidity of visual impairment. In most persons with MPGNII/DDD, hypocomplementemia due to continuous C3 degradation can be documented in plasma by low APH 50 values, low Cs levels, and the appearance of the Cs degradation product Csd. Renal transplantation is associated with disease recurrence in virtually all allografts and a high percentage of transplants ultimately fail. MPGNII/DDD is a complex disease. We hypothesize that: i) its pathophysiology is related to dysregulation of the alternative pathway (AP) C3 convertase, which leads to uncontrolled activation of the AP of complement;2) uncontrolled activation of the AP of complement occurs on a permissive genetic background;and 3) damage to the GBM and Bruch's membrane occurs because these two membranes have only marginal protection from AP-mediated complement injury. We provide preliminary evidence to support this hypothesis by showing that specific mutations and/or alleles of Factor H, Factor H-Related 5 and Cs are associated with MPGNII/DDD. For two of the Factor H-associated alleles, the AK224 and H402, we have completed functional studies that demonstrate differences in the mutant proteins as compared to wild type protein. In this grant we will complete three specific aims to investigate in greater detail the role of the AP of complement in MPGNII/DDD.
The specific aims are: 1.
Specific Aim i : To examine the hypothesis that alleles/mutations in several complement-related genes are associated with MPGNII/DDD 2.
Specific Aim 2 : To examine the hypothesis that the associated alleles/mutations identified in Specific Aim ! affect the AP of complement at a functional level 3.
Specific Aim 3 : To examine the hypothesis that exogenous murine Factor H (mFH) can rescue the MPGNII/DDD phenotype in the Factor H deficient mouse (C/ft-/-)
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