In collaboration with the Junior Group of Cellular Immunobiology (Dr. Mihaly Jozsi)

Absence of Factor H in plasma causes damage kidney damage in form of Membranoproliferative glomerulonephritis type II (MPGN II), which is also termed dense deposit disease. This rare disease is characterized by complement containing dense deposits within the basement membrane of the glomerular capillary wall and followed by capillary wall thickening, mesangial cell proliferation and glomerular fibrosis. So far for distinct scenarios, all of them leading to complement dysregulation, have been linked to membranoproliferative glomerulonephritis: (I) absence of Factor H in plasma, (II) presence of mutated, functionally defective Factor H protein, (III) the inactivation of Factor H by a circulating inhibitor and (IV) the presence of the autoantibody C3 nephritic Factor (C3NeF).

Absence of Factor H in plasma as cause for MPGN II has been observed in humans and in animals, whereby pigs represent natural mutants and mice in which the Factor H gene was deleted represent a genetically designed animal model. The genetic defect leading to Factor H deficiency has been analyzed in five patients, from four families. In a native American single nucleotide mutations affect Cys residues C518R of one and C941Y of the second allele (18). Factor H is composed of 20 complement control protein (CCP) modules, also known as short consensus repeats (SCR). The absence of conserved framework Cys residues within CCP 9 and CCP 16 affects disulphide bond formation. Two members of another family show homozygous mutations in CCP 2 (R127L), and the other individuals have either amino acid exchange in CCP 4 (C431S) or in CCP 11 (C673S). In addition two patients with a circulating, but functionally defective Factor H protein were described and the Factor H gene mutation results in deletion of a single amino acid residue (K224) in SCR-domain 4. The deficient pigs display homozygous mutations of L493V and I1166R located within CCP 9 and CCP 20. These non framework mutations result in a block of protein secretion. The mutant protein is expressed, but retained in the endoplasmic reticulum and accumulates in the cytoplasm.

We are interested to characterize and analyze the pathomechanism of this disease in order to understand how a defective complement regulator results in the local damage, which is specific for the glomerular basement membrane of the kidney. In addition we have set up a registry for MPGN to collect material which and genomic DNA of the HUS patients which will allow us to search for additional marker genets which are mutated in this diseases. This set up will be used to develop reliable diagnostic test for MPGN patients, to improve existing, and to establish novel therapeutic approaches for MPGN.(www. MPGN-registry.de)

Cooperation

Prof. Giuseppe Remuzzi, Bergamo, Italy
Prof. Tim Goodship Newcastle, UK
Prof. Christoph Licht, Hospital for Sick children, Toronto, Canada
Prof. Richard Smith, University of Iowa, USA

Selected Literature

Licht C, Heinen S, Jozsi M, Löschmann I, Saunders RE, Perkins SJ, Skerka C, Kirschfink M, Hoppe B, Zipfel PF (2006). Deletion of Lys224 in Regulatory Domain 4 of Factor H Reveals a Novel Pathomechanism for Dense Deposit Disease (MPGNII). Kidney Int 70, 42-50.

Reviews

Licht C, Schlötzer-Schrehardt U, Zipfel PF, Hoppe B (2007). Membranoproliferative Glomerulonephritis II - Genetically Determined by Factor H Defect? Pediatr Nephrol 22, 2-9.

Appel GB, Cook T, Hageman G, Jennette C, Kashgarian M, Kirschfink M, Lambris, JD, Lanning L, Lutz HU, Meri S, Rose N, Salant DJ, Sethi S, Smith RHJ, Smoyer W, Tully HT, Tully SP, Walker P, Welsh M, Würzner R, Zipfel PF (2005). Membranoproliferative Glomerulonephritis Type 2 (Dense Deposit Disease): An Update. J Am Soc Nephrol 16, 1392-1403

Funding