title: Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).
abstract: We report a novel pathomechanism for membranoproliferative glomerulonephritis type II (MPGN II) caused by a mutant Factor H protein expressed in the plasma. Genetic analyses of two patients revealed deletion of a single Lys residue (K224) located within the complement regulatory region in domain 4 of Factor H. This deletion resulted in defective complement control: mutant protein purified from the plasma of patients showed severely reduced cofactor and decay-accelerating activity, as well as reduced binding to the central complement component C3b. However, cell-binding activity of the mutant protein was normal and comparable to wild-type Factor H. The patients are daughters of consanguineous parents. As both patients but also their healthy mother were positive for C3 nephritic factor, the mutant Factor H protein is considered relevant for unrestricted activation of the disease-causing activation of the alternative complement pathway. Replacement of functional Factor H by fresh frozen plasma (10-15 ml/kg/14 days) was well tolerated, prevented so far disease progression in both patients, and is in the long run expected to preserve kidney function.
authors.affiliation: Children's Hospital of the University of Cologne, Pediatric Nephrology, Cologne, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Licht
authors.forename: S
authors.initials: S
authors.lastname: Heinen
authors.forename: M
authors.initials: M
authors.lastname: Józsi
authors.forename: I
authors.initials: I
authors.lastname: Löschmann
authors.forename: R E
authors.initials: RE
authors.lastname: Saunders
authors.forename: S J
authors.initials: SJ
authors.lastname: Perkins
authors.forename: R
authors.initials: R
authors.lastname: Waldherr
authors.forename: C
authors.initials: C
authors.lastname: Skerka
authors.forename: M
authors.initials: M
authors.lastname: Kirschfink
authors.forename: B
authors.initials: B
authors.lastname: Hoppe
authors.forename: P F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D003178:Complement C3 Nephritic Factor / Q000032:analysis / Q000378:metabolism; D017242:Complement Factor H / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D003241:Consanguinity; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D010375:Pedigree; D010949:Plasma / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D003178:Complement C3 Nephritic Factor; D017242:Complement Factor H; D008239:Lysine