Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).
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.
Licht
C
C
Children's Hospital of the University of Cologne, Pediatric Nephrology, Cologne, Germany.
Heinen
S
S
Józsi
M
M
Löschmann
I
I
Saunders
R E
RE
Perkins
S J
SJ
Waldherr
R
R
Skerka
C
C
Kirschfink
M
M
Hoppe
B
B
Zipfel
P F
PF
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
D003178:Complement C3 Nephritic Factor; D017242:Complement Factor H; D008239:Lysine