Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).

Article Details

Citation

Licht C, Heinen S, Jozsi M, Loschmann I, Saunders RE, Perkins SJ, Waldherr R, Skerka C, Kirschfink M, Hoppe B, Zipfel PF

Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).

Kidney Int. 2006 Jul;70(1):42-50. Epub 2006 Apr 12.

PubMed ID
16612335 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Complement factor HP08603Details