We describe the case of a female patient with hereditary complete C4 deficiency and systemic lupus erythematosus. She had suffered from lupus nephritis in early childhood. At the age of 23 years she developed severe lupus with skin disease and life-threatening cerebral vasculitis. Her cerebral disease was unresponsive to high-dose steroids, intravenous immunoglobulin, fresh frozen plasma and plasma exchange. Improvement was achieved with immunoadsorption in combination with mycophenolate mofetil. The patient made a complete recovery and is maintained in complete remission on mycophenolate and low-dose steroids.
[Show abstract][Hide abstract] ABSTRACT: Although a heterozygous deficiency of either complement component C4A or C4B is common, and each has a frequency of approximately 20% in a Caucasian population, complete deficiencies of both C4A and C4B proteins are extremely rare. In this paper the clinical courses for seven complete C4 deficiency patients are described in detail, and the molecular defects for complete C4 deficiencies are elucidated. Three patients with homozygous HLA A24 Cw7 B38 DR13 had systemic lupus erythematosus, mesangial glomerulonephritis, and severe skin lesions or membranous nephropathy. Immunofixation, genomic restriction fragment length polymorphisms, and pulsed field gel electrophoresis experiments revealed the presence of monomodular RP-C4-CYP21-TNX (RCCX) modules, each containing a solitary, long C4A mutant gene. Sequencing of the mutant C4A genes revealed a 2-bp, GT deletion in exon 13 that leads to protein truncation. The other four patients with homozygous HLA A30 B18 DR7 had SLE, severe kidney disorders including mesangial or membranoproliferative glomerulonephritis, and/or Henoch Schoenlein purpura. Molecular genetic analyses revealed an unusual RCCX structure with two short C4B mutant genes, each followed by an intact gene for steroid 21-hydroxylase. Nine identical, intronic mutations were found in each mutant C4B. In particular, the 8127 g-->a mutation present at the donor site of intron 28 may cause an RNA splice defect. Analyses of 12 complete C4 deficiency patients revealed two hot spots of deleterious mutations: one is located at exon 13, the others within a 2.6-kb genomic region spanning exons 20-29. Screening of these mutations may facilitate epidemiologic studies of C4 in infectious, autoimmune, and kidney diseases.
The Journal of Immunology 08/2004; 173(4):2803-14. DOI:10.4049/jimmunol.173.4.2803 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For over half a century low serum complement C4 concentrations have been recognized as a manifestation of systemic lupus erythematosus (SLE). However, the role of C4 in human SLE remains elusive. This is partly because of the unusually complex C4 genetics with frequent variations in gene number, gene size, protein isoforms, and expression levels. In this chapter we describe the strong association of complete C4A and C4B deficiencies and human SLE, and discuss the possible role of homozygous and partial deficiencies of C4A, which are present in 32-55% of SLE patients. Accumulated evidence provides support for the interpretation that C4A deficiency is a genetic risk factor for SLE. To explain the differences in SLE prevalence and disease severity among different ethnic groups, however, more elaborate analyses are needed to characterize the C4A and C4B gene dosages, RP-C4-CYP21-TNX (RCCX) modular variations, and quantitative and qualitative diversities of C4A and C4B proteins in SLE patients and controls.
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