CHARACTERIZATION OF NONEXPRESSED C4 GENES IN A CASE OF COMPLETE C4 DEFICIENCY - IDENTIFICATION OF A NOVEL POINT MUTATION LEADING TO A PREMATURE STOP CODON

The genetic basis of complete C4 deficiency in a patient with SLE was investigated. Previous studies have demonstrated that this patient has two different major histocompatibility complex (MHC) haplotypes that each contain a major deletion and a nonexpressed C4 gene. In the prese nt study, non-expression of the C4 genes was explained by the finding of two distinct C4 gene mutations. A previously described two base pai r insertion in exon 29 of the C4 gene was detected in the paternal MHC haplotype [HLA-A2, B40, SC00, DR6]. The maternal haplotype [HLA-A30, B18, F1C00, DR3] carried a C4 gene with a one base pair deletion in ex on 20 generating a premature stop codon. This mutation was neither fou nd in 10 individuals with known non-expressed C4 genes nor in 9 indivi duals homozygous for the complotype F1C30. The isotype and allotype sp ecific regions of the patient's C4 genes were sequenced, and both cont ained C4A3a sequence. In conclusion, two different MHC haplotypes rese mbling the extended haplotypes [HLA-A2, B40, SC02, DR6] and [HLA-A30, B18, F1C30, DR3] both contained a non-expressed C4A gene that was due to either of two distinct mutations, demonstrating the heterogeneous g enetic background of C4 deficiency. (C) American Society for Histocomp atibility and Immunogenetics, 1998. Published by Elsevier Science Inc.