Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus

A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported. A 22-year-old Japanese male was diagnosed as having SLE and his medical history revealed recurrent tonsillitis and pneumonia. He was diagnosed as having C3D because of undetectable serum C3 level. His parents were consanguineous. Sequence analysis of C3D cDNA revealed a homozygous deletion of exon 39 (84 bp). A single base substitution (AG to GG) in the 3′-splice acceptor site of intron 38 was identified by sequencing the genomic DNA. Expression of C3Δ(ex39) cDNA, the C3cDNA lacking exon 39, in COS-7 cells revealed that C3Δ(ex39) was retained in endoplasmic reticulum-Golgi intermediate compartment because of defective secretion. These data indicate that a novel AG → GG 3′-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3.