Clinical presentations and molecular basis of complement C1r deficiency in a male African-American patient with...

Homozygous deficiencies of early components for complement activation are among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). Eleven cases of C1r deficiency are documented but this is the first report on the molecular basis of C1r deficiency. The proband is an African-American male who developed SLE at 3 months of age. He had a discoid lupus rash and diffuse proliferative glomerulonephritis. Serum complement analysis of the patient showed zero CH50 activity, undetectable C1r, and reduced levels of C1s, but highly elevated levels of complement C4, C2, and C1-inhibitor. The coding regions of the mutant C1R gene with 11 exons located at chromosome 12p13 were polymerase chain reaction (PCR)-amplified and sequenced to completion. DNA sequencing revealed a homozygous C→T mutation at nucleotide-6392 in exon 10 of the C1R gene, resulting in a nonsense mutation from Arg-380 (R380X). The patient's clinically normal mother was heterozygous for this mutation. A sequence-specific primer (SSP) PCR coupled with StuI-restriction fragment length polymorphism (RFLP) was developed to detect the novel mutation. Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects.