Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases

We have investigated the molecular basis of selective and complete Cis defi ciency in 2-year-old girl with complex autoimmune diseases including lupus- like syndrome, Hashimoto's thyroiditis, and autoimmune hepatitis. This pati ent's complement profile was characterized by the absence of CH50 activity, C1 functional activity < 10%, and undetectable levels of Cis Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of geno mic DNA by PCR followed by direct sequence analysis revealed a homozygous n onsense mutation in the Cis gene exon XII at codon 534, caused by a nucleot ide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction si te for endonuclease Fok-1 created by the mutation to detect this mutation i n the genomic DNA of seven healthy family members. Four additional heterozy gotes for the mutation were identified in two generations. Our data charact erize for the first time the genetic defect of a selective and complete Cis deficiency in a Caucasian patient.