Two Novel Genetic Mutations Resulting In A Complete Deficiency Of Complement Component

The most common complement deficiency in Caucasians is C2. Type I deficiency results from a deletion that prevents protein production and Type II from point mutations that alter the protein secretion from the cells producing it. A 35 m.o. female with recurrent upper respiratory illness was shown to have absent CH50 activity, very low C2 protein levels, and no C2 function. Other C components were normal. Unique primers for each of the 18 exons of C2 were designed and the amplified products of the entire gene were sequenced. To confirm heterozygosity for each mutation, clones were made from the PCR product and then sequenced for each exon that showed a change. Genetic testing revealed two separate and unique mutations in the C2 gene. The mother is a carrier of a single base-pair insertion in exon 16, leading to a premature stop codon and a decrease of approximately 50% in C2 function and protein. The father is a carrier of a single nucleotide polymorphism (A to G) in exon 8, resulting in a 50% decrease in circulating C2. Of the five siblings tested, three expressed both mutations (exons 8 and 16), whereas the other two had only the exon 8 SNP. We describe a family with a combination of previously undescribed genetic defects that, when combined, result in C2 deficiency. Application of sequencing and cloning using designed primers for each exon was necessary to identify the unique abnormalities in this family.