A NOVEL TYPE-II COMPLEMENT C2 DEFICIENCY ALLELE IN AN AFRICAN-AMERICAN FAMILY

A 9-yr-old African-American male presenting with severe recurrent pyog enic infections was found to have C2 deficiency (C2D), Analysis of his genomic DNA demonstrated that he carried one type I C2D allele associ ated with the HLA-A25, B18, DR15 haplotype, Screening all 18 exons of the C2 gene by exon-specific PCR/single-strand conformation polymorphi sm indicated abnormal bands in exons 3, 7, and 6, the latter apparentl y caused by the 28-bp deletion of the typical type I C2D allele, Nucle otide (nt) sequencing of the PCR-amplified exons 3 and 7 revealed a he terozygous G to A transition at nt 392, causing a C111Y mutation, and a heterozygous G to C transversion at nt 954, causing a E298D mutation and a polymorphic MaeII site. Cys(111) is the invariable third half-c ystine of the second complement control protein module of C2, Pulse-ch ase biosynthetic labeling experiments indicated that the C111Y mutant C2 was retained by transfected COS cells and secreted only in minimal amounts. Therefore, this mutation causes a type II C2D, In contrast, t he E298D mutation affected neither the secretion of C2 from transfecte d cells nor its specific hemolytic activity. Analysis of genomic DNA f rom members of the patient's family indicated that 1) the proband as w ell as one of his sisters inherited the type I C2D allele from their f ather and the novel type II C2D allele from their mother; 2) the polym orphic MaeII site caused by the G954C transversion is associated with the type I C2D allele; and 3) the novel C111Y mutation is associated i n this family with the haplotype HLA-A28, B58, DR12.