MOLECULAR-BASIS OF SUBTOTAL COMPLEMENT C6 DEFICIENCY - A CARBOXY-TERMINALLY TRUNCATED BUT FUNCTIONALLY ACTIVE C6

Individuals with subtotal complement C6 deficiency possess a C6 molecu le that is 14% shorter than normal C6 and present in low but detectabl e concentrations (1-2% of the normal mean), We now show that this dysm orphic C6 is bactericidally active and lacks an epitope that was mappe d to the most carboxy-terminal part of C6 using C6 cDNA fragments expr essed as fusion proteins in the pUEX expression system, We thus predic ted that the abnormal C6 molecule might be carboxy-terminally truncate d and sought a mutation in an area similar to 14% from the carboxy-ter minal end of the coding sequence, By sequencing PCR-amplified products from this region, we found, in three individuals from two families, a mutation that might plausibly be responsible for the defect, All thre e have an abnormal 5' splice donor site of intron 15, which would prob ably prevent splicing, An in-frame stop codon is found 17 codons downs tream from the intron boundary, which would lead to a truncated polype ptide 13.5% smaller than normal C6, This result was unexpected, as ear lier studies mapped the C5b binding site, or a putative enzymatic regi on, to this part of C6, Interestingly, all three subjects were probabl y heterozygous for both subtotal C6 and complete C6 deficiency.