Unique Phenotypes of C1s Deficiency and Abnormality Caused by Two Compound Heterozygosities in a Japanese Family

A deficiency in the early components of complement is associated with an increased susceptibility to pyrogenic infections and multiple autoimmune diseases. We previously reported a Japanese case of selective C1s deficiency resulting from a compound heterozygosity for a 4-bp deletion in exon X and a nonsense mutation Glu597X in exon XII of the C1s gene. In this previous case, the patient suffered from unique symptoms including virus-associated hemophagocytic syndrome and died after a long period of loss of consciousness. In the present study, we report another patient from the same family, with C1s abnormality caused by a distinct compound-heterozygous genotype and who had a novel missense mutation Gly630Glu transmitted from the mother's side and a previously identified nonsense mutation Glu597X from the father's side. Thus three distinct mutations of the C1s gene were clustered and resulted in two distinct genotypes for C1s deficiency and C1s abnormality within this one family. The present patient showed symptoms that were similar in part to our previous patient, which were different from those of the cases reported in other families. The biochemical properties of C1s in the patient's serum and the recombinant form were closely related to the undetectable or very low activity of complement activation. These results suggested that the uniqueness and severity of the symptoms observed here in the two patients might be under the control of a common C1s allele and distinct counterparts, respectively. The Journal of Immunology, 2009, 182: 1681-1688.