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

Abstract

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.

Lupus nephritis associated with complete C1s deficiency efficiently treated with rituximab: A case report

“…On one hand, it appears to mediate tissue damage through activation of the classical pathway by immune complexes, and on the other hand, complete deficiencies in C1q, C1r, C2, or C4 have been associated with SLE. Excluding the present case, selective complete C1s deficiency has been reported in only 8 cases so far (3–7). One patient had SLE without renal involvement and two had SLE and renal disease (one had IgG and C1q deposition in the glomeruli and one had chronic renal failure associated with proteinuria and hematuria, but renal biopsy was not performed in this last case).…”

Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases

“…This patient developed unique symptoms including virus-associated hemophagocytic syndrome and died after a long period of a comatose state. A mutation documented in another patient from the same family was a heterozygous G → T mutation in exon 12 leading to E597X and on the other allele, a novel missense mutation G630Q ( 90 ). This patient displayed symptoms that were similar to the other, related patient, including fever of unknown origin and short-term disturbances of consciousness.…”

Comparison of Immunopathology and Locomotor Recovery in C57BL/6, BUB/BnJ, and NOD-SCID Mice after Contusion Spinal Cord Injury

“…Taken together, these data suggest that complement activity does not necessarily correlate with protein expression levels between strains. One possible explanation for this phenomenon is that point mutations may reduce protein activity, as has been demonstrated in human populations (Abe et al, 2009;Arnold et al, 2009;Lopez-Lera et al, 2009;Wu et al, 2009).…”