Molecular basis of human complement C1s deficiency

This is the first report on the molecular basis of human complement C1s def iciency. Two abnormalities in the C1s gene were identified in a Japanese fa mily, including one patient, by using exon-specific PCR, single-strand conf ormation polymorphism analysis, and nucleotide sequencing, A deletion of 4 bp, TTTG, was identified in exon X when using genomic DNA from the patient, his father, and his paternal grandmother, They were all heterozygous for t he mutation. The mutant gene encodes a truncated C1s from the N terminus to the short consensus repeat domain. By further sequencing the PCR products, a nonsense mutation from G to T was identified at codon 608 in exon XII in the patient, his mother, and his sister, They were all heterozygous for th e nonsense mutation. The mutant gene encodes a truncated form of C1s that l acks the C-terminal 80 amino acids, These results indicate that the patient was a compound heterozygote with the 4-bp deletion on the paternal allele and the nonsense mutation on the maternal allele, The levels of serum C1s s eem to be correlated to the genotypes of the C1s gene in which no C1s was d etected in the patient, and one-half of the normal level in the family memb ers who are heterozygous for either mutation. The present study demonstrate s that the disease is inherited in an autosomal recessive mode.