Complement component C7 deficiency in a Spanish family

Abstract

SUMMARYDifferent genetic mutations have been described in complement component C7 deficiency, a molecular defect which is clinically associated with an increased susceptibility to neisserial recurrent infections, although some cases remain asymptomatic. In this work we report the genetic bases of C7 deficiency in one Spanish family. Exon-specific PCR and sequencing revealed a novel point mutation at nucleotide 615 (exon 6) leading to a stop codon (UGG to UGA) in the patient, his mother, and sister. This transversion causes the premature truncation of the C7 protein (W183X). Additionally, we detected a missense mutation at position 1135 (exon 9) located in the first nucleotide of the codon GGG (CGG), resulting in an amino acid change (G357R) in the patient, his father, as well as in his sister. This latter mutation had been previously described in individuals from Moroccan Sephardic Jewish ancestry. Since both heterozygous mutations were found in the patient as well as in his asymptomatic sister, we analyse other meningococcal defence mechanisms such as polymorphisms of the opsonin receptors on polymorphonuclear cells. Results showed that the patient and his sister bore identical combinations of Fc g RIIA-H/R131 and Fc g RIIIB-NA1/2 allotypes. Our results provide further evidence that the molecular pathogenesis of C7 deficiency as well as susceptibility to meningococcal disease are heterogeneous, since different families carry different molecular defects, although many of the C7 defects appear to be homogeneous in individuals from certain geographical areas. The missense mutation G357R would make an interesting topic of analysis with regard to meningococcal disease susceptibility in the Spanish population.

Complement component C7 deficiency in two Spanish families

“…Halle and coworkers found the G357R mutation among Israeli Moroccan Jewish individuals 18 . The mutation was found also in two siblings with C7 deficiency from a highly inbred Arab population living in the lower Galilee region of Israel, a place where Sephardic Jews have lived for many generations 19 and very recently in two heterozygous C7 deficient siblings in our population 14 . Interestingly, patient 1 was from Gypsy ethnical background.…”

“…and the position of mutations described to date (numbered from 1 to 15), and the two novel mutations found in our study (16,17). Mutations described previously: 1, G>A transition at the 3′ acceptor site of intron 1; 17 2, R198Q; 21 3, deletion of around 6·8 kbp including exons 7 and 8; 17 ; 22 4, a G>A transversion at the 5′ splice donor site of intron 7; 21,23 5, G357R; 14,17–19 6, R499S; 24 7, 1929delC; 21 8, E631X; 13 9, E660Q; 21 10, R665H; 21 11, 2137delTG or 2138delGT/2139delTG; 12 12, C728X; 12 13, 2350delG; 21 14, T>C transversion at the splice donor site of intron 16; 21,23 15, W183X 14 . Circled mutations 5, 16 and 17 indicate mutations found in the patients in this study.…”

“…The C to G transversion results in the change of Gly for Arg (G357R) This mutation had been detected in individuals of Moroccan Sephardic Jewish ancestry. Very recently we found this mutation in two heterozygous C7‐deficient siblings from the Spanish population 14 . Sequencing of PCR‐amplified exons 9 and 10 derived from genomic DNA of the family of the patient revealed that her father was heterozygous for the deletion K416 X 419, and her mother heterozygous for the C1135G transversion leading to the missense mutation G357R.…”

“…Primers for exon‐specific PCR for exons 1–17 of the C7 gene were described previously 12 . Taking into account those C7 defects previously described in our population exons 6, 9 and 14 were amplified and sequenced in first place 13,14 . Briefly, PCR was performed by using 5 µl of DNA, 1 µ m of each primer, 25 µ m dinucleotide triphosphates (Amersham Pharmacia Biotech AB, Uppsala, Sweden), 0·25 U Taq polymerase (Amersham Pharmacia Biotech AB) and the standard buffer provided by the supplier in a total reaction volume of 50 µl.…”

Structural homology and expression tendency of the natural immune response of the terminal complement components to inoculations in pigs: a review

“…The activation of the complement cascades allows the killing of microbes and the regulation of other immune processes. Many studies have indicated deficiencies in complement components with effects on human/ animal health, for instance, bacterial meningitis infection of hosts (Eng 1980;Haeney et al 1980;Ross and Densen 1984;Inai et al 1989;Fukumori and Horiuchi 1998;Zhu et al 2000;Vazquez-Bermudez et al 2003). These authors have also demonstrated that most deficiencies are associated with polymorphisms present in the molecular structure of at least one complement component.…”