Complement component C7 deficiency in a Spanish family

Abstract

Different 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 FcgammaRIIA-H/R131 and FcgammaRIIIB-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.

Fig. 1

Definition of the mutations in (a) exon 6 and (b) exon 9. Partial DNA sequence of genomic DNA of the patient and his parents and sister. The normal and defective DNA sequences as well as the deduced amino acid sequences are given.

Fig. 2

Pedigree of the C7 deficient family. The data on C7 gene markers, C7 gene defects, as well as FcγRIIA-H/R131 and FcγRIIIB-NA1/2 polymorphisms are presented as vertical haplotypes.

Fig. 3

Schematic diagram of the molecular structure of normal C7 (adapted from [6]) and the position of mutations described to date (numbered from 1 to 14), and the novel mutation found in our Spanish family (15). Mutations described previously: 1, G> A transition at 3′ acceptor site of intron 1 [8]; 2, R198Q [24]; 3, deletion of around 6·8 kbp including exons 7 and 8 [–25]; 4, a G> A transversion at 5′ splice donor site of intron 7 [24,26]; 5, G357R [8]; 6, R499S [28]; 7, 1929delC [24]; 8, E631X [27]; 9, E660Q [24]; 10, R665H [24]; 11, 2137delTG or 2138delGT/2139delTG [17]; 12, C728X [17]; 13, 2350delG [24]; 14, T> C transversion at splice donor site of intron 16 [24,26]; 15, W183X (present case). Modules are designated according to the recommendations of a workshop [29], as follows: T1, thrombospondin, type 1; LA, LDL receptor, type A; EG, epidermal growth factor-like; CP, complement control protein; and FM, complement factor I, MAC proteins.