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.

Summary Different genetic mutations have been described in complement component C7 deficiency, a molecular defect clinically associated with an increased susceptibility to neisserial recurrent infections. In this work we report the genetic basis of C7 deficiency in two different Spanish families (family 1 and family 2). In family 1, of Gypsy ethnical background, exon‐specific polymerase chain reaction and sequencing revealed a not previously described single base deletion of nucleotide 1309 (exon 10) in the patient, as well as in her father, leading to a stop codon that causes the premature truncation of the C7 protein (K416 X 419). Additionally, the patient and her mother displayed a missense mutation at position 1135 (exon 9) located in the first nucleotide of the codon GGG (CGG), resulting in a change of amino acid (G357R). This mutation was firstly described in individuals of Moroccan Sephardic Jewish ancestry and has been also reported among Spaniards. In family 2, another novel mutation was found in homozygosity in two siblings; a two base‐pair deletion of nucleotides 1922 and 1923 in exon 14 leading to the generation of a downstream stop codon causing the truncation of the C7 protein product (S620 X 630). Our results provide more evidence for the heterogeneous molecular basis of C7 deficiency as well as for the subsequent susceptibility to meningococcal disease, since different families carry different molecular defects. On the other hand, certain C7 defects appear to be prevalent in individuals from certain populations or living in defined geographical areas.

We have analyzed the distribution of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) transmembrane alleles among 58 Spanish patients with Behçet's disease (BD) and in 194 ethnically matched healthy controls. The study included the characterization of A4, A5, A5.1, A6 "new" and "old" and A9 MICA-TM alleles using polymerase chain reaction. As previously reported, the serological B51 specificity was increased among this BD patient group (36.25% vs. 19.6% in controls; P=0.009; OR=2.33). The MICA-TM alleles A6 ("new" and "old"), in linkage disequilibrium with HLA-B51 and HLA-B14 respectively, were only slightly increased among patients (70.7% vs. 61.3% in controls; P=NS). We conclude that, in contrast to previous finding reporting a strong association of MICA-TM genes and Behçet disease in Japanese patients, in our population HLA-B51 is more closely associated to Behçet susceptibility than MICA-TM genes. Finally, our data show that in Spain, as occurs in other populations, some MICA-TM alleles exhibit strong linkage disequilibrium with certain alleles of the HLA-B locus.

In this work, we report the genetic basis of C7 deficiency in two different Spanish families. In family 1, by using exon‐specific polymerase chain reaction and sequencing, a recently described mutation was found in homozygosity in the patient; a single base change in exon 15 (C2107T) leading to a stop codon that causes truncation of the C‐terminal portion of C7 (Q681X). Patient’s father, mother and sister were heterozygous for this mutation. Interestingly, patient’s parents were not related. In family 2, a new single base mutation in exon 2 (G90A), leading to a stop codon that causes the premature truncation of C7 (W8X), was found in the patient, mother and sister 1. Additionally, patient 2, her father and sisters, displayed a missense mutation in exon 9 (G1135C) resulting in a change of aminoacid (G357R). Although sister 1 bore the same mutations in the C7 gene that patient 2, she remains asymptomatic. Because both mutations were found in the patient and her sister, we analyse other defence mechanisms such as FcγR polymorphisms as well as mannose‐binding lectin alleles (MBL2 gene) and MBL levels. Results showed that both siblings bore identical combinations of FcγR allotypes and different MBL2 alleles, exhibiting patient 2 a MBL‐insufficient genotype. Normal MBL levels were found in patient 1 and in two previously studied C7‐deficient siblings, suggesting the involvement of other mechanisms of immunity distinct of FcγR variants and the MBL pathway, for the absence of meningococcal recurrent infections in certain C7‐deficient individuals.