C7 deficiency in an Irish family: a deletion defect which is predominant in the Irish

Abstract

Human deficiencies of terminal complement components are known to be associated with increased susceptibility to Neisseria meningitidis infection. Polymorphic DNA marker studies in complement deficient investigations allow identification of haplotypes associated with the deficiency and enable the possible identification of heterozygote carriers of the defect. We report studies of an Irish family in which the index case had suffered recurrent meningococcal disease and was found to be deficient in the seventh component of complement (C7). The availability of all family members enabled us to determine the segregating haplotypes. The defects in the family segregated with two very closely related C6 and C7 DNA haplotypes, one of which is known to be associated with the large Irish C7 DNA deletion defect. The index case and two C7 deficient siblings were found to be homozygous for this defect, a deletion that spans approx. 6.8 kbp and encompasses exons 7 and 8. The deletion defect of exons 7 and 8 of C7 has been found in homozygous form in another C7 deficient Irish individual, and is present in heterozygous form in C7 deficient members of a third Irish family. Therefore, this deletion defect occurs in five of the six deficient chromosomes of these three unrelated Irish families, raising the interesting question of how prevalent this defect may be within the Irish community.

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

“…This patient also had chronic otitis media that was only partially responsive to medical treatment; S. aureus and Bacteroides faecalis were cultured from middle ear pus (353). Complete deficiencies of C7 have been reported in several cases, and the molecular basis includes mutations at a 3Ј splice acceptor site in intron 1 (125), a mutation at a 5Ј splice donor site of intron 16, several point mutations (124,489), and deletion of part of the gene (326).…”

Complement C7 deficiency: seven further molecular defects and their associated marker haplotypes

“…In particular, the recent discovery of the molecular basis of C6 deficiency in the Western Cape, South Africa showed that the defect was associated with a single haplotype in 27 unrelated chromosomes and with variation at single loci in 3 other chromosomes. Also, 7 out of 8 C7-deficient Israeli chromosomes with a common defect share one haplotype (Fernie et al 1997a) and 4 out of 5 C7-deficient Irish with a common defect share a haplotype (Fernie et al 1997a;O'Hara et al 1998). In summary, 38 chromosomes show association and 5 show only minor variations from the common associated haplotypes.…”

Reference Typing Report for Complement Components C6, C7 and C9 Including Mutations Leading to Deficiencies

“…Six defects, including the one responsible for C7SD in C6/C7SD and as isolated C7D, have been reported previously [65,75,76,78]. At this meeting a further 7 defects were described [63,77], making a total of 13 different known C7 defects.…”

“…Nevertheless, C7D can occur with a relatively high frequency in certain populations. A defect at nucleotide position 1135 in exon 9 has been found in eight independent chromosomes in Jews of Moroccan Sephardic descent living in Israel, and an unusual deletion of around 6.8 kbp, including exons 7 and 8, has been found in five independent chromosomes in Ireland [76,78].…”