REPEATED MENINCOCCAL
INFECTION CAUSED BY FAMILIAR COMPLEMENT I DEFICIENCY IN TWO
DUTCH FAMILIES
GENETIC CODE
OF A NEW MUTATION CAUSING COMPLEMENT I DEFICIENCY
C. Klomp; A.P. Abbes; E.J.M. Bruggeman; J.F. van Gils; H. Engel
Isala Clinics/ Pediatric Department, The Netherlands
Two children from non-related families were both twice admitted to
our hospital being treated for meningococcal sepsis. Due to the recurrent
appearance of meningococcal infection both children were investigated for
complement deficiency using quantitative assays. In both cases a deficiency
of complement factor I was found. Further investigation of both families
revealed in one of the families with 10 children that 4 children were
homozygous deficient for complement factor I. Both parents were
heterozygous carriers. In the other family both parents were also
heterozygous carriers and one of their two children was homozygous
deficient, the other child was a heterozygous carrier.
Complement factor I deficiency is a rare autosomally recessive
inherited disease causing life-threatening bacterial infections. Complement
factor I is responsible for the inhibition of the complement cascade by
inactivation of C3b. In case of a complement factor I deficiency, an
overusage of C3b results in a deficiency of complement factors what
ultimately results in an ineffective clearing of bacterial infections by
phagocytosis, especially meningococcal infections.
We investigated the molecular defect by PCR and DNA sequence
analysis. The IF gene, encoding the complement factor I, has been localized
on chromosome 4q25. The complete DNA sequence was analyzed and in exon 4 a
G to C mutation in both families was identified. This mutation results in a
substitution in codon 188 from glycine to alanine (Gly188Ala). The
aminoacid substitution is localized in the CD5 domain of factor I, the
effect of the mutation on the 3-dimensional structure or function of factor
I is not kown yet.
The results at the molecular level are in complete agreement with
the above-described inheritance. In addition, the Gly188Ala mutation was
not found in 50 normal individuals.
The Gly188Ala mutation is the first mutation found in the
Netherlands. Up to now, only 2 distinct mutations have been described
before. Since both families carry the same mutation in combination with a
rare inherited disease, we suggest that both Dutch families are
interrelated by a common ancestor.
The identification of the mutation offers now the opportunity of
presymptomatic screening for both families.