The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• The ninth component of human complement (C9) is crucial for forming the membrane attack complex.
• Deficiency in terminal complement components, including C9, is linked to increased susceptibility to Neisseria infections.

Purpose of the Study:

• To investigate the genetic basis of C9 deficiency in a Swiss family.
• To identify specific mutations responsible for inherited C9 deficiency.

Main Methods:

• Exon-specific PCR and direct DNA sequencing were employed to identify mutations.
• Family studies were conducted on three first-degree relatives with heterozygous C9 deficiency.
• DNA sequencing of exon-intron junctions and DNA marker studies using C6, C7, and C9 gene polymorphisms were performed.

Main Results:

• Two distinct point mutations, both resulting in TGA stop codons, were identified as the cause of C9 deficiency.
• A C to A exchange at cDNA position 166 in exon 2 and a C to T exchange at cDNA position 464 in exon 4 were found.
• Independent segregation of these mutations in heterozygous relatives confirmed their role in complete C9 deficiency.
• Exon-intron junction sequencing provided revised boundaries for exons 4-6 and 10-11.
• Linkage of C9 mutations with specific haplotypes was confirmed through DNA marker studies.

Conclusions:

• The identified point mutations are sufficient to cause complete C9 deficiency.
• The study refined the understanding of human complement component gene structure and linkage.
• This research provides genetic insights into C9 deficiency and its associated health risks.