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Characterization and organization of the genes encoding the A-, B- and C-chains of human complement subcomponent C1q.
G C Sellar1, D J Blake, K B Reid
1Department of Biochemistry, University of Oxford, U.K.
Insights
Researchers mapped the human complement C1q genes (A, B, and C chains) on chromosome 1p. This study details gene structure, location, and evolutionary links to collagen, aiding understanding of C1q function.
Area of Science:
- Immunogenetics
- Molecular Biology
- Complement System
Background:
- Human complement subcomponent C1q is crucial for innate and adaptive immunity.
- Understanding the genetic basis of C1q is essential for diagnosing and treating complement deficiencies.
Purpose of the Study:
- To isolate and characterize the genes encoding the A-, B-, and C-chains of human C1q.
- To determine the genomic organization and structure of the C1q genes.
- To investigate potential evolutionary relationships between C1q and collagen molecules.
Main Methods:
- cDNA cloning from a monocyte library.
- Cosmid cloning to isolate overlapping genomic DNA.
- Southern-blot analysis for gene copy number.
- DNA sequencing of the C-chain gene.
- Comparative sequence analysis with collagen types.
Main Results:
- Isolated cDNA clones for C1q A-chain and used a B-chain clone to identify overlapping cosmid clones containing all three C1q genes (A, B, C).
- The three C1q genes are located contiguously on chromosome 1p in the order A-C-B, oriented 5' to 3'.
- Each gene (approx. 2.5-3.2 kb) contains a single intron within a conserved glycine codon in the collagen-like region.
- Sequence analysis revealed structural similarities between C1q globular domains and the C-terminal regions of Type VIII and Type X collagens.
Conclusions:
- The human C1q genes are clustered and co-oriented on chromosome 1p.
- The intron-exon structure and conserved glycine residues suggest functional importance.
- Structural similarities indicate evolutionary relationships between C1q and certain collagen types, potentially impacting molecular function and evolution.
Abstract:
A partial cDNA clone for the A-chain of human complement subcomponent C1q was isolated from a monocyte library. Use of the A-chain cDNA clone, and a previously characterized B-chain cDNA clone [Reid (1985) Biochem. J. 231, 729-735] allowed the isolation of overlapping cosmid clones that were shown to contain the genes encoding the A-, B- and C-chains of human C1q. The three genes were found to be aligned, 5'----3', in the same orientation, in the order A-C-B on a 24 kb stretch of DNA on chromosome 1p. The A-, B- and C-chain genes are approx. 2.5, 2.6 and 3.2 kb long respectively, and each contains one intron, located within a codon for a glycine residue found half-way along the collagen-like region present in each chain. These glycine residues are located just before the point where the triple-helical portions of the C1q molecule appear to bend when viewed in the electron microscope. Southern-blot analyses indicated that there is only one gene per chain, and preliminary examination of genomic DNA from several C1q-deficient patients showed no evidence for major deletions or insertions within the A-, B- or C-chain genes. The DNA sequence of the coding region of the C-chain gene allows the completion of the entire derived amino acid sequence for the human C1q molecule. The globular, C-terminal, regions of the chains of C1q show a strong similarity in amino acid sequence to the non-collagen-like, C-terminal, regions of the type VIII and type X collagens, indicating structural and evolutionary relationships between these three molecules.