Spontaneous somatic mutations. Structural studies on mutant immunoglobulins

Area of Science:

• Immunology
• Molecular Biology
• Protein Chemistry

Background:

• Immunoglobulin heavy chains are crucial for antibody function.
• Understanding mutations in immunoglobulin genes provides insights into protein structure and disease.

Purpose of the Study:

• To determine the precise amino acid sequence alterations in immunoglobulin heavy chains of MOPC 21 mutant clones IF2 and IF1.
• To compare these alterations to the wild-type sequence and elucidate the mechanisms of mutation.

Main Methods:

• Isolation and comparison of cyanogen bromide fragments of heavy chains from mutant and wild-type MOPC 21.
• Analysis of amino acid sequences to identify deletions and other structural changes.
• Assessment of disulfide bond formation between heavy and light chains.

Main Results:

• Mutant IF2 exhibits an internal deletion of 96 amino acids (residues 121-215) and lacks heavy-light chain disulfide bonds, likely due to CH1 deletion.
• Mutant IF1 shows a deletion of 83 COOH-terminal amino acids (residues 358-440), with minimal apparent size difference on gels.
• IF1's mutation is likely a nonsense mutation, while IF2's deletion suggests an error of recombination, similar to human heavy chain diseases.

Conclusions:

• The study precisely defines the molecular basis of mutations in MOPC 21 immunoglobulin heavy chains.
• IF2's deletion pattern resembles human heavy chain diseases, suggesting a common mechanism.
• The findings provide structural insights into immunoglobulin heavy chain variability and potential disease-related alterations.